1.A.1 The Voltage-gated Ion Channel (VIC) Superfamily

Proteins of the VIC family are ion-selective channel proteins found in a wide range of bacteria, archaea, eukaryotes and viruses. They are often homo- or heterooligomeric structures with several dissimilar subunits (e.g., α1-α2-δ-β Ca2+ channels, αβ1β2 Na+ channels or (α)4-β K+ channels), but the channel and the primary receptor is usually associated with the α (or α1) subunit. Functionally characterized members are specific for K+, Na+ or Ca2+. The K+ channels usually consist of homotetrameric structures with each α-subunit possessing six transmembrane spanners (TMSs). Many voltage-sensitive K+ channels function with β-subunits that modify K+ channel gating. These nonintegral β-subunits are oxidoreductases that coassemble with the tetrameric α-subunits in the endoplasmic reticulum and remain tightly adherent to the α-subunit tetramer. The high resolution β-subunit structure is available (Gulbis et al., 1999). Non-homologous β-subunits of Na+ and Ca2+ channels function in regulation (Hanlon and Wallace, 2002).  Voltage-gated Ca2+ (Cav) channels have 4 subunits which have all been examined phylogenetically from evolutionary standpoints (Moran and Zakon 2014).  Members of the VIC (1.A.1), RIR-CaC (2.A.3) and TRP-CC (1.A.4) Families have similar transmembrane domain structures, but very different cytosolic doman structures (Mio et al. 2008).  How membrane proteins sense voltage (the membrane potential) has been reviewed (Bezanilla 2008). The involvement of glycosylation in the function and expression of these channels has also been reviewed (Lazniewska and Weiss 2017).  Ion channel disfunction in semen may account for male infertility (Carkci et al. 2017). The spatial expression of K+ channels in mammalian cells has been reviewed (Capera et al. 2019).  Large-conductance Ca2+- and voltage-gated K+ channels form and break interactions with membrane lipids during each gating cycle (Tian et al. 2019). Pulsed electric fields can create pores in the voltage sensors of voltage-gated ion channels (Rems et al. 2020). Curcumin, a multi-ion channel blocker preferentially blocks late Na+ current and prevents I/R-induced arrhythmias (Song et al. 2020). The contribution of ion channels to multiple stages of tumorigenesis has been reviewed (Fan and Huang 2020). Structures of K+ channels have revealed aspects of ion selectivity, conduction, channel gating, and modulation (Jiang 2021). Sensors, mediators and targets important for potassium homeostasis have been reviewed (McDonough and Fenton 2022). The 70-year search for the voltage sensing mechanism of ion channels has been reviewed (Catacuzzeno and Franciolini 2022). It has been argued that the pore domains of voltage-gated ion channels are autonomously folded units (Arrigoni et al. 2022).

The α-subunits of the Ca2+ and Na+ channels are usually four times as large as the K+ channel α-subunits and possess 4 units, each with 6 TMSs separated by a hydrophilic loop, for a total of 24 TMSs. These large channel proteins form heterotetrameric-unit structures equivalent to the homotetrameric structures of most K+ channels. All four units of the Ca2+ and Na+ channels are homologous to the single unit in the homotetrameric K+ channels. Some Na+ and Ca2+ channels are half sized with two 6 TMS units, forming dimers (see subfamily 1.A.1.11).  Ion flux via the eukaryotic channels is generally controlled by the transmembrane electrical potential (hence the designation, voltage-sensitive) although some are controlled by ligand or receptor binding. The 6 TMS VIC family members have a gating charge transfer center in the voltage sensors (Tao et al., 2010).  Structural aspects of the calcium channels, revealing the architectural features that underlie their feedback regulatory mechanisms have been reviewed (Minor and Findeisen 2010).  The evolution of VIC superfamily channels with a special emphasis on the metazoan lineage has been reviewed (Moran et al. 2015).  Evolutioin of the 4 TMS voltage sensor has also been reviewed (Freites and Tobias 2015).  Blockade of Na+ channels (NaVs) enables control of pathological firing patterns that occur in a diverse range of conditions such as chronic pain, epilepsy, and cardiac arrhythmias (Bagal et al. 2015). Crotonoside regulates sodium and calcium channels in rabbit ventricular myocytes, diminishing arrhythmias (Liu et al. 2020). The structures and pharmacology of voltage-gated sodium and calcium channels, including the basis for their voltage-dependent activation, fast and slow inactivation, ion conductance and selectivity have been reviewed (Catterall et al. 2020). Voltage-gated sodium channels are prominent targets of marine toxins (Mackieh et al. 2021). A mutation (i.e., V1848I) in the sixth TMS of Domain IV of the sodium channel gives rise to indoxacarb resistance-associated mutation of Liriomyza trifolii, a pervasive plant pathogen (Li et al. 2022).

Voltage-gated sodium channels (VGSCs) are heteromeric transmembrane protein complexes. Nine homologous members, SCN1A-11A, make up the VGSC gene family. Sodium channel isoforms display a wide range of kinetic properties endowing different neuronal types with distinctly varied firing properties. Among the VGSCs isoforms, Nav1.7, Nav1.8 and Nav1.9 are preferentially expressed in the peripheral nervous system. These isoforms are known to be crucial in the conduction of nociceptive stimuli with mutations in these channels thought to be the underlying cause of a variety of heritable pain disorders (Kanellopoulos and Matsuyama 2016). Na+ channels are associated with neuropathic pain (Devor 2006). A 4 x 6 TMS template is shared among voltage-gated sodium (Nav1 and Nav2) and calcium channels (Cav1, Cav2, and Cav3) and leak channel (NALCN) plus homologs from yeast, different single-cell protists (heterokont and unikont) and algae (green and brown) (Fux et al. 2018). The asymmetrically arranged pores of 4x6 TMS channels allows for a changeable ion selectivity via a single lysine residue change in the high field strength site of the ion selectivity filter in Domains II or III.  Modeling has provided clues for rational drug design (Montini et al. 2018). Mexiletine, a class Ib antiarrhythmic drug, is used clinically to reduce or prevent myotonia and is neuroprotective. It binds to the upper part of the pore in the open state and lower part in the closed state. High-affinity binding in the open states of Nav1.4 and Nav1.5 is caused by a pi-pi interactions with Phe (Nakagawa et al. 2019). VGSCs are involved in a variety of diseases, including epilepsy, cardiac arrhythmias, and neuropathic pain, and therefore are therapeutic targets for the development of anticonvulsant, antiarrhythmic, and local anesthetic drugs. Xu et al. 2019 reviewed advances in understanding the structures and biological functions of VGSCs and summarized eight pharmacologically distinct ligand-binding sites in VGSCs and representative isoform-selective VGSC modulators. They also review studies on molecular modeling and computer-aided drug design for VGSCs.

There are four known K+ channel families in mammals (humans): (1) The voltage dependent K+ channels designated as Kv channels, which consist of twelve subfamilies. (2) The two pore domain channels, the K2P, which consist of fourteen subfamilies. (3) The calcium activated K+ channels, KCa channels, which consist of five subfamilies. (4) The inward rectifier K+ channels, the Kir, which include seven subfamilies, designated Kir 1 - Kir 7 with fifteen members. The diversity of voltage-dependent K+ channels in human pulmonary artery smooth muscle cells have been tabulated and reviewed (Platoshyn et al. 2004). G-protein coupled receptors (GPCRs) modulate a number of K+ channels. The most intensively studied and characterized are the K+ inward rectifier Kir 3 subfamily (Kir3.1-Kir3.4) (Gohar, 2006).  The Kv channels' voltage dependences are set in part by charged amino-acid residues of the extracellular linkers which electrostatically affect the charged amino-acid residues of the voltage sensor, S4 (Elinder et al. 2016). Kv-type channels can be consdered to be allosteric machines in which gating may be dynamically influenced by some long-range interactional/allosteric mechanisms (Barros et al. 2019). Molecular dynamics simulations directly predict the response of a voltage-gated K+ channels within a phospholipid bilayer membrane to applied transmembrane voltages (Tronin et al. 2019). Distinct lipid bilayer compositions have general and protein-specific effects on K+ channel function (Winterstein et al. 2021). A diversity of voltage-dependent K+ channels play roles in human pulmonary artery smooth muscle cells (Platoshyn et al. 2004). Pharmacological modulation of transglutaminase 2 to the closed conformation age-dependently lowers blood pressure and, by opening potassium channels, potentiates endothelium-dependent vasorelaxation (Pinilla et al. 2021).

BK-type Ca2+ channels and lipid phosphatases have a transmembrane voltage sensor domain (VSD) that moves in response to physiological variations of the membrane potential to control their activities. However, VSD movements and coupling to the channel or phosphatase activities may differ depending on various interactions between the VSD and its host molecules (Cui 2010). BK-type voltage, Ca²+ and Mg²+ activated K+ channels contain the VSD and a large cytosolic domain (CTD) that binds Ca²+and Mg²+. VSD movements are coupled to BK channel opening with a unique allosteric mechanism and are modulated by Ca²+ and Mg²+ binding via interactions between the channel pore, VSD and CTD. It is energetically advantageous for the pore to be controlled by multiple stimuli (Cui 2010). Insight regarding four types of tetrameric channels with 6 TMSs architectures, Eag1, SK2/SK4, TRPV5/TRPV6 and KCNQ1-5, and their regulation by calmodulin (CaM) have been described structurally (Núñez et al. 2020). Different CaM regions, N-lobe, C-lobe and the EF3/EF4-linker, play prominent signaling roles in different complexes, leading to the realization that crucial non-canonical interactions between CaM and its target channel proteins are apparent in the full-channel structures. Different mechanisms to control gating are used, including direct and indirect mechanical actuation over the pore, allosteric control, indirect effects through lipid binding, as well as direct plugging of the pore. Although each CaM lobe engages through apparently similar α-helices, they do so using different docking strategies (Núñez et al. 2020).

The erg or Kv11 channel is a subfamily of the voltage-dependent K+ channel superfamily and includes three members: Kv11.1 (erg1), Kv11.2 (erg2) and Kv11.3 (erg3) channels. The most studied member of this subfamily is Kv11.1 that regulates the duration of the cardiac action potential. Mutations in this channel have been associated with cardiac arrhythmias and sudden death (Bronstein-Sitton, 2006). All charge-translocating proteins follow two molecular coupling mechanisms: direct- or indirect-coupling, depending on whether the translocated charge is involved in the driving reaction. Calisto et al. 2021 explored these two coupling mechanisms by thoroughly examining the different types of charge-translocating membrane proteins. The lateral voltage can regulate the transmembrane current in both ion-channel-incorporated and fullerene-incorporated lipid bilayer systems (Ma et al. 2021).

Five types of Ca2+ channels are expressed in the CNS of mammals: The L-type (Cav1), N-type (Cav2.2), P/Q-type (Cav2.1), R-type (Cav2.3), and the T-type (Cav3). Each Cav channel is a multimeric protein composed of a pore forming α1 subunit and the auxiliary β (Cavβ), α2δ and γ subunits. There are four known Cavβ subunits, in addition to four α2δ subunits and eight γ subunits. The best characterized Ca2+ channels that are regulated by GPCRs are the N-type and the P/Q-type which have significant roles in neuronal communication. This mechanism is the basis of synaptic modulation caused by endogenous hormones as well as exogenously applied agents (such as analgesia caused by morphine). The identification of the types of Ca2+ channels that are modulated by GPCRs was enabled by the use of specific toxins: ω-Conotoxin GVIA for the N-type channels and ω-Agatoxin-IVA for the P/Q-type channels. Many Ca2+ channels are regulated by GPCRs (Gohar, 2006). Endodgenous membrane phosphatidylinositol 4,5-biphosphate, PIP2, activates high voltage activated L-, N- and P/Q type Ca2+ channels, and PIP2 depletion inhibits these Ca2+ channels (Suh et al., 2010). Isoliensinine (IL) extracted from lotus seed has a good therapeutic effect on cardiovascular diseases. It does so by inhibiting INaL and ICaL in ventricular myocytes, which indicates it has potential antiarrhythmic action (Liu et al. 2021). Analgesic plant- and fungus-derived analgesic natural products target voltage-gated sodium and calcium channels (Calderon-Rivera et al. 2022).

In type-2 diabetes, the tight link between glucose sensing and insulin secretion is impaired due to mutations in a KATP channel. K+ channels that are sensitive to ATP are plasma membrane protein complexes composed of four Kir6.2 (KCNJ11) pore-forming subunits surrounded by four SUR1 (sulphanylurea receptor, of the ABC superfamily) auxiliary subunits. These protein complexes sense the amount of glucose entering a beta cell in the pancreas since the activity of KATP channels depends on the amount of ATP in the cytoplasm, which in turn depends on the amount of glucose absorbed by the beta cell. The activity of KATP channels is negatively correlated to the amount of ATP. KATP channels are the main channels that are open during resting conditions. Closure of KATP channels by increased ATP concentrations leads to membrane depolarization, which causes opening of voltage dependent Ca2+ (Cav) channels, leading to Ca2+ influx. The main Cav channels that control insulin secretion are L-type channels of the Cav1 subfamily (Cav1.2 and/or Cav1.3) (Cherki et al., 2006).

Ion channelopathies are inherited diseases in which alterations in control of ion conductance through the central pore of ion channels impair cell function, leading to periodic paralysis, cardiac arrhythmia, renal failure, epilepsy, migraine and ataxia (Kullmann and Waxman, 2010). However, Sokolov et al. (2007) have shown that, in contrast with this well-established paradigm, three mutations in gating-charge-carrying arginine residues in an S4 segment of NaV1.4 (TC #1.A.1.10.4) that cause hypokalaemic periodic paralysis induce a hyperpolarization-activated cationic leak through the voltage sensor of the skeletal muscle NaV1.4 channel. This 'gating pore current' is active at the resting membrane potential and closed by depolarizations that activate the voltage sensor. It has similar permeability to Na+, K+ and Cs+, but the organic monovalent cations tetraethylammonium and N-methyl-D-glucamine are much less permeant. The inorganic divalent cations Ba2+, Ca2+ and Zn2+ are not detectably permeant and block the gating pore at millimolar concentrations. The results reveal gating pore current in naturally occurring disease mutations of an ion channel and show a clear correlation between mutations that cause gating pore current and hypokalemic periodic paralysis. The involvement of channel protein in neurodegenerative disorders has been reviewed (Kumar et al. 2016).

Several putative K+-selective channel proteins of the VIC family have been identified in prokaryotes. The structures of two of them, the 2 TMS voltage-insensitive KcsA K+ channel of Streptomyces lividans and the 6 TMS KvAP voltage-sensitive K+ channel of Aeropyrum pernix, have been solved to 3.2 Å resolution (TC #1.A.1.1.1 and 1.A.1.17.1, respectively) (Cuello et al., 2004; Doyle et al., 1998; Jiang et al., 2003a,b; Ruta et al., 2003). Both proteins possess four identical subunits, each with two transmembrane helices, arranged in the shape of an inverted teepee or cone, forming the channel. The cone cradles the 'selectivity filter' P domain in its outer end. The narrow selectivity filter is only 12 Å long, whereas the remainder of the channel is wider and lined with hydrophobic residues. The first TMS (S1) is at the contact interface between the voltage sensing and pore domains (Cuello et al., 2004). A large water-filled cavity and helix dipoles stabilize K+ in the pore. The selectivity filter has two bound K+ ions about 7.5 Å apart from each other. Ion conduction is proposed to result from a balance of electrostatic attractive and repulsive forces. Evolutionary relationships between K+ channels and certain K+:cation symporters has been reviewed and discussed (Durell et al., 1999).

KcsA channels twist around the axis of the pore. Conformational changes are prevented by an open-channel blocker, tetrabuthylammonium. Random clockwise and counterclockwise twisting in the range of several tens of degrees originate in the transmembrane domain and are transmitted to the cytoplasmic domain. This twisting motion may play a role in gating (Shimizu et al., 2008). This coupling suggests a mechanical interplay between the transmembrane and cytoplasmic domains. Artificial cell membrane systems provide a platform for reconstituting ion channels (Komiya et al. 2020).

The open-state conformation of the KcsA K+ channel has been studied using the Monte Carlo normal mode following simulations. Gating involves rotation and unwinding of the TM2 bundle, lateral movement of the TM2 helices away from the channel axis, and disappearance of the TM2 bundle. The gating transition is intrinsically multidimensional and described by a rough free-energy landscape (Delemotte et al. 2015).  The open-state conformation of KcsA exhibits a wide inner vestibule, with a radius approximately 5-7 Å and inner helices bent at the A98-G99 hinge. Computed conformational changes demonstrate that spin labeling and X-ray experiments illuminate different stages in gating: transition begins with clockwise rotation of the TM2 helices ending at a final state with the TM2 bend hinged near residues A98-G99. The concordance between the computational and experimental results provides atomic-level insight into the structural rearrangements of the channel's inner pore (Miloshevsky and Jordan, 2007).

Interconversion between conductive and non-conductive forms of the K+ channel selectivity filter underlies a variety of gating events. Cuello et al. (2010) reported the crystal structure of the Streptomyces lividans K+ channel, KcsA, in its open-inactivated conformation. They investigated the mechanism of C-type inactivation gating at the selectivity filter from channels 'trapped' in a series of partially open conformations. Five conformer classes were identified with openings ranging from 12 Å in closed KcsA to 32 Å when fully open. A correlation was observed between the degree of gate opening and the conformation and ion occupancy of the selectivity filter. A gradual filter backbone reorientation leads first to a loss of the S2 ion binding site and a subsequent loss of the S3 binding site, presumably abrogating ion conduction. The S4 helix may undergo a transition from an alpha-helical conformation to a short-lived different secondary structure transiently before reaching the active state in the activation process (Bassetto et al. 2019).

The archaeal voltage-dependent K+ channel (TC #1.A.1.17.1) has been characterized (Ruta et al., 2003). It exhibits the properties of a classical neuronal K+ channel including structural conservation in the voltage sensor as revealed by specific high affinity tarantula venom toxin binding. This toxin evolved to inhibit animal Kv channels.  The first four transmembrane helices (S1-S4) of any 6 TMS VIC family member, undergoes the first conformational changes in response to membrane voltage variations, and the S4 segment of each domain, which contains several positively charged residues interspersed with hydrophobic amino acids, is located within the membrane electric field and plays an essential role in voltage sensing (Miceli et al. 2015).

Three other bacterial VIC family channels have been characterized functionally. One is the 2 TMS LctB channel of Bacillus stearothermophilus (TC #1.A.1.1.2; Wolters et al., 1999), the second is the 6 TMS Kch channel of E. coli (TC #1.A.1.13.1; Ungar et al., 2001), and the third is the Bacillus halodurans 6 TMS voltage-gated Na+ channel (TC #1.A.1.14.1; Ren et al., 2001). This last-mentioned protein, called NaChBac, is most similar in sequence to voltage-gated Ca2+ channels (TC #1.A.1.11.1-3). A family of these 6 TMS voltage-gated Na+ channels (22-54% identical) is widespread in bacteria, suggesting a fundamental function (Koishi et al., 2004). These three proteins are all distantly related to KcsA of S. lividans, particularly LctB. Kch has been shown to form tetramers that may function to maintain the membrane potential in the early stationary phase of growth (Ungar et al., 2001).

Prokaryotic voltage-gated sodium channels form homotetramers with each subunit contributing six transmembrane α-helices (S1-S6). Helices S5 and S6 form the ion-conducting pore, and helices S1-S4 function as the voltage sensor with helix S4 thought to be the essential element for voltage-dependent activation. The crystal structures have provided insight into voltage-gated K channels, revealing a characteristic domain arrangement in which the voltage sensor domain of one subunit is close to the pore domain of an adjacent subunit in the tetramer. Shimomura et al. (2011) showed that the domain arrangement in NaChBac, (TC# 1.A.1.14.1), is similar to that in voltage-gated K+ channels. The domain arrangement and vertical mobility of helix S4 in NaChBac indicated that the structure and mechanism of voltage-dependent activation in prokaryotic Na+ channels are similar to those in canonical voltage-gated K+ channels (Shimomura et al., 2011).

In eukaryotes, each VIC family channel type has several subtypes based on pharmacological and electrophysiological data. Thus, there are six types of Ca2+ channels (L, N, P, Q, R and T). There are at least ten types of K+ channels, each responding in different ways to different stimuli: voltage-sensitive [Ka, Kv, Kvr, Kvs and Ksr], Ca2+-sensitive [BKCa, IKCa and SKCa] and receptor-coupled [KM and KACh+ channels (I, II, III, μ1, H1 and PN3). Cyclic nucleotide-responsive channels (families 1.A.1.4 and 1.A.1.5) contain centrally located CAP_ED domains, although the cyclic nucleotide regulatory properties have only been reported for family 1.A.5, not 1.A.4. Tetrameric channels from both prokaryotic and eukaryotic organisms are known in which each α-subunit possesses 2 TMSs rather than 6, and these two TMSs are homologous to TMSs 5 and 6 of the 6 TMS unit found in the voltage-sensitive channel proteins. KcsA of S. lividans is an example of such a 2 TMS channel protein. These channels may include the KNa (Na+-activated) and KVol (cell volume-sensitive) K+ channels, as well as distantly related channels such as the Tok1 K+ channel of yeast. The TWIK-1 and -2, TREK-1, TRAAK, and TASK-1 and -2 K+ channels all exhibit a duplicated 2 TMS unit and may therefore form a homodimeric channel. About 50 of these 4 TMS proteins are encoded in the C. elegans genome. Because of insufficient sequence similarity with proteins of the VIC family, inward rectifier K+ IRK channels (ATP-regulated; G-protein-activated) which possess a P domain and two flanking TMSs are placed in a distinct family (TC #1.A.2). However, substantial sequence similarity in the P region suggests that they are homologous. The β, γ, and δ subunits of VIC family members, when present, frequently play regulatory roles in channel activation/deactivation.

The function of voltage-dependent K+ channels is dependent on the negatively charged phosphodiester of phospholipid molecules. A non-voltage-dependent K+ channel does not exhibit the same dependence. It was proposed that the phospholipid membrane, by providing stabilizing interactions between positively charged voltage-sensor arginine residues and negatively charged lipid phosphodiester groups, provides an appropriate environment for the energetic stability and operation of the voltage-sensing machinery. The usage of arginine residues in voltage sensors is an adaptation to the phospholipid composition of cell membranes (Schmidt et al., 2006). The X-ray structure of a voltage-dependent K+ channel (Kv) can explain charge stabilization within the membrane and thus suggests the mechanism for coupling voltage-sensor movements to pore gating (Long et al., 2007).

Voltage-gated ion channels derive their voltage sensitivity from the movement of specific charged residues in response to a change in transmembrane potential. Several studies on mechanisms of voltage sensing in ion channels support the idea that these gating charges move through a well-defined permeation pathway. This gating pathway in a voltage-gated ion channel can also be mutated to transport free cations, including protons (Chanda and Chanda and Bezanilla, 2008). The discovery of proton channels homologous to voltage-sensing domains suggests that the same gating pathway is used by voltage-dependent proton transporters. The voltage sensor depends on the movement of charges in an electric field. Gating currents of the voltage sensor depend on the movements of positively charged arginines through the hydrophobic plug of a voltage sensor domain. Transient movements of these permanently charged arginines, caused by a change in the transmembrane potential further drag the S4 segment and induce opening/closing of the ion conduction pore by moving the S4-S5 linker. Thus, moving permanent charge induces capacitive current flow (Horng et al. 2018). Salt bridge interactions between S4-arginines and the negatively charged residues in other TMSs in the voltage sensor domain appear to contribute more to stabilizing the energy than the van der Waals interactions between nonpolar residues (Boonamnaj et al. 2021).

The voltage-sensing domains (VSDs) of K+ channels have been shown to undergo large rearrangements during gating, whereas the S4 segment may remain positioned between the central pore and the remainder of the VSD in both states (Grabe et al., 2007). In the Shaker K+ channel (1.A.1.2.6), mutation of the first arginine residue of the S4 helix to a smaller uncharged residue makes the VSD permeable to ions in the resting conformation ('S4 down'). There are four omega pores per channel, consistent with one conduction path per VSD. Permeating ions from the extracellular medium enter the VSD at its peripheral junction with the pore domain, and then plunge into the core of the VSD in a curved conduction pathway (Tombola et al. 2007).

Amongst the nine voltage-gated K(+) channel (Kv) subunits expressed in Arabidopsis, AtKC1 does not seem to form functional Kv channels. Co-expression of AtKC1 (1.A.1.4.9), AKT1 (1.A.1.4.1) and/or KAT1 (1.A.1.4.7) genes in tobacco mesophyll protoplasts showed that AtKC1 remains in the endoplasmic reticulum unless it is co-expressed with AKT1 (Duby et al., 2008). Heteromeric AtKC1-AKT1 channels display functional properties different from those of homomeric AKT1 channels. In particular, the activation threshold voltage of the former channels is more negative than that of the latter ones preferred to AKT1-AKT1 homodimers during the process of tetramer assembly. Thus, AtKC1 is a Kv subunit, which downregulates the physiological activity of other Kv channel subunits (Duby et al., 2008).

Shaker-type K+ channels in plants display distinct voltage-sensing properties despite sharing sequence and structural similarity. For example, an Arabidopsis K+ channel (SKOR) and a tomato K+ channel (LKT1) share high amino acid sequence similarity and identical domain structures; however, SKOR conducts outward K+ current and is activated by positive membrane potentials (depolarization), whereas LKT1 conducts inward current and is activated by negative membrane potentials (hyperpolarization). The structural basis for the 'opposite' voltage-sensing properties of SKOR and LKT1 was determined in SKOR channel single amino acid mutations that converted the outward-conducting channel into an inward-conducting channel. Domain-swapping and random mutagenesis produced similar results, suggesting functional interactions between several regions of the SKOR protein that lead to specific voltage-sensing properties. Thus, dramatic changes in rectifying properties can be caused by single amino acid mutations.

The structure of the transmembrane regions of the bacterial cyclic nucleotide-regulated channel MlotiK1 (TC# 1.A.1.25.1), a non-voltage-gated 6 TM channel, has been determined (Clayton et al., 2008). The S1-S4 domain and its associated linker serve as a clamp to constrain the gate of the pore and possibly function in concert with ligand-binding domains to regulate the opening of the pore. Motions of the S6 inner helices can gate the ion conduction pathway at a position along the pore closer to the selectivity filter than the canonical helix bundle crossing.

Carbon monoxide (CO) is a lethal gas, but it is also a physiological signaling molecule capable of regulating a variety of proteins. Among them, large-conductance Ca2+- and voltage-gated K+ (Slo1 BK) channels, important in vasodilation and neuronal firing, have been suggested to be directly stimulated by CO. In fact, CO activates Slo1 BK channels (Hou et al, 2008) in the absence of Ca2+ in a voltage-sensor-independent manner. The stimulatory action of CO requires an aspartic acid and two histidine residues located in the cytoplasmic RCK1 domain. CO probably acts as a partial agonist for the high-affinity divalent cation sensor in the RCK1 domain of the Slo1 BK channel (1.A.1.3.2).

Ca2+-activated BK channels (e.g., 1.A.1.3.3) modulate neuronal activities, including spike frequency adaptation and synaptic transmission. Ca2+-binding sites and the activation gate are spatially separated in the channel protein. By studying an Asp-to-Gly mutation (D434G) associated with human syndrome of generalized epilepsy and paroxysmal dyskinesia (GEPD), Yang et al. (2010) showed that a cytosolic motif immediately following the activation gate S6 helix, known as the AC region, mediates the allosteric coupling between Ca2+ binding and channel opening. The GEPD mutation inside the AC region increases BK channel activity by enhancing this allosteric coupling. Ca2+ sensitivity is enhanced by increases in solution viscosity that reduce protein dynamics. The GEPD mutation alters such a response, suggesting that a less flexible AC region may be more effective in coupling Ca2+ binding to channel opening.

The voltage sensors in VIC family cation channels use a sliding-helix mechanism for electromechanical coupling in which outward movement of gating charges in the S4 transmembrane segments catalyzed by sequential formation of ion pairs pulls the S4-S5 linker, bends the S6 segment, and opens the pore (Catterall, 2010). Impairment of voltage-sensor function by mutations in Na+ channels contributes to several ion channelopathies, and gating pore current conducted by mutant voltage sensors in Na(V)1.4 channels is the primary pathophysiological mechanism in hypokalemic periodic paralysis. Confinement of water within a hydrophobic cavity can drive a cooperative dewetting transition. For a nanometer-scale pore, the dewetting transition leads to a stable dry state that is physically open but impermeable to ions (Yazdani et al. 2020). This phenomenon is often referred to as hydrophobic gating. Numerous ion channels utilize hydrophobic gating in their activation and regulation. Yazdani et al. 2020 reviewed recent theoretical, simulation, and experimental studies that together establish the principles of hydrophobic gating and discuss how channels of various sizes, topologies, and biological functions can utilize these principles to control the thermodynamic properties of water within their interior pores for gating and regulation.

In animals, calcium regulates heartbeat, muscle contraction, neuronal communication, hormone release, cell division, and gene transcription. Major entryways for Ca2+ in excitable cells are high-voltage activated (HVA) Ca2+ channels, Cav (Buraei and Yang, 2010). These are plasma membrane proteins composed of several subunits, including α1, α2δ, β, and γ. Although the principal α1 subunit contains the channel pore, gating machinery and most drug binding sites, the cytosolic auxiliary β subunit plays an essential role in regulating the surface expression and gating properties of HVA Ca2+ channels. Cavβ is also crucial for the modulation of HVA Ca2+ channels by G proteins, kinases, and the Ras-related RGK GTPases. Additional proteins modulate HVA Ca2+ channels by binding to Cavβ, and it may carry out Ca2+ channel-independent functions, including directly regulating gene transcription. All four subtypes of Cavβ, encoded by different genes, have a modular organization, consisting of three variable regions, a conserved guanylate kinase (GK) domain, and a conserved Src-homology 3 (SH3) domain, placing them into the membrane-associated guanylate kinase (MAGUK) protein family. Crystal structures of Cavβs reveal how they interact with Cavα1 (Buraei and Yang, 2010).

Regulator of K+ conductance (RCK) domains control the activity of a variety of K+ transporters and channels, including the human large conductance Ca2+-activated K+ channel that is important for blood pressure regulation and control of neuronal firing, and MthK, a prokaryotic Ca2+-gated K+ channel that has yielded structural insight toward mechanisms of RCK domain-controlled channel gating. In MthK, a gating ring of eight RCK domains regulates channel activation by Ca2+. Pau et al. (2011) showed that each RCK domain contributes to three different regulatory Ca2+-binding sites, two of which are located at the interfaces between adjacent RCK domains. The additional Ca2+-binding sites, resulting in a stoichiometry of 24 Ca2+ions per channel, is consistent with the steep relation between [Ca2+] and MthK channel activity. Comparison of Ca2+-bound and unliganded RCK domains suggests a physical mechanism for Ca2+-dependent conformational changes that underlie gating in this class of channels.

The mechanism of ion channel voltage gating - how channels open and close in response to voltage changes - has been debated since Hodgkin and Huxley's seminal discovery that the crux of nerve conduction is ion flow across cellular membranes. Using all-atom molecular dynamics simulations, Jensen et al. (2012) showed how a voltage-gated potassium channel (KV) switches between activated and deactivated states. On deactivation, pore hydrophobic collapse rapidly halts ion flow. Subsequent voltage-sensing domain (VSD) relaxation, including inward, 15-angstrom S4-helix motion, completes the transition. On activation, outward S4 motion tightens the VSD-pore linker, perturbing linker-S6-helix packing. Fluctuations allow water, then potassium ions, to reenter the pore; linker-S6 repacking stabilizes the open pore. Jensen et al. (2012) proposed a mechanistic model for the sodium/potassium/calcium voltage-gated ion channel superfamily that reconciles apparently conflicting experimental data.

In yeast and filamentous fungi, the Ca2+ channel, Cch1 forms a complex with an auxiliary subunit Mid1 to form the active complex (1.A.1.11.10). Mid1 was originally reported to have Ca2+ channel activity because when produced in Chinese hamster ovary cells, it produced channel activity (Kanzaki et al., 1999). However, it is now clear from many studies that Mid1 is required for Cch1-mediated Ca2+ flux and probably has no inherent channel activity (Ma et al., 2011; Martin et al., 2011; Cavinder and Trail, 2012). Mid1 was originally assigned to TC family: 1.A.16, The Yeast Stretch-Activated Cation-selective Ca2+ Channel, Mid1 (Mid1) Family, but this assignment has been deleted from TCDB, and Mid1 proteins have been incorporated into TC subfamily 1.A.1.11.

Hyperpolarization activated and cyclic nucleotide-gated (HCN) ion channels as well as cyclic nucleotide-gated (CNG) ion channels are essential for the regulation of cardiac cells, neuronal excitability, and signaling in sensory cells (Börger et al. 2014). Both classes are composed of four subunits. Each subunit comprises a transmembrane region, intracellular N- and C-termini, and a C-terminal cyclic nucleotide-binding domain (CNBD). Binding of cyclic nucleotides to the CNBD promotes opening of both CNG and HCN channels. In the case of CNG channels, binding of cyclic nucleotides to the CNBD is sufficient to open the channel. In contrast, HCN channels open upon membrane hyperpolarization and their activity is modulated by binding of cyclic nucleotides, shifting the activation potential to more positive values. Several high-resolution structures of CNBDs from HCN and CNG channels are available.  Börger et al. 2014 reported the complete backbone and side chain resonance assignments of the murine HCN2 CNBD with part of the C-linker.

Plant Shaker channels are members of the 6 transmembrane-1 pore (6TM-1P) cation channel superfamily as are the animal Shaker (Kv) and HCN channels. All these channels are voltage-gated K+ channels: Kv channels are outward-rectifiers, opened at depolarized voltages, and HCN channels are inward-rectifiers, opened by membrane hyperpolarization. Among plant Shaker channels, are outward-rectifiers, inward-rectifiers and weak-rectifiers with weak voltage dependence (Nieves-Cordones and Gaillard 2014). Despite the absence of crystal structures of plant Shaker channels, functional analyses coupled to homology modeling, mostly based on Kv and HCN crystals, have permitted the identification of several regions contributing to plant Shaker channel gating. In a recent mini-review, Nieves-Cordones and Gaillard 2014 updated information on the voltage-gating mechanism of plant Shaker channels which seem to be comparable to that proposed for HCN channels.

The membrane dipole potential (Psid) constitutes one of three electrical potentials generated by cell membranes. Psid arises from the unfavorable parallel alignment of phospholipid and water dipoles, and varies in magnitude both longitudinally and laterally across the bilayer according to membrane composition and phospholipid packing density. Pearlstein et al. 2016 proposed that dynamic counter-balancing between Psid and the transmembrane potential (Δψ) governs the conformational state transitions of voltage-gated ion channels.

In the cell membrane, ion channels and enzymes are able to sense voltage. Sodium, Ca2+ and K+ voltage-dependent channels of the VIC superfamily have a conserved positively charged transmembrane (S4) segment that moves in response to changes in membrane voltage.S4 forms part of a domain that crystallizes as a well-defined structure consisting of the first four transmembrane (S1-S4) segments of the protein, the voltage sensor domain (VSD). VSD movements are allosterically coupled to pore opening to various degrees, depending on the type of channel. How many charges are moved during channel activation, how much they move, and which are the molecular determinants that mediate the electromechanical coupling between the VSD and the pore domains are discussed by Gonzalez et al. 2012.

The family of P-loop channels is characterized by four membrane re-entering extracellular P-loops that connect eight transmembrane helices.  X-ray and cryo-EM structures of the open- and closed-state channels show conserved state-dependent folding despite the fact that the sequences are diverse. In homologous sodium, calcium, TRPV and two-pore channels, the pore-lining helices contain conserved asparagines that may or may not include pi-helix bulges. Comparison of the sequence- and 3D-alignemnts suggests that the asparagines appeared in evolution as insertions that are accommodated in two ways: by pi-helix bulges, which preserve most of inter-segment contacts, or by twists of the C-terminal thirds and switch of inter-segment contacts (Tikhonov and Zhorov 2017). 

Several VIC superfamily K+ channels are affected by molybdenum disulfide nanoflakes (MoS2) (Gu et al. 2017).  For example, MoS2 binds to the extracellular loops of KcsA, which indirectly destroys the delicate structure of the selectivity filter, causing a strong leak of K+ ions.  In the binding mode with Kir3.2, a MoS2 nanoflake completely covers the entrance to the channel pore, affecting ion conduction. For the Kv1.2 chimera, the MoS2 nanoflake prefers to bind into a crevice located at the extracellular side of the Voltage Sensor Domain (VSD). This crevice involves the N-terminal segment of S4, which directly controls the gating process of the Kv1.2 chimera channel by electromechanical coupling of the VSD to the transmembrane electric field (Gu et al. 2017).

Many potassium-channel openers (agonists) share a distinct biaryl-sulfonamide motif. The negatively charged variants of these compounds bind to the top of the voltage-sensor domain, between transmembrane segments 3 and 4, to open the channel. Although biaryl-sulfonamide compounds open some potassium channels, they have also been reported to block sodium and calcium channels (Liin et al. 2018).  The biaryl-sulfonamide motif seems to be a general ion-channel activator motif. Voltage-dependent potassium channels are essential for the generation of nerve impulses.

Voltage sensitivity is conferred by charged residues located mainly in the fourth transmembrane segment (S4) of each of the four identical subunits that make up the channel. These charged segments relocate when the potential difference across the membrane changes, controlling the ability of the pore to conduct ions (Starace and Bezanilla 2004). In the crystal structure of the Aeropyrum pernix potassium channel KvAP, the S4 and part of the third (S3B) transmembrane alpha-helices are connected by a hairpin turn in an arrangement termed the 'voltage-sensor paddle'. This structure was proposed to move through the lipid bilayer during channel activation, transporting positive charges across a large fraction of the membrane. However  Starace and Bezanilla 2004 showed that replacing the first S4 arginine by histidine in the Shaker potassium channel creates a proton pore when the cell is hyperpolarized. Formation of this pore does not support the paddle model, as protons would not have access to a lipid-buried histidine. Thus, at hyperpolarized potentials, water and protons from the internal and external solutions must be separated by a narrow barrier in the channel protein that focuses the electric field to a small voltage-sensitive region.

Voltage-dependent activation of voltage-gated cation channels results from the outward movement of arginine-bearing helices within proteinaceous voltage sensors. The arginine side chains in the voltage-sensing residues in potassium channels may make electrostatic or steric contributions to voltage sensing. Infield et al. 2018 functionally characterized engineered Shaker K+ channels, and observed effects on both voltage sensitivity and gating kinetics following substitution of the fourth S4 charged arginine with neutral citrulline, which caused substantial changes in the conductance-voltage relationship and channel kinetics. This suggested that a positive charge is required at this position for efficient voltage sensor deactivation and channel closure.

Toxins of voltage-gated ion channels are broadly divided into two categories—pore blockers that physically occlude the channel pore and gating modifiers that alter channel gating by interfering with the voltage sensor domains (VSDs). Whereas small-molecule neurotoxins such as tetrodotoxin (TTX) and saxitoxin (STX) function as pore blockers, most peptidic Nav channel toxins are gating modifiers that trap the channel in a particular stage of the gating cycle through interactions with one or more VSDs. Shen et al. 2018 determined the structure of NavPaS, the Na+ channel from the American cockroach, bound to a peptide toxin, Dc1a, from the venom of the desert bush spider, Diguetia canitries that specifically binds VSDII of insect Navs to promote chanell opeining, as well as TTX or STX that bind to and block the pore.  Dc1a binds in a cleft between VSDII and hte pore region, causing structural rearrangements (see 8.B.30 for the Dc1a toxin descrption.

Calcium channels play roles in tumorigenesis and progression. Zhong et al. 2019 reviewed the evidence for a linkage between calcium channels and major characteristics of tumors such as multi-drug resistance (MDR), metastasis, apoptosis, proliferation, evasion of immune surveillance, and the alterations of tumor microenvironment. Ion channels also play active roles in phagocytosis. The participation of some channels in cell proliferation during interphase and mitosis has been discussed (Rosendo-Pineda et al. 2020). Pozdnyakov et al. 2018 characterized the functional determinants (selectivity filter, voltage sensor, Nav-like inactivation gates, Cavbeta-interaction motifs, and calmodulin-binding regions) of 277 eukaryotic VIC family members and constructed a phylogenetic tree. This allowed them to uncovere lineage-specific structural gains and losses in the course of evolution and suggest the ancient structural features of these channels.

Voltage-gated sodium channels are targets for a range of pharmaceutical drugs developed for the treatment of neurological diseases. Cannabidiol (CBD), the non-psychoactive compound isolated from cannabis plants, has been approved for treatment of two types of epilepsy associated with sodium channel mutations. CBD binds at a site at the interface of the fenestrations and the central hydrophobic cavity of the channel (Sait et al. 2020). Binding at this site blocks the TM sodium ion translocation pathway, providing a molecular mechanism for channel inhibition. The closely-related psychoactive tetrahydrocannabinol seems not to have the same effects on these channels. The TRPV2 channel may also be a target site for CBD.

K2P K+ channels contribute to many processes including anesthesia, pain, arrythmias, ischemia, hypertension, migraine, intraocular pressure regulation, and lung injury responses. Structural studies of six homomeric K2Ps have established the basic architecture of this channel sub-family, revealed key moving parts involved in K2P function, uncovered the importance of asymmetric pinching and dilation motions in the K2P selectivity filter (SF) C-type gate, and defined two K2P structural classes based on the absence or presence of an intracellular gate (Natale et al. 2021). Further, a series of structures characterizing K2P:modulator interactions have revealed a striking polysite pharmacology housed within an approximately 70 kDa channel. Binding sites for small molecules or lipids that control channel function are found at every layer of the channel structure, starting from its extracellular side through the portion that interacts with the membrane bilayer inner leaflet. This framework provides the basis for understanding how gating cues sensed by different channel parts control function, and how small molecules and lipids modulate K2P activity (Natale et al. 2021).

In in vitro experiments on isolated rat hippocampal neurons, Tsorin et al. 2022 studied the electrophysiological mechanisms of the antiarrhythmic effects of N-deacetyllappaconitine monochlorhydrate (DALCh), active metabolite of lappaconitine hydrobromide (allapinin). Electrical activity of neurons was recorded by the patch-clamp method in the whole cell configuration. DALCh increased the duration of both slow and fast depolarization phases and decreased the amplitude of the action potential. DALCh effectively inhibited transmembrane currents of Na+ ions and partially K+ ions through the corresponding transmembrane voltage-gated ion channels. Thus, DALCh, in contrast to lappaconitine hydrobromide, belongs not to the 1C, but to the 1A class of antiarrhythmics according to the Vaughan-Williams classification (Tsorin et al. 2022).

The generalized transport reaction catalyzed by members of the VIC family is:

cation (out) ⇌ cation (in).

This family belongs to the VIC Superfamily.



and ?. (2012). RETRACTED ARTICLE: Deprotonation of arginines in S4 is involved in NaChBac gating. J Membr Biol. 245(11):761.

and Abbott GW. (2016). KCNE1 and KCNE3: The yin and yang of voltage-gated K(+) channel regulation. Gene. 576(1 Pt 1):1-13.

and Atlas D. (201). The voltage-gated calcium channel functions as the molecular switch of synaptic transmission. Annu Rev Biochem. 82:607-35.

and Rothberg BS. (2012). The BK channel: a vital link between cellular calcium and electrical signaling. Protein Cell. 3(12):883-92.

and Thevenod F. (2010). Catch me if you can! Novel aspects of cadmium transport in mammalian cells. Biometals. 23(5):857-75.

Abbott, G.W. (2017). β Subunits Control the Effects of Human Kv4.3 Potassium Channel Phosphorylation. Front Physiol 8: 646.

Adams, S.L., G. Chang, M.A. Fouda, S. Kumar, and B. Sun. (2022). Absolute Quantification of Nav1.5 Expression by Targeted Mass Spectrometry. Int J Mol Sci 23:.

Agarkova, I., D. Dunigan, J. Gurnon, T. Greiner, J. Barres, G. Thiel, and J.L. Van Etten. (2008). Chlorovirus-mediated membrane depolarization of Chlorella alters secondary active transport of solutes. J. Virol. 82: 12181-12190.

Agwa, A.J., L.V. Blomster, D.J. Craik, G.F. King, and C.I. Schroeder. (2018). Efficient Enzymatic Ligation of Inhibitor Cystine Knot Spider Venom Peptides: Using Sortase A To Form Double-Knottins That Probe Voltage-Gated Sodium Channel Na1.7. Bioconjug Chem. [Epub: Ahead of Print]

Akopian, A.N., L. Sivilotti, and J.N. Wood. (1996). A tetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurons. Nature 379: 257-262.

Alexander, S.P.H. and J.A. Peters. (1997). Receptor and ion channel nomenclature supplement. Trends Pharmacol. Sci., Elsevier, pp. 76-84.

Altrichter, S., M. Haase, B. Loh, A. Kuhn, and S. Leptihn. (2016). Mechanism of the Spontaneous and Directional Membrane Insertion of a 2-Transmembrane Ion Channel. ACS Chem Biol. [Epub: Ahead of Print]

Amarouch, M.Y., H. Kurt, L. Delemotte, and H. Abriel. (2020). Biophysical Characterization of Epigallocatechin-3-Gallate Effect on the Cardiac Sodium Channel Na1.5. Molecules 25:.

Amin, A.S., Y.J. Reckman, E. Arbelo, A.M. Spanjaart, P.G. Postema, R. Tadros, M.W. Tanck, M.P. Van den Berg, A.A.M. Wilde, and H.L. Tan. (2018). SCN5A mutation type and topology are associated with the risk of ventricular arrhythmia by sodium channel blockers. Int J Cardiol. [Epub: Ahead of Print]

An, F.A., M.R. Bowlby, M. Betty, J. Cao, H. Ling, G. Mendoza, J.W. Hinson, K.I. Mattsson, B.W. Strassle, J.S. Trimmer, and K.J. Rhodes. (2000). Modulation of A-type potassium channels by a family of calcium sensors. Nature 403: 553.

Anderson, P.A.V. and R.M. Greenberg. (2001). Phylogeny of ion channels: clues to structure and function. Comp. Biochem. Physiol. B 129: 17-18.

Andolfo, I., R. Russo, F. Manna, B.E. Shmukler, A. Gambale, G. Vitiello, G. De Rosa, C. Brugnara, S.L. Alper, L.M. Snyder, and A. Iolascon. (2015). Novel Gardos channel mutations linked to dehydrated hereditary stomatocytosis (xerocytosis). Am J Hematol 90: 921-926.

Anwar, T. and G. Samudrala. (2018). Bioinformatics Analysis and Functional Prediction of Transmembrane Proteins in. Genes (Basel) 9:.

Aoki, I., M. Tateyama, T. Shimomura, K. Ihara, Y. Kubo, S. Nakano, and I. Mori. (2018). SLO potassium channels antagonize premature decision making in. Commun Biol 1: 123.

Aqvist, J. and V. Luzhkov. (2000). Ion permeation mechanism of the potassium channel. Nature 404: 881-884.

Arrigoni, C., M. Lolicato, D. Shaya, A. Rohaim, F. Findeisen, L.K. Fong, C.M. Colleran, P. Dominik, S.S. Kim, J.P. Schuermann, W.F. DeGrado, M. Grabe, A.A. Kossiakoff, and D.L. Minor, Jr. (2022). Quaternary structure independent folding of voltage-gated ion channel pore domain subunits. Nat Struct Mol Biol 29: 537-548.

Aryal, P., F. Abd-Wahab, G. Bucci, M.S. Sansom, and S.J. Tucker. (2015). Influence of lipids on the hydrophobic barrier within the pore of the TWIK-1 K2P channel. Channels (Austin) 9: 44-49.

Aryal, P., V. Jarerattanachat, M.V. Clausen, M. Schewe, C. McClenaghan, L. Argent, L.J. Conrad, Y.Y. Dong, A.C. Pike, E.P. Carpenter, T. Baukrowitz, M.S. Sansom, and S.J. Tucker. (2017). Bilayer-Mediated Structural Transitions Control Mechanosensitivity of the TREK-2 K2P Channel. Structure. [Epub: Ahead of Print]

Ashmole, I., D.V. Vavoulis, P.J. Stansfeld, P.R. Mehta, J.F. Feng, M.J. Sutcliffe, and P.R. Stanfield. (2009). The response of the tandem pore potassium channel TASK-3 (K(2P)9.1) to voltage: gating at the cytoplasmic mouth. J. Physiol. 587: 4769-4783.

Atsuta, Y., R.R. Tomizawa, M. Levin, and C.J. Tabin. (2019). L-type voltage-gated Ca channel Ca1.2 regulates chondrogenesis during limb development. Proc. Natl. Acad. Sci. USA 116: 21592-21601.

Aubert Mucca, M., O. Patat, S. Whalen, L. Arnaud, G. Barcia, J. Buratti, B. Cogné, D. Doummar, C. Karsenty, S. Kenis, E. Leguern, G. Lesca, C. Nava, M. Nizon, A. Piton, S. Valence, L. Villard, S. Weckhuysen, B. Keren, and C. Mignot. (2022). Patients with -related intellectual disability without distinctive features of Zimmermann-Laband/Temple-Baraitser syndrome. J Med Genet 59: 505-510.

Azeem, F., R. Zameer, M.A. Rehman Rashid, I. Rasul, S. Ul-Allah, M.H. Siddique, S. Fiaz, A. Raza, A. Younas, A. Rasool, M.A. Ali, S. Anwar, and M.H. Siddiqui. (2021). Genome-wide analysis of potassium transport genes in Gossypium raimondii suggest a role of GrHAK/KUP/KT8, GrAKT2.1 and GrAKT1.1 in response to abiotic stress. Plant Physiol. Biochem 170: 110-122. [Epub: Ahead of Print]

Bachnoff, N., M. Cohen-Kutner, M. Trus, and D. Atlas. (2013). Intra-membrane Signaling Between the Voltage-Gated Ca2+-Channel and Cysteine Residues of Syntaxin 1A Coordinates Synchronous Release. Sci Rep 3: 1620.

Bagal, S.K., B.E. Marron, R.M. Owen, R.I. Storer, and N.A. Swain. (2015). Voltage gated sodium channels as drug discovery targets. Channels (Austin) 9: 360-366.

Bagnéris, C., P.G. Decaen, B.A. Hall, C.E. Naylor, D.E. Clapham, C.W. Kay, and B.A. Wallace. (2013). Role of the C-terminal domain in the structure and function of tetrameric sodium channels. Nat Commun 4: 2465.

Bagriantsev, S.N., R. Peyronnet, K.A. Clark, E. Honoré, and D.L. Minor, Jr. (2011). Multiple modalities converge on a common gate to control K2P channel function. EMBO. J. 30: 3594-3606.

Bai, H.W., S. Eom, H.D. Yeom, K.V.A. Nguyen, J. Lee, S.O. Sohn, and J.H. Lee. (2018). Molecular basis involved in the blocking effect of antidepressant metergoline on C-type inactivation of Kv1.4 channel. Neuropharmacology 146: 65-73. [Epub: Ahead of Print]

Baig, A.M., J. Iqbal, and N.A. Khan. (2013). In vitro efficacies of clinically available drugs against growth and viability of an Acanthamoeba castellanii keratitis isolate belonging to the T4 genotype. Antimicrob. Agents Chemother. 57: 3561-3567.

Baker, K.A., C. Tzitzilonis, W. Kwiatkowski, S. Choe, and R. Riek. (2007). Conformational dynamics of the KcsA potassium channel governs gating properties. Nat Struct Mol Biol 14: 1089-1095.

Balagué, C., B. Lin, C. Alcon, G. Flottes, S. Malmström, C. Köhler, G. Neuhaus, G. Pelletier, F. Gaymard, and D. Roby. (2003). HLM1, an essential signaling component in the hypersensitive response, is a member of the cyclic nucleotide-gated channel ion channel family. Plant Cell 15: 365-379.

Balajthy, A., P. Hajdu, G. Panyi, and Z. Varga. (2017). Sterol Regulation of Voltage-Gated K+ Channels. Curr Top Membr 80: 255-292.

Balduini, A., C. Fava, C.A. Di Buduo, V. Abbonante, A. Meneguzzi, P.M. Soprano, F. Taus, M. Castelli, A. Giontella, M. Dovizio, S. Tacconelli, P. Patrignani, and P. Minuz. (2021). Expression and functional characterization of the large-conductance calcium and voltage-activated potassium channel K 1.1 in megakaryocytes and platelets. J Thromb Haemost. [Epub: Ahead of Print]

Balss, J., P. Papatheodorou, M. Mehmel, D. Baumeister, B. Hertel, N. Delaroque, F.C. Chatelain, D.L. Minor, Jr, J.L. Van Etten, J. Rassow, A. Moroni, and G. Thiel. (2008). Transmembrane domain length of viral K+ channels is a signal for mitochondria targeting. Proc. Natl. Acad. Sci. USA 105: 12313-12318.

Bang, H., Y. Kim, and D. Kim. (2000). TREK-2, a new member of the mechanosensitive tandem-pore K+ channel family. J. Biol. Chem. 275: 17412-17419.

Barber AF., Carnevale V., Raju SG., Amaral C., Treptow W. and Klein ML. (2012). Hinge-bending motions in the pore domain of a bacterial voltage-gated sodium channel. Biochim Biophys Acta. 1818(9):2120-5.

Barmeyer, C., C. Rahner, Y. Yang, F.J. Sigworth, H.J. Binder, and V.M. Rajendran. (2010). Cloning and identification of tissue-specific expression of KCNN4 splice variants in rat colon. Am. J. Physiol. Cell Physiol. 299: C251-263.

Barros, F., L.A. Pardo, P. Domínguez, L.M. Sierra, and P. de la Peña. (2019). New Structures and Gating of Voltage-Dependent Potassium (Kv) Channels and Their Relatives: A Multi-Domain and Dynamic Question. Int J Mol Sci 20:.

Barros, F., P. de la Peña, P. Domínguez, L.M. Sierra, and L.A. Pardo. (2020). The EAG Voltage-Dependent K Channel Subfamily: Similarities and Differences in Structural Organization and Gating. Front Pharmacol 11: 411.

Bartolomé-Martín, D., I. Ibáñez, D. Piniella, E. Martínez-Blanco, S.G. Pelaz, and F. Zafra. (2019). Identification of potassium channel proteins Kv7.2/7.3 as common partners of the dopamine and glutamate transporters DAT and GLT-1. Neuropharmacology. [Epub: Ahead of Print]

Bassetto, C.A.Z., Jr, J.L. Carvalho-de-Souza, and F. Bezanilla. (2019). Metal Bridge in S4 Segment Supports Helix Transition in Shaker Channel. Biophys. J. [Epub: Ahead of Print]

Basu, D. and E.S. Haswell. (2017). Plant mechanosensitive ion channels: an ocean of possibilities. Curr. Opin. Plant Biol. 40: 43-48.

Bauer, C.K. and J.R. Schwarz. (2018). Ether-à-go-go K channels: effective modulators of neuronal excitability. J. Physiol. 596: 769-783.

Bauer, C.K., P.E. Schneeberger, F. Kortüm, J. Altmüller, F. Santos-Simarro, L. Baker, J. Keller-Ramey, S.M. White, P.M. Campeau, K.W. Gripp, and K. Kutsche. (2019). Gain-of-Function Mutations in KCNN3 Encoding the Small-Conductance Ca-Activated K Channel SK3 Cause Zimmermann-Laband Syndrome. Am J Hum Genet 104: 1139-1157.

Becchetti, A., S. Crescioli, F. Zanieri, G. Petroni, R. Mercatelli, S. Coppola, L. Gasparoli, M. D'Amico, S. Pillozzi, O. Crociani, M. Stefanini, A. Fiore, L. Carraresi, V. Morello, S. Manoli, M.F. Brizzi, D. Ricci, M. Rinaldi, A. Masi, T. Schmidt, F. Quercioli, P. Defilippi, and A. Arcangeli. (2017). The conformational state of hERG1 channels determines integrin association, downstream signaling, and cancer progression. Sci Signal 10:.

Becker, C., D. Geiger, B. Dunkel, A. Roller, A. Bertl, A. Latz, A. Carpaneto, P. Dietrich, M.R.G. Roelfsema, C. Voelker, D. Schmidt, B. Mueller-Roeber, K. Czempinski, and R. Hedrich. (2004). AtTPK4, an Arabidopsis tandem-pore K+ channel, poised to control the pollen membrane voltage in a pH- and Ca2+-dependent manner. Proc. Natl. Acad. Sci. USA 101: 15621-15626.

Behringer, E.J. and M.A. Hakim. (2019). Functional Interaction among K and TRP Channels for Cardiovascular Physiology: Modern Perspectives on Aging and Chronic Disease. Int J Mol Sci 20:.

Bell, D.C., H. Yao, R.C. Saenger, J.H. Riley, and S.A. Siegelbaum. (2004). Changes in local S4 environment provide a voltage-sensing mechanism for mammalian hyperpolarization-activated HCN channels. J Gen Physiol 123: 5-19.

Ben Mahmoud, A., R. Ben Mansour, F. Driss, S. Baklouti-Gargouri, O. Siala, E. Mkaouar-Rebai, and F. Fakhfakh. (2015). Evaluation of the effect of c.2946+1G>T mutation on splicing in the SCN1A gene. Comput Biol Chem 54: 44-48.

Ben Soussia, I., S. El Mouridi, D. Kang, A. Leclercq-Blondel, L. Khoubza, P. Tardy, N. Zariohi, M. Gendrel, F. Lesage, E.J. Kim, D. Bichet, O. Andrini, and T. Boulin. (2019). Mutation of a single residue promotes gating of vertebrate and invertebrate two-pore domain potassium channels. Nat Commun 10: 787.

Bennett, V., and J. Healy. (2008). Being there: cellular targeting of voltage-gated sodium channels in the heart. J. Cell. Biol. 180: 13-15.

Berkefeld, H. and B. Fakler. (2013). Ligand-Gating by Ca2+ Is Rate Limiting for Physiological Operation of BKCa Channels. J. Neurosci. 33: 7358-7367.

Berkefeld, H., C.A. Sailer, W. Bildl, V. Rohde, J.O. Thumfart, S. Eble, N. Klugbauer, E. Reisinger, J. Bischofberger, D. Oliver, H.G. Knaus, U. Schulte, and B. Fakler. (2006). BKCa-Cav channel complexes mediate rapid and localized Ca2+-activated K+ signaling. Science 314: 615-620.

Bertaccini EJ., Dickinson R., Trudell JR. and Franks NP. (2014). Molecular modeling of a tandem two pore domain potassium channel reveals a putative binding site for general anesthetics. ACS Chem Neurosci. 5(12):1246-52.

Bertl, A., J. Ramos, J. Ludwig, H. Lichtenberg-Fraté, J. Reid, H. Bihler, F. Calero, P. Martinez, and P.O. Ljungdahl. (2003). Characterization of potassium transport in wild-type and isogenic yeast strains carrying all combinations of trk1, trk2 and tok1 null mutations. Mol. Microbiol. 47: 767-780.

Bezanilla, F. (2000). The voltage sensor in voltage-dependent ion channels. Physiol. Rev. 80: 555-592.

Bezanilla, F. (2008). How membrane proteins sense voltage. Nat Rev Mol. Cell Biol. 9: 323-332.

Bezine, M., S. Maatoug, R. Ben Khalifa, M. Debbabi, A. Zarrouk, Y. Wang, W.J. Griffiths, T. Nury, M. Samadi, A. Vejux, J. de Sèze, T. Moreau, R. Kharrat, M. El Ayeb, and G. Lizard. (2018). Modulation of Kv3.1b potassium channel level and intracellular potassium concentration in 158N murine oligodendrocytes and BV-2 murine microglial cells treated with 7-ketocholesterol, 24S-hydroxycholesterol or tetracosanoic acid (C24:0). Biochimie. [Epub: Ahead of Print]

Bianchi L., S.M. Kwok, M. Driscoll, F. Sesti. (2003). A potassium channel-MiRP complex controls neurosensory function in Caenorhabditis elegans. J Biol. Chem. 278:12415-12424.

Biel M., S. Michalakis. (2007). Function and dysfunction of CNG channels: insights from channelopathies and mouse models. Mol Neurobiol. 35: 266-277.

Biel, M., C. Wahl-Schott, S. Michalakis, and X. Zong. (2009). Hyperpolarization-activated cation channels: from genes to function. Physiol. Rev. 89: 847-885.

Bignucolo, O. and S. Bernèche. (2020). The Voltage-Dependent Deactivation of the KvAP Channel Involves the Breakage of Its S4 Helix. Front Mol Biosci 7: 162.

Biswas, S., I. Deschênes, D. Disilvestre, Y. Tian, V.L. Halperin, and G.F. Tomaselli. (2008). Calmodulin regulation of Nav1.4 current: role of binding to the carboxyl terminus. J. Gen. Physiol. 131: 197-209.

Blasic, J.R., D.L. Worcester, K. Gawrisch, P. Gurnev, and M. Mihailescu. (2015). Pore Hydration States of KcsA Potassium Channels in Membranes. J. Biol. Chem. 290: 26765-26775.

Bocksteins, E., N. Ottschytsch, J.P. Timmermans, A.J. Labro, and D.J. Snyders. (2011). Functional interactions between residues in the S1, S4, and S5 domains of Kv2.1. Eur Biophys. J. 40: 783-793.

Boonamnaj, P., R.B. Pandey, and P. Sompornpisut. (2021). Interaction fingerprint of transmembrane segments in voltage sensor domains. Biophys Chem 277: 106649. [Epub: Ahead of Print]

Borger C., Schunke S., Lecher J., Stoldt M., Winkhaus F., Kaupp UB. and Willbold D. (2015). Resonance assignment of the ligand-free cyclic nucleotide-binding domain from the murine ion channel HCN2. Biomol NMR Assign. 9(2):243-6.

Börjesson, S.I. and F. Elinder. (2011). An electrostatic potassium channel opener targeting the final voltage sensor transition. J Gen Physiol 137: 563-577.

Bosmans, F., M. Puopolo, M.F. Martin-Eauclaire, B.P. Bean, and K.J. Swartz. (2011). Functional properties and toxin pharmacology of a dorsal root ganglion sodium channel viewed through its voltage sensors. J Gen Physiol 138: 59-72.

Boukhabza, M., J. El Hilaly, N. Attiya, A. El-Haidani, Y. Filali-Zegzouti, D. Mazouzi, and M.Y. Amarouch. (2016). In Silico Evaluation of the Potential Antiarrhythmic Effect of Epigallocatechin-3-Gallate on Cardiac Channelopathies. Comput Math Methods Med 2016: 7861653.

Boulton, S., M. Akimoto, S. Akbarizadeh, and G. Melacini. (2017). Free Energy Landscape Remodeling of the Cardiac Pacemaker Channel Explains the Molecular Basis of Familial Sinus Bradycardia. J. Biol. Chem. [Epub: Ahead of Print]

Brailoiu, E., R. Hooper, X. Cai, G.C. Brailoiu, M.V. Keebler, N.J. Dun, J.S. Marchant, and S. Patel. (2010). An ancestral deuterostome family of two-pore channels mediates nicotinic acid adenine dinucleotide phosphate-dependent calcium release from acidic organelles. J. Biol. Chem. 285: 2897-2901.

Brams M., Kusch J., Spurny R., Benndorf K. and Ulens C. (2014). Family of prokaryote cyclic nucleotide-modulated ion channels. Proc Natl Acad Sci U S A. 111(21):7855-60.

Bramswig, N.C., A.M. Bertoli-Avella, B. Albrecht, A.I. Al Aqeel, A. Alhashem, N. Al-Sannaa, M. Bah, K. Bröhl, C. Depienne, N. Dorison, D. Doummar, N. Ehmke, H.M. Elbendary, S. Gorokhova, D. Héron, D. Horn, K. James, B. Keren, A. Kuechler, S. Ismail, M.Y. Issa, I. Marey, M. Mayer, J. McEvoy-Venneri, A. Megarbane, C. Mignot, S. Mohamed, C. Nava, N. Philip, C. Ravix, A. Rolfs, A.A. Sadek, L. Segebrecht, V. Stanley, C. Trautman, S. Valence, L. Villard, T. Wieland, H. Engels, T.M. Strom, M.S. Zaki, J.G. Gleeson, H.J. Lüdecke, P. Bauer, and D. Wieczorek. (2018). Genetic variants in components of the NALCN-UNC80-UNC79 ion channel complex cause a broad clinical phenotype (NALCN channelopathies). Hum Genet 137: 753-768.

Brennecke, J.T. and B.L. de Groot. (2018). Mechanism of Mechanosensitive Gating of the TREK-2 Potassium Channel. Biophys. J. 114: 1336-1343.

Brettmann, J.B., D. Urusova, M. Tonelli, J.R. Silva, and K.A. Henzler-Wildman. (2015). Role of protein dynamics in ion selectivity and allosteric coupling in the NaK channel. Proc. Natl. Acad. Sci. USA 112: 15366-15371.

Brohawn, S.G., E.B. Campbell, and R. MacKinnon. (2014). Physical mechanism for gating and mechanosensitivity of the human TRAAK K+ channel. Nature 516: 126-130.

Brohawn, S.G., J. del Mármol, and R. MacKinnon. (2012). Crystal structure of the human K2P TRAAK, a lipid- and mechano-sensitive K+ ion channel. Science 335: 436-441.

Brontein-Sitton, N. (2006). The ether-a-go-go Related Gene (erg) Voltage-Gated K+ Channels: A Common Structure with Uncommon Characteristics. Modulator. 21: 13-15.

Bruening-Wright, A., F. Elinder, and H.P. Larsson. (2007). Kinetic relationship between the voltage sensor and the activation gate in spHCN channels. J Gen Physiol 130: 71-81.

Bruening-Wright, A., W.S. Lee, J.P. Adelman, and J. Maylie. (2007). Evidence for a Deep Pore Activation Gate in Small Conductance Ca2+-activated K+ Channels. J. Gen. Physiol. 130(6):601-610.

Buraei, Z. and J. Yang. (2010). The ß subunit of voltage-gated Ca2+ channels. Physiol. Rev. 90: 1461-1506.

Burashnikov, A., H. Barajas-Martinez, D. Hu, V.M. Robinson, M. Grunnet, and C. Antzelevitch. (2020). The SK Channel Inhibitors NS8593 and UCL1684 Prevent the Development of Atrial Fibrillation via Atrial-selective Inhibition of Sodium Channel Activity. J Cardiovasc Pharmacol. [Epub: Ahead of Print]

Bustos, D., M. Bedoya, D. Ramírez, G. Concha, L. Zúñiga, N. Decher, E.W. Hernández-Rodríguez, F.V. Sepúlveda, L. Martínez, and W. González. (2020). Elucidating the Structural Basis of the Intracellular pH Sensing Mechanism of TASK-2 KP Channels. Int J Mol Sci 21:.

Butterwick, J.A. and R. MacKinnon. (2010). Solution structure and phospholipid interactions of the isolated voltage-sensor domain from KvAP. J. Mol. Biol. 403: 591-606.

Bystroff, C. (2018). Intramembranal disulfide cross-linking elucidates the super-quaternary structure of mammalian CatSpers. Reprod Biol. [Epub: Ahead of Print]

Cai, K., H. Gao, X. Wu, S. Zhang, Z. Han, X. Chen, G. Zhang, and F. Zeng. (2019). The Ability to Regulate Transmembrane Potassium Transport in Root Is Critical for Drought Tolerance in Barley. Int J Mol Sci 20:.

Cai, S.Q., L. Hernandez, Y. Wang, K.H. Park, and F. Sesti. (2005). MPS-1 is a K+ channel β-subunit and a serine/threonine kinase. Nat Neurosci 8: 1503-1509.

Calderon-Rivera, A., S. Loya-Lopez, K. Gomez, and R. Khanna. (2022). Plant and fungi derived analgesic natural products targeting voltage-gated sodium and calcium channels. Channels (Austin) 16: 198-215.

Calisto, F., F.M. Sousa, F.V. Sena, P.N. Refojo, and M.M. Pereira. (2021). Mechanisms of Energy Transduction by Charge Translocating Membrane Proteins. Chem Rev 121: 1804-1844.

Cang, C., B. Bekele, and D. Ren. (2014). The voltage-gated sodium channel TPC1 confers endolysosomal excitability. Nat Chem Biol 10: 463-469.

Cang, C., Y. Zhou, B. Navarro, Y.J. Seo, K. Aranda, L. Shi, S. Battaglia-Hsu, I. Nissim, D.E. Clapham, and D. Ren. (2013). mTOR regulates lysosomal ATP-sensitive two-pore Na+ channels to adapt to metabolic state. Cell 152: 778-790.

Canto-Bustos, M., E. Loeza-Alcocer, R. González-Ramírez, M.A. Gandini, R. Delgado-Lezama, and R. Felix. (2014). Functional expression of T-type Ca2+ channels in spinal motoneurons of the adult turtle. PLoS One 9: e108187.

Capera, J., C. Serrano-Novillo, M. Navarro-Pérez, S. Cassinelli, and A. Felipe. (2019). The Potassium Channel Odyssey: Mechanisms of Traffic and Membrane Arrangement. Int J Mol Sci 20:.

Capera, J., M. Navarro-Pérez, A.S. Moen, I. Szabó, and A. Felipe. (2022). The Mitochondrial Routing of the Kv1.3 Channel. Front Oncol 12: 865686.

Carkci, S., E.O. Etem, S. Ozaydin, A. Karakeci, A. Tektemur, T. Ozan, and I. Orhan. (2017). Ion channel gene expressions in infertile men: A case-control study. Int J Reprod Biomed (Yazd) 15: 749-756.

Carraretto, L., E. Formentin, E. Teardo, V. Checchetto, M. Tomizioli, T. Morosinotto, G.M. Giacometti, G. Finazzi, and I. Szabó. (2013). A thylakoid-located two-pore K+ channel controls photosynthetic light utilization in plants. Science 342: 114-118.

Carrasquel-Ursulaez, W., I. Segura, I. Díaz-Franulic, F. Echeverría, Y. Lorenzo-Ceballos, N. Espinoza, M. Rojas, J.A. Garate, E. Perozo, O. Alvarez, F.D. Gonzalez-Nilo, and R. Latorre. (2022). Mechanism of voltage sensing in Ca- and voltage-activated K (BK) channels. Proc. Natl. Acad. Sci. USA 119: e2204620119.

Casida, J.E. and K.A. Durkin. (2013). Neuroactive insecticides: targets, selectivity, resistance, and secondary effects. Annu Rev Entomol 58: 99-117.

Castellano, A., M.D. Chiara, B. Mellström, A. Molina, F. Monje, J.R. Naranjo, and J. López-Barneo. (1997). Identification and functional characterization of a K+ channel α-subunit with regulatory properties specific to brain. J. Neurosci. 17: 4652-4661.

Catacuzzeno, L. and F. Franciolini. (2022). The 70-year search for the voltage-sensing mechanism of ion channels. J. Physiol. [Epub: Ahead of Print]

Catterall, W.A. (2010). Ion channel voltage sensors: structure, function, and pathophysiology. Neuron. 67: 915-928.

Catterall, W.A., M.J. Lenaeus, and T.M. Gamal El-Din. (2020). Structure and Pharmacology of Voltage-Gated Sodium and Calcium Channels. Annu Rev Pharmacol Toxicol 60: 133-154.

Catterall, W.A., S. Dib-Hajj, M.H. Meisler, and D. Pietrobon. (2008). Inherited neuronal ion channelopathies: new windows on complex neurological diseases. J. Neurosci. 28: 11768-11777.

Cavinder, B. and F. Trail. (2012). Role of Fig1, a component of the low-affinity calcium uptake system, in growth and sexual development of filamentous fungi. Eukaryot. Cell. 11: 978-988.

Cha, A., G.E. Snyder, P.R. Selvin, and F. Bezanilla. (1999). Atomic scale movement of the voltage sensing region in a potassium channel measured via spectroscopy. Nature 402: 809-813.

Chahine, M., S. Pilote, V. Pouliot, H. Takami, and C. Sato. (2004). Role of arginine residues on the S4 segment of the Bacillus halodurans Na+ channel in voltage-sensing. J. Membr. Biol. 201: 9-24.

Chancey, J.H., P.E. Shockett, and J.P. O''Reilly. (2007). Relative resistance to slow inactivation of human cardiac Na+ channel hNav1.5 is reversed by lysine or glutamine substitution at V930 in D2-S6. Am. J. Physiol. Cell Physiol. 293: C1895-1905.

Chanda, B., and F. Bezanilla (2008). A common pathway for charge transport through voltage-sensing domains. Neuron 57: 345-51.

Chang, X. and Y. Dong. (2021). CACNA1C is a prognostic predictor for patients with ovarian cancer. J Ovarian Res 14: 88.

Charalambous, K. and B.A. Wallace. (2011). NaChBac: The Long Lost Sodium Channel Ancestor. Biochemistry 50: 6742-6752.

Charpentier, M., J. Sun, T.V. Martins, G.V. Radhakrishnan, K. Findlay, E. Soumpourou, J. Thouin, A.A. Véry, D. Sanders, R.J. Morris, and G.E. Oldroyd. (2016). Nuclear-localized cyclic nucleotide-gated channels mediate symbiotic calcium oscillations. Science 352: 1102-1105.

Charpentier, M., R. Bredemeier, G. Wanner, N. Takeda, E. Schleiff, and M. Parniske. (2008). Lotus japonicus CASTOR and POLLUX are ion channels essential for perinuclear calcium spiking in legume root endosymbiosis. Plant Cell 20: 3467-3479.

Chartrand, E., A.A. Arnold, A. Gravel, S. Jenna, and I. Marcotte. (2010). Potential role of the membrane in hERG channel functioning and drug-induced long QT syndrome. Biochim. Biophys. Acta. 1798: 1651-1662.

Chauhan, D.S., D.K. Swain, N. Shah, H.P. Yadav, U.P. Nakade, V.K. Singh, R. Nigam, S. Yadav, and S.K. Garg. (2017). Functional and molecular characterization of voltage gated sodium channel Nav 1.8 in bull spermatozoa. Theriogenology 90: 210-218.

Checchetto, V., A. Segalla, G. Allorent, N. La Rocca, L. Leanza, G.M. Giacometti, N. Uozumi, G. Finazzi, E. Bergantino, and I. Szabò. (2012). Thylakoid potassium channel is required for efficient photosynthesis in cyanobacteria. Proc. Natl. Acad. Sci. USA 109: 11043-11048.

Checchetto, V., E. Formentin, L. Carraretto, A. Segalla, G.M. Giacometti, I. Szabo, and E. Bergantino. (2013). Functional characterization and determination of the physiological role of a calcium-dependent potassium channel from cyanobacteria. Plant Physiol. 162: 953-964.

Checchetto, V., E. Teardo, L. Carraretto, E. Formentin, E. Bergantino, G.M. Giacometti, and I. Szabo. (2013). Regulation of photosynthesis by ion channels in cyanobacteria and higher plants. Biophys Chem 182: 51-57.

Chemin, J., A. Patel, F. Duprat, M. Zanzouri, M. Lazdunski, and E. Honoré. (2005). Lysophosphatidic acid-operated K+ channels. J. Biol. Chem. 280: 4415-4421.

Chemin, J., C. Girard, F. Duprat, F. Lesage, G. Romey, and M. Lazdunski. (2003). Mechanisms underlying excitatory effects of group 1 metabotropic glutamate receptors via inhibition of 2P domain K+ channels. EMBO J. 22: 5403-5411.

Chen, B., P. Liu, H. Zhan, and Z.W. Wang. (2011). Dystrobrevin controls neurotransmitter release and muscle Ca2+ transients by localizing BK channels in Caenorhabditis elegans. J. Neurosci. 31: 17338-17347.

Chen, H., J. Kronengold, Y. Yan, V.R. Gazula, M.R. Brown, L. Ma, G. Ferreira, Y. Yang, A. Bhattacharjee, F.J. Sigworth, L. Salkoff, and L.K. Kaczmarek. (2009). The N-terminal domain of Slack determines the formation and trafficking of Slick/Slack heteromeric sodium-activated potassium channels. J. Neurosci. 29: 5654-5665.

Chen, H., J. Pan, D.M. Gandhi, C. Dockendorff, Q. Cui, B. Chanda, and K.A. Henzler-Wildman. (2019). NMR Structural Analysis of Isolated Shaker Voltage-Sensing Domain in LPPG Micelles. Biophys. J. 117: 388-398.

Chen, J., S.C. Cassar, D. Zhang, and M. Gopalakrishnan. (2005). A novel potassium channel encoded by Ectocarpus siliculosus virus. Biochem. Biophys. Res. Commun. 326: 887-893.

Chen, J., Z. Liu, J.P. Creagh, R. Zheng, and T.V. McDonald. (2019). Physical and Functional Interaction Sites in Cytoplasmic Domains of KCNQ1 and KCNE1 Channel Subunits. Am. J. Physiol. Heart Circ Physiol. [Epub: Ahead of Print]

Chen, M., D. Yin, S. Guo, D.Z. Xu, Z. Wang, Z. Chen, M. Rubart-von der Lohe, S.F. Lin, T.H. Everett, J.N. Weiss, and P.S. Chen. (2018). Sex-Specific Activation of SK Current by Isoproterenol Facilitates Action Potential Triangulation and Arrhythmogenesis in Rabbit Ventricles. J. Physiol. [Epub: Ahead of Print]

Chen, M., S. Li, M. Hao, J. Chen, Z. Zhao, S. Hong, J. Min, J. Tang, M. Hu, and L. Hong. (2020). T-type calcium channel blockade induces apoptosis in C2C12 myotubes and skeletal muscle via endoplasmic reticulum stress activation. FEBS Open Bio 10: 2122-2136.

Chen, X., M.Y. Ruan, and S.Q. Cai. (2015). KChIP-like auxiliary subunits of Kv4 channels regulate excitability of muscle cells and control male turning behavior during mating in Caenorhabditis elegans. J. Neurosci. 35: 1880-1891.

Chen, X., Q. Wang, F. Ni, and J. Ma. (2010). Structure of the full-length Shaker potassium channel Kv1.2 by normal-mode-based X-ray crystallographic refinement. Proc. Natl. Acad. Sci. USA 107: 11352-11357.

Cherki, R., L. Luques, Y. Anis, and A. Meir. (2006). Ion Channels in Endocrine Pancreatic Cell and their Role in Diabetes. Modulator. 21: 16-21.

Cho, S.W., K.Y. Choi, and C.S. Park. (2004). A new putative cyclic nucleotide-gated channel gene, cng-3, is critical for thermotolerance in Caenorhabditis elegans. Biochem. Biophys. Res. Commun. 325: 525-531.

Cho, T., A. Ishii-Kato, Y. Fukata, Y. Nakayama, K. Iida, M. Fukata, and H. Iida. (2016). Coupling of a voltage-gated Ca2+ channel homologue with a plasma membrane H+ -ATPase in yeast. Genes Cells. [Epub: Ahead of Print]

Choi, S.W., K.S. Kim, D.H. Shin, H.Y. Yoo, H. Choe, T.H. Ko, J.B. Youm, W.K. Kim, Y.H. Zhang, and S.J. Kim. (2013). Class 3 inhibition of hERG K+ channel by caffeic acid phenethyl ester (CAPE) and curcumin. Pflugers Arch 465: 1121-1134.

Chotoo, C.K., G.A. Silverman, D.C. Devor, and C.J. Luke. (2013). A small conductance calcium-activated K+ channel in C. elegans, KCNL-2, plays a role in the regulation of the rate of egg-laying. PLoS One 8: e75869.

Chowdhury, S., B.W. Jarecki, and B. Chanda. (2014). A molecular framework for temperature-dependent gating of ion channels. Cell 158: 1148-1158.

Chung, J.J., B. Navarro, G. Krapivinsky, L. Krapivinsky, and D.E. Clapham. (2011). A novel gene required for male fertility and functional CATSPER channel formation in spermatozoa. Nat Commun 2: 153.

Churamani, D., R. Hooper, E. Brailoiu, and S. Patel. (2012). Domain assembly of NAADP-gated two-pore channels. Biochem. J. 441: 317-323.

Clapham, D.E. (1999). Unlocking family secrets: K+ channel transmembrane domains. Cell 97: 547-550.

Clark, M.D., G.F. Contreras, R. Shen, and E. Perozo. (2020). Electromechanical coupling in the hyperpolarization-activated K channel KAT1. Nature. [Epub: Ahead of Print]

Clayton, G.M., S. Altieri, L. Heginbotham, V.M. Unger, and J.H. Morais-Cabral. (2008). Structure of the transmembrane regions of a bacterial cyclic nucleotide-regulated channel. Proc. Natl. Acad. Sci. USA 105: 1511-1515.

Cohen, A., Y. Ben-Abu, S. Hen, and N. Zilberberg. (2008). A novel mechanism for human K2P2.1 channel gating. Facilitation of C-type gating by protonation of extracellular histidine residues. J. Biol. Chem. 283: 19448-19455.

Cohen, L., Y. Moran, A. Sharon, D. Segal, D. Gordon, and M. Gurevitz. (2009). Drosomycin, an innate immunity peptide of Drosophila melanogaster, interacts with the fly voltage-gated sodium channel. J. Biol. Chem. 284: 23558-23563.

Cohen-Kutner, M., D. Nachmanni, and D. Atlas. (2010). CaV2.1 (P/Q channel) interaction with synaptic proteins is essential for depolarization-evoked release. Channels (Austin) 4: 266-277.

Colosimo, E., A. Gambardella, M. Mantegazza, A. Labate, R. Rusconi, E. Schiavon, F. Annesi, R.R. Cassulini, S. Carrideo, R. Chifari, M.P. Canevini, R. Canger, S. Franceschetti, G. Annesi, E. Wanke, and A. Quattrone. (2007). Electroclinical features of a family with simple febrile seizures and temporal lobe epilepsy associated with SCN1A loss-of-function mutation. Epilepsia 48: 1691-1696.

Cong, B., G. Han, X.H. Huang, S.H. Liu, C.L. Liu, X.Z. Lin, P.Q. He, and H. Gasaino. (2009). Molecular cloning and tissue expression patterns of a small conductance calcium-activated potassium channel gene in turbot (Scophthalmus maximus L.). Fish Shellfish Immunol 27: 221-229.

Coskun, C. and N. Purali. (2016). Cloning and molecular characterization of a putative voltage-gated sodium channel gene in the crayfish. Invert Neurosci 16: 2.

Coutelier, M., I. Blesneac, A. Monteil, M.L. Monin, K. Ando, E. Mundwiller, A. Brusco, I. Le Ber, M. Anheim, A. Castrioto, C. Duyckaerts, A. Brice, A. Durr, P. Lory, and G. Stevanin. (2015). A Recurrent Mutation in CACNA1G Alters Cav3.1 T-Type Calcium-Channel Conduction and Causes Autosomal-Dominant Cerebellar Ataxia. Am J Hum Genet 97: 726-737.

Cox, J.J., F. Reimann, A.K. Nicholas, G. Thornton, E. Roberts, K. Springell, G. Karbani, H. Jafri, J. Mannan, Y. Raashid, L. Al-Gazali, H. Hamamy, E.M. Valente, S. Gorman, R. Williams, D.P. McHale, J.N. Wood, F.M. Gribble, and C.G. Woods. (2006). An SCN9A channelopathy causes congenital inability to experience pain. Nature 444: 894-898.

Cregg, R., A. Momin, F. Rugiero, J.N. Wood, and J. Zhao. (2010). Pain channelopathies. J. Physiol. 588: 1897-1904.

Cribbs L.L., B.L. Martin, E.A. Schroder, B.B. Keller, B.P. Delisle, J. Satin. (2001). Identification of the t-type calcium channel (Cav3.1d) in developing mouse heart. Circ. Res. 88: 403-407.

Cuello, L.G., D.M. Cortes, and E. Perozo. (2004). Molecular architecture of the KvAP voltage-dependent K+ channel in a lipid bilayer. Science 306: 491-495.

Cuello, L.G., V. Jogini, D.M. Cortes, and E. Perozo. (2010). Structural mechanism of C-type inactivation in K+ channels. Nature 466: 203-208.

Cui, J. (2010). BK-type calcium-activated potassium channels: coupling of metal ions and voltage sensing. J. Physiol. 588: 4651-4658.

Czempinski K., S. Zimmermann, T. Ehrhardt, B. Muller-Rober. (1997). New structure and function in plant K+ channels: KCO1, an outward rectifier with a steep Ca2+ dependency. EMBO J. 16:2565-75.

Czirják, G., D. Vuity, and P. Enyedi. (2008). Phosphorylation-dependent binding of 14-3-3 proteins controls TRESK regulation. J. Biol. Chem. 283: 15672-15680.

Czirjak, G., Z.E. Toth, and P. Enyedi. (2004). The two-pore domain K+ channel, TRESK, is activated by the cytoplasmic calcium signal through calcineurin. J. Biol. Chem. 279: 18550-18558.

D''Avanzo, N., A.J. Miles, A.M. Powl, C.G. Nichols, B.A. Wallace, and A.O. O''Reilly. (2022). The T1-tetramerisation domain of Kv1.2 rescues expression and preserves function of a truncated NaChBac sodium channel. FEBS Lett. [Epub: Ahead of Print]

D'Adamo, M.C., C. Gallenmüller, I. Servettini, E. Hartl, S.J. Tucker, L. Arning, S. Biskup, A. Grottesi, L. Guglielmi, P. Imbrici, P. Bernasconi, G. Di Giovanni, F. Franciolini, L. Catacuzzeno, M. Pessia, and T. Klopstock. (2014). Novel phenotype associated with a mutation in the KCNA1(Kv1.1) gene. Front Physiol 5: 525.

Dabby, R., M. Sadeh, R. Gilad, Y. Lampl, S. Cohen, S. Inbar, and E. Leshinsky-Silver. (2011). Chronic non-paroxysmal neuropathic pain - Novel phenotype of mutation in the sodium channel SCN9A gene. J Neurol Sci 301: 90-92.

Dai, G., T.K. Aman, F. DiMaio, and W.N. Zagotta. (2019). The HCN channel voltage sensor undergoes a large downward motion during hyperpolarization. Nat Struct Mol Biol 26: 686-694.

Dai, G., T.K. Aman, F. DiMaio, and W.N. Zagotta. (2021). Electromechanical coupling mechanism for activation and inactivation of an HCN channel. Nat Commun 12: 2802.

Das, A. and H. Raghuraman. (2021). Conformational heterogeneity of the voltage sensor loop of KvAP in micelles and membranes: A fluorescence approach. Biochim. Biophys. Acta. Biomembr 183568. [Epub: Ahead of Print]

Das, A., S. Chatterjee, and H. Raghuraman. (2019). Structural Dynamics of the Paddle Motif Loop in the Activated Conformation of KvAP Voltage Sensor. Biophys. J. [Epub: Ahead of Print]

Davies, A.G., J.T. Pierce-Shimomura, H. Kim, M.K. VanHoven, T.R. Thiele, A. Bonci, C.I. Bargmann, and S.L. McIntire. (2003). A central role of the BK potassium channel in behavioral responses to ethanol in C. elegans. Cell 115: 655-666.

Davies, L.A., C. Hu, N.A. Guagliardo, N. Sen, X. Chen, E.M. Talley, R.M. Carey, D.A. Bayliss, and P.Q. Barrett (2008). TASK channel deletion in mice causes primary hyperaldosteronism. Proc. Natl. Acad. Sci. U.S.A. 105: 2203-2208.

de Kovel, C.G.F., S. Syrbe, E.H. Brilstra, N. Verbeek, B. Kerr, H. Dubbs, A. Bayat, S. Desai, S. Naidu, S. Srivastava, H. Cagaylan, U. Yis, C. Saunders, M. Rook, S. Plugge, H. Muhle, Z. Afawi, K.M. Klein, V. Jayaraman, R. Rajagopalan, E. Goldberg, E. Marsh, S. Kessler, C. Bergqvist, L.K. Conlin, B.L. Krok, I. Thiffault, M. Pendziwiat, I. Helbig, T. Polster, I. Borggraefe, J.R. Lemke, M.J. van den Boogaardt, R.S. Møller, and B.P.C. Koeleman. (2017). Neurodevelopmental Disorders Caused by De Novo Variants in KCNB1 Genotypes and Phenotypes. JAMA Neurol. [Epub: Ahead of Print]

de la Cruz, I.P., J.Z. Levin, C. Cummins, P. Anderson, and H.R. Horvitz. (2003). sup-9, sup-10, and unc-93 may encode components of a two-pore K+ channel that coordinates muscle contraction in Caenorhabditis elegans. J. Neurosci. 23: 9133-9145.

de la Cruz, I.P., L. Ma, and H.R. Horvitz. (2014). The Caenorhabditis elegans iodotyrosine deiodinase ortholog SUP-18 functions through a conserved channel SC-box to regulate the muscle two-pore domain potassium channel SUP-9. PLoS Genet 10: e1004175.

de la Peña, P., P. Domínguez, and F. Barros. (2018). Functional characterization of Kv11.1 (hERG) potassium channels split in the voltage-sensing domain. Pflugers Arch. [Epub: Ahead of Print]

De Marchi, U., N. Sassi, B. Fioretti, L. Catacuzzeno, G.M. Cereghetti, I. Szabò, and M. Zoratti. (2009). Intermediate conductance Ca2+-activated potassium channel (KCa3.1) in the inner mitochondrial membrane of human colon cancer cells. Cell Calcium 45: 509-516.

de Prelle, B., P. Lybaert, and D. Gall. (2022). A Minimal Model Shows that a Positive Feedback Loop Between sNHE and SLO3 can Control Mouse Sperm Capacitation. Front Cell Dev Biol 10: 835594.

Debnath, D.K., R.V. Basaiawmoit, K.L. Nielsen, and D.E. Otzen. (2011). The role of membrane properties in Mistic folding and dimerisation. Protein Eng Des Sel 24: 89-97.

Decher N., M. Maier, W. Dittrich, J. Gassenhuber, A. Bruggemann, A.E. Busch, K. Steinmeyer. (2001) Characterization of TASK-4, a novel member of the pH-sensitive, two-pore domain potassium channel family. FEBS Lett. 492:84-9.

Delemotte, L., M.A. Kasimova, M.L. Klein, M. Tarek, and V. Carnevale. (2015). Free-energy landscape of ion-channel voltage-sensor-domain activation. Proc. Natl. Acad. Sci. USA 112: 124-129.

Delemotte, L., W. Treptow, M.L. Klein, and M. Tarek. (2010). Effect of sensor domain mutations on the properties of voltage-gated ion channels: molecular dynamics studies of the potassium channel Kv1.2. Biophys. J. 99: L72-74.

Demidchik, V., S. Shabala, S. Isayenkov, T.A. Cuin, and I. Pottosin. (2018). Calcium transport across plant membranes: mechanisms and functions. New Phytol 220: 49-69.

Derebe, M.G., W. Zeng, Y. Li, A. Alam, and Y. Jiang. (2011). Structural studies of ion permeation and Ca2+ blockage of a bacterial channel mimicking the cyclic nucleotide-gated channel pore. Proc. Natl. Acad. Sci. USA 108: 592-597.

Desai, R., J. Kronengold, J. Mei, S.A. Forman, and L.K. Kaczmarek. (2008). Protein kinase C modulates inactivation of Kv3.3 channels. J. Biol. Chem. 283: 22283-22294.

DeSimone, C.V., V.V. Zarayskiy, V.E. Bondarenko, and M.J. Morales. (2011). Heteropoda toxin 2 interaction with Kv4.3 and Kv4.1 reveals differences in gating modification. Mol Pharmacol 80: 345-355.

Devor, M. (2006). Sodium channels and mechanisms of neuropathic pain. J Pain 7: S3-S12.

Di, L., S. Srivastava, O. Zhdanova, Y. Sun, Z. Li, and E.Y. Skolnik. (2010). Nucleoside diphosphate kinase B knock-out mice have impaired activation of the K+ channel KCa3.1, resulting in defective T cell activation. J. Biol. Chem. 285: 38765-38771.

Díaz-Franulic, I., V. González-Pérez, H. Moldenhauer, N. Navarro-Quezada, and D. Naranjo. (2018). Gating-induced large aqueous volumetric remodeling and aspartate tolerance in the voltage sensor domain of Shaker K channels. Proc. Natl. Acad. Sci. USA 115: 8203-8208.

Dib-Hajj, S.D., T.R. Cummins, J.A. Black, and S.G. Waxman. (2007). From genes to pain: Na v 1.7 and human pain disorders. Trends Neurosci. 30(11):555-63.

Dickinson, M.S., J. Lu, M. Gupta, I. Marten, R. Hedrich, and R.M. Stroud. (2022). Molecular basis of multistep voltage activation in plant two-pore channel 1. Proc. Natl. Acad. Sci. USA 119:.

Dickinson, M.S., S. Pourmal, M. Gupta, M. Bi, and R.M. Stroud. (2021). Symmetry Reduction in a Hyperpolarization-Activated Homotetrameric Ion Channel. Biochemistry. [Epub: Ahead of Print]

Ding, J., J.W. Zhang, Y.X. Guo, Y.X. Zhang, Z.H. Chen, and Q.X. Zhai. (2019). Novel mutations in SCN9A occurring with fever-associated seizures or epilepsy. Seizure 71: 214-218.

Dixit, G., I.D. Sahu, W. Renyolds, T. Wadsworth, B.D. Harding, C.K. Jaycox, C. Dabney-Smith, C.R. Sanders, and G.A. Lorigan. (2019). Probing the Dynamics and Structural Topology of Reconstituted Human KCNQ1 Voltage Sensor Domain (Q1-VSD) in Lipid Bilayers using EPR Spectroscopy. Biochemistry. [Epub: Ahead of Print]

Dixon, R.E., E.P. Cheng, J.L. Mercado, and L.F. Santana. (2012). L-type ca(2+) channel function during timothy syndrome. Trends Cardiovasc Med 22: 72-76.

Dobler, T., A. Springauf, S. Tovornik, M. Weber, A. Schmitt, R. Sedlmeier, E. Wischmeyer, and F. Döring. (2007). TRESK two-pore-domain K+ channels constitute a significant component of background potassium currents in murine dorsal root ganglion neurones. J. Physiol. 585: 867-879.

Docampo R., Moreno SN. and Plattner H. (2014). Intracellular calcium channels in protozoa. Eur J Pharmacol. 739:4-18.

Doherty, T., Y. Su, and M. Hong. (2010). High-resolution orientation and depth of insertion of the voltage-sensing S4 helix of a potassium channel in lipid bilayers. J. Mol. Biol. 401: 642-652.

Dong, Y.Y., A.C. Pike, A. Mackenzie, C. McClenaghan, P. Aryal, L. Dong, A. Quigley, M. Grieben, S. Goubin, S. Mukhopadhyay, G.F. Ruda, M.V. Clausen, L. Cao, P.E. Brennan, N.A. Burgess-Brown, M.S. Sansom, S.J. Tucker, and E.P. Carpenter. (2015). K2P channel gating mechanisms revealed by structures of TREK-2 and a complex with Prozac. Science 347: 1256-1259.

Döring, J.H., J. Schröter, J. Jüngling, S. Biskup, K.A. Klotz, T. Bast, T. Dietel, G.C. Korenke, S. Christoph, H. Brennenstuhl, G. Rubboli, R.S. Møller, G. Lesca, Y. Chaix, S. Kölker, G.F. Hoffmann, J.R. Lemke, and S. Syrbe. (2021). Refining Genotypes and Phenotypes in -Related Neurological Disorders. Int J Mol Sci 22:.

Douglas, R.M., J.C. Lai, S. Bian, L. Cummins, E. Moczydlowski, and G.G. Haddad. (2006). The calcium-sensitive large-conductance potassium channel (BK/MAXI K) is present in the inner mitochondrial membrane of rat brain. Neuroscience 139: 1249-61.

Downey, P., I. Szabó, N. Ivashikina, A. Negro, F. Guzzo, P. Ache, R. Hedrich, M. Terzi, and F. Lo Schiavo. (2000). KDC1, a novel carrot root hair K+channel: cloning, characterization, and expression in mammalian cells. J. Biol. Chem. 275: 394420-39426.

Doyle, D.A, J.M. Cabral, R.A. Pfuetzner, A. Kuo, J.M. Gulbis, S.L. Cohen, B.T. Chait, and R. MacKinnon. (1998). The structure of the potassium channel: molecular basis of K+ conduction and selectivity. Science 280: 69-77.

Drenth, J.P., and S.G. Waxman. (2007). Mutations in sodium-channel gene SCN9A cause a spectrum of human genetic pain disorders. J. Clin. Invest. 117: 3603-3609.

Dreyer, I. and N. Uozumi. (2011). Potassium channels in plant cells. FEBS J. 278: 4293-4303.

Du Y., Nomura Y., Zhorov BS. and Dong K. (2015). Rotational Symmetry of Two Pyrethroid Receptor Sites in the Mosquito Sodium Channel. Mol Pharmacol. 88(2):273-80.

Du, Y., D. Garden, B. Khambay, B.S. Zhorov, and K. Dong. (2011). Batrachotoxin, pyrethroids, and BTG 502 share overlapping binding sites on insect sodium channels. Mol Pharmacol 80: 426-433.

Du, Y., W. Song, J.R. Groome, Y. Nomura, N. Luo, and K. Dong. (2010). A negative charge in transmembrane segment 1 of domain II of the cockroach sodium channel is critical for channel gating and action of pyrethroid insecticides. Toxicol Appl Pharmacol 247: 53-59.

Duan, J.J., J.H. Ma, P.H. Zhang, X.P. Wang, A.R. Zou, and D.N. Tu. (2007). Verapamil blocks HERG channel by the helix residue Y652 and F656 in the S6 transmembrane domain. Acta Pharmacol Sin 28: 959-967.

Duarri, A., J. Jezierska, M. Fokkens, M. Meijer, H.J. Schelhaas, W.F. den Dunnen, F. van Dijk, C. Verschuuren-Bemelmans, G. Hageman, P. van de Vlies, B. Küsters, B.P. van de Warrenburg, B. Kremer, C. Wijmenga, R.J. Sinke, M.A. Swertz, H.H. Kampinga, E. Boddeke, and D.S. Verbeek. (2012). Mutations in potassium channel kcnd3 cause spinocerebellar ataxia type 19. Ann Neurol 72: 870-880.

Duby, G., E. Hosy, C. Fizames, C. Alcon, A. Costa, H. Sentenac, and J.B. Thibaud. (2008). AtKC1, a conditionally targeted Shaker-type subunit, regulates the activity of plant K+ channels. Plant J. 53(1):115-123.

Durdagi, S., J. Subbotina, J. Lees-Miller, J. Guo, H.J. Duff, and S.Y. Noskov. (2010). Insights into the molecular mechanism of hERG1 channel activation and blockade by drugs. Curr. Med. Chem. 17: 3514-3532.

Durell, S.R., Y. Hao, T. Nakamura, E.P. Bakker, and H.R. Guy. (1999). Evolutionary relationship between K+ channels and symporters. Biophys. J. 77: 775-788.

Durkina, A.V., O.G. Bernikova, M.A. Gonotkov, N.J. Mikhaleva, K.A. Sedova, I.A. Malykhina, V.S. Kuzmin, I.O. Velegzhaninov, and J.E. Azarov. (2022). Melatonin treatment improves ventricular conduction via upregulation of Nav1.5 channel proteins and sodium current in the normal rat heart. J Pineal Res e12798. [Epub: Ahead of Print]

Dvorak, N.M., P.A. Wadsworth, P. Wang, J. Zhou, and F. Laezza. (2021). Development of Allosteric Modulators of Voltage-Gated Na+ Channels: A Novel Approach for an Old Target. Curr Top Med Chem. [Epub: Ahead of Print]

Edwards A., A.B. Heckmann, F. Yousafzai, G. Duc, J.A. Downie. (2007). Structural implications of mutations in the pea SYM8 symbiosis gene, the DMI1 ortholog, encoding a predicted ion channel. Mol Plant Microbe Interact. 20: 1183-1191.

Eigenbrod, O., K.Y. Debus, J. Reznick, N.C. Bennett, O. Sánchez-Carranza, D. Omerbašić, D.W. Hart, A.J. Barker, W. Zhong, H. Lutermann, J.V. Katandukila, G. Mgode, T.J. Park, and G.R. Lewin. (2019). Rapid molecular evolution of pain insensitivity in multiple African rodents. Science 364: 852-859.

Eldstrom, J., H. Xu, D. Werry, C. Kang, M.E. Loewen, A. Degenhardt, S. Sanatani, G.F. Tibbits, C. Sanders, and D. Fedida. (2010). Mechanistic basis for LQT1 caused by S3 mutations in the KCNQ1 subunit of IKs. J Gen Physiol 135: 433-448.

Elinder, F., M. Madeja, H. Zeberg, and P. Århem. (2016). Extracellular Linkers Completely Transplant the Voltage Dependence from Kv1.2 Ion Channels to Kv2.1. Biophys. J. 111: 1679-1691.

Ellekvist, P., J. Maciel, G. Mlambo, C.H. Ricke, H. Colding, D.A. Klaerke, and N. Kumar. (2008). Critical role of a K+ channel in Plasmodium berghei transmission revealed by targeted gene disruption. Proc. Natl. Acad. Sci. USA 105: 6398-6402.

Elter, A., A. Hartel, C. Sieben, B. Hertel, E. Fischer-Schliebs, U. Lüttge, A. Moroni, and G. Thiel. (2007). A plant homolog of animal chloride intracellular channels (CLICs) generates an ion conductance in heterologous systems. J. Biol. Chem. 282: 8786-8792.

Enyedi, P. and G. Czirják. (2010). Molecular background of leak K+ currents: two-pore domain potassium channels. Physiol. Rev. 90: 559-605.

Enyedi, P., I. Veres, G. Braun, and G. Czirják. (2014). Tubulin Binds to the Cytoplasmic Loop of TRESK Background K+ Channel In Vitro. PLoS One 9: e97854.

Estacion, M., J.E. O'Brien, A. Conravey, M.F. Hammer, S.G. Waxman, S.D. Dib-Hajj, and M.H. Meisler. (2014). A novel de novo mutation of SCN8A (Nav1.6) with enhanced channel activation in a child with epileptic encephalopathy. Neurobiol Dis 69: 117-123.

Evans, E.G.B., J.L.W. Morgan, F. DiMaio, W.N. Zagotta, and S. Stoll. (2020). Allosteric conformational change of a cyclic nucleotide-gated ion channel revealed by DEER spectroscopy. Proc. Natl. Acad. Sci. USA. [Epub: Ahead of Print]

Faillace, M.P., R.O. Bernabeu, and J.I. Korenbrot. (2004). Cellular processing of cone photoreceptor cyclic GMP-gated ion channels: a role for the S4 structural motif. J. Biol. Chem. 279: 22643-22653.

Fan, C., N. Sukomon, E. Flood, J. Rheinberger, T.W. Allen, and C.M. Nimigean. (2020). Ball-and-chain inactivation in a calcium-gated potassium channel. Nature 580: 288-293.

Fan, J.J. and X. Huang. (2020). Ion Channels in Cancer: Orchestrators of Electrical Signaling and Cellular Crosstalk. Rev Physiol Biochem Pharmacol. [Epub: Ahead of Print]

Fantin, S.M., H. Huang, C.R. Sanders, and B.T. Ruotolo. (2020). Collision-Induced Unfolding Differentiates Functional Variants of the KCNQ1 Voltage Sensor Domain. J Am Soc Mass Spectrom. [Epub: Ahead of Print]

Fawcett, G.L., C.M. Santi, A. Butler, T. Harris, M. Covarrubias, and L. Salkoff. (2006). Mutant analysis of the Shal (Kv4) voltage-gated fast transient K+ channel in Caenorhabditis elegans. J. Biol. Chem. 281: 30725-30735.

Fedida, D. and J.C. Hesketh. (2001). Gating of voltage-dependent potassium channels. Prog. Biophys. Mol. Biol. 75: 165-199.

Feinshreiber, L., D. Chikvashvili, I. Michaelevski, and I. Lotan. (2009). Syntaxin modulates Kv1.1 through dual action on channel surface expression and conductance. Biochemistry 48: 4109-4114.

Feng, Z.-P., J. Hamid, C. Doering, S.E. Jarvis, G.M. Bosey, E. Bourinet, T.P. Snutch, and G.W. Zamponi. (2001). Amino acid residues outside of the pore region contribute to N-type calcium channel permeation. J. Biol. Chem. 276: 5726-5730.

Fernández-Trillo, J., F. Barros, A. Machín, L. Carretero, P. Domínguez, and P. de la Peña. (2011). Molecular determinants of interactions between the N-terminal domain and the transmembrane core that modulate hERG K+ channel gating. PLoS One 6: e24674.

Fink M., F. Lesage, F. Duprat, C. Heurteaux, R. Reyes, M. Fosset, M. Lazdunski. (1998). A neuronal two P domain K+ channel stimulated by arachidonic acid and polyunsaturated fatty acids. EMBO J. 17:3297-308.

Fischer, T.Z. and S.G. Waxman. (2010). Familial pain syndromes from mutations of the NaV1.7 sodium channel. Ann. N.Y. Acad. Sci. 1184: 196-207.

Fischer, W.B. and M.S. Sansom. (2002). Viral ion channels: structure and function. Biochim. Biophys. Acta 1561: 27-45.

Ford, K.J. and G.W. Davis. (2014). Archaerhodopsin voltage imaging: synaptic calcium and BK channels stabilize action potential repolarization at the Drosophila neuromuscular junction. J. Neurosci. 34: 14517-14525.

Freeman, S.A., S. Uderhardt, A. Saric, R.F. Collins, C.M. Buckley, S. Mylvaganam, P. Boroumand, J. Plumb, R.N. Germain, D. Ren, and S. Grinstein. (2020). Lipid-gated monovalent ion fluxes regulate endocytic traffic and support immune surveillance. Science 367: 301-305.

Freites JA. and Tobias DJ. (2015). Voltage Sensing in Membranes: From Macroscopic Currents to Molecular Motions. J Membr Biol. 248(3):419-30.

Freites, J.A., D.J. Tobias, and S.H. White. (2006). A voltage-sensor water pore. Biophys. J. 91: L90-92.

Fujinami, S., T. Sato, J.S. Trimmer, B.W. Spiller, D.E. Clapham, T.A. Krulwich, I. Kawagishi, and M. Ito. (2007). The voltage-gated Na+ channel NavBP co-localizes with methyl-accepting chemotaxis protein at cell poles of alkaliphilic Bacillus pseudofirmus OF4. Microbiology. 153: 4027-4038.

Fujiu, K., Y. Nakayama, A. Yanagisawa, M. Sokabe, and K. Yoshimura. (2009). Chlamydomonas CAV2 encodes a voltage- dependent calcium channel required for the flagellar waveform conversion. Curr. Biol. 19: 133-139.

Fukasaku, M., J. Kimura, and O. Yamaguchi. (2016). Swelling-activated and arachidonic acid-induced currents are TREK-1 in rat bladder smooth muscle cells. Fukushima J Med Sci. [Epub: Ahead of Print]

Furini, S. and C. Domene. (2012). On conduction in a bacterial sodium channel. PLoS Comput Biol 8: e1002476.

Fux, J.E., A. Mehta, J. Moffat, and J.D. Spafford. (2018). Eukaryotic Voltage-Gated Sodium Channels: On Their Origins, Asymmetries, Losses, Diversification and Adaptations. Front Physiol 9: 1406.

Galindo, B.E., A.T. Neill, and V.D. Vacquier. (2005). A new hyperpolarization-activated, cyclic nucleotide-gated channel from sea urchin sperm flagella. Biochem. Biophys. Res. Commun. 334: 96-101.

Galindo, B.E., J.L. de la Vega-Beltrán, P. Labarca, V.D. Vacquier, and A. Darszon. (2007). Sp-tetraKCNG: A novel cyclic nucleotide gated K+ channel. Biochem. Biophys. Res. Commun. 354: 668-675.

Gamal El-Din, T.M. and M.J. Lenaeus. (2022). Fenestropathy of Voltage-Gated Sodium Channels. Front Pharmacol 13: 842645.

Gandini, M.A., I.A. Souza, L. Ferron, A.M. Innes, and G.W. Zamponi. (2021). The de novo CACNA1A pathogenic variant Y1384C associated with hemiplegic migraine, early onset cerebellar atrophy and developmental delay leads to a loss of Cav2.1 channel function. Mol Brain 14: 27.

Gao, Q., C. Yang, L. Meng, Z. Wang, D. Chen, Y. Peng, K. Yang, and Z. Bian. (2020). Activated KCNQ1 channel promotes fibrogenic response in hereditary gingival fibromatosis via clustering and activation of Ras. J Periodontal Res. [Epub: Ahead of Print]

Gao, Q.F., L.L. Gu, H.Q. Wang, C.F. Fei, X. Fang, J. Hussain, S.J. Sun, J.Y. Dong, H. Liu, and Y.F. Wang. (2016). Cyclic nucleotide-gated channel 18 is an essential Ca2+ channel in pollen tube tips for pollen tube guidance to ovules in Arabidopsis. Proc. Natl. Acad. Sci. USA 113: 3096-3101.

García Segarra, N., I. Gautschi, L. Mittaz-Crettol, C. Kallay Zetchi, L. Al-Qusairi, M.X. Van Bemmelen, P. Maeder, L. Bonafé, L. Schild, and E. Roulet-Perez. (2014). Congenital ataxia and hemiplegic migraine with cerebral edema associated with a novel gain of function mutation in the calcium channel CACNA1A. J Neurol Sci 342: 69-78.

Garciadeblas, B., J. Barrero-Gil, B. Benito, and A. Rodríguez-Navarro. (2007). Potassium transport systems in the moss Physcomitrella patens: pphak1 plants reveal the complexity of potassium uptake. Plant J. 52: 1080-1093.

Gardella, E., F. Becker, R.S. Møller, J. Schubert, J.R. Lemke, L.H. Larsen, H. Eiberg, M. Nothnagel, H. Thiele, J. Altmüller, S. Syrbe, A. Merkenschlager, T. Bast, B. Steinhoff, P. Nürnberg, Y. Mang, L. Bakke Møller, P. Gellert, S. Heron, L. Dibbens, S. Weckhuysen, H.A. Dahl, S. Biskup, N. Tommerup, H. Hjalgrim, H. Lerche, S. Beniczky, and Y.G. Weber. (2015). Benign infantile seizures and paroxysmal dyskinesia caused by an SCN8A mutation. Ann Neurol. [Epub: Ahead of Print]

Gardner, A., W. Wu, S. Thomson, E.M. Zangerl-Plessl, A. Stary-Weinzinger, and M. Sanguinetti. (2017). Molecular basis of altered hERG1 channel gating induced by ginsenoside Rg3. Mol Pharmacol. [Epub: Ahead of Print]

Garg, P., A. Gardner, V. Garg, and M.C. Sanguinetti. (2013). Structural basis of ion permeation gating in Slo2.1 K+ channels. J Gen Physiol 142: 523-542.

Garneau, L., H. Klein, M.F. Lavoie, E. Brochiero, L. Parent, and R. Sauvé. (2014). Aromatic-aromatic interactions between residues in KCa3.1 pore helix and S5 transmembrane segment control the channel gating process. J Gen Physiol 143: 289-307.

Garrett, S. and J.J. Rosenthal. (2012). RNA editing underlies temperature adaptation in K+ channels from polar octopuses. Science 335: 848-851.

Garten, M., S. Aimon, P. Bassereau, and G.E. Toombes. (2015). Reconstitution of a Transmembrane Protein, the Voltage-gated Ion Channel, KvAP, into Giant Unilamellar Vesicles for Microscopy and Patch Clamp Studies. J Vis Exp.

Gaymard, F., G. Pilot, B. Lacombe, D. Bouchez, D. Bruneau, J. Boucherez, N. Michaux-Ferriere, J.B. Thibaud, and H. Sentenac. (1998). Identification and disruption of a plant shaker-like outward channel involved in K+ release into the xylem sap. Cell 94: 647-655.

Gazzarrini, S., J.L. Van Etten, D. DiFrancesco, G. Thiel, and A. Moroni. (2002). Voltage-dependence of virus-encoded miniature K+ channel Kcv. J. Membrane Biol. 187: 15-25.

Gazzarrini, S., M. Kang, A. Abenavoli, G. Romani, C. Olivari, D. Gaslini, G. Ferrara, J.L. van Etten, M. Kreim, S.M. Kast, G. Thiel, and A. Moroni. (2009). Chlorella virus ATCV-1 encodes a functional potassium channel of 82 amino acids. Biochem. J. 420: 295-303.

Geiger D., Becker D., Vosloh D., Gambale F., Palme K., Rehers M., Anschuetz U., Dreyer I., Kudla J. and Hedrich R. (2009). Heteromeric AtKC1{middle dot}AKT1 channels in Arabidopsis roots facilitate growth under K+-limiting conditions. J Biol Chem. 284(32):21288-95.

Geng, Y. and K.L. Magleby. (2014). Single-channel kinetics of BK (Slo1) channels. Front Physiol 5: 532.

Gessner, G., Y.M. Cui, Y. Otani, T. Ohwada, M. Soom, T. Hoshi, and S.H. Heinemann. (2012). Molecular mechanism of pharmacological activation of BK channels. Proc. Natl. Acad. Sci. USA 109: 3552-3557.

Gilch, S., O. Meyer, and I. Schmidt. (2010). Electron paramagnetic studies of the copper and iron containing soluble ammonia monooxygenase from Nitrosomonas europaea. Biometals 23: 613-622.

Gill, C.H., A. Randall, S.A. Bates, K. Hill, D. Owen, P.M. Larkman, W. Cairns, S.P. Yusaf, P.R. Murdock, P.J. Strijbos, A.J. Powell, C.D. Benham, and C.H. Davies. (2004). Characterization of the human HCN1 channel and its inhibition by capsazepine. Br J Pharmacol 143: 411-421.

Giordanetto, F., L. Knerr, and A. Wållberg. (2011). T-type calcium channels inhibitors: a patent review. Expert Opin Ther Pat 21: 85-101.

Giorgetti, A., A.V. Nair, P. Codega, V. Torre, and P. Carloni. (2005). Structural basis of gating of CNG channels. FEBS Lett. 579: 1968-1972.

Glaaser, I.W., J.R. Bankston, H. Liu, M. Tateyama, and R.S. Kass. (2006). A carboxyl-terminal hydrophobic interface is critical to sodium channel function. Relevance to inherited disorders. J. Biol. Chem. 281: 24015-24023.

Glauner, K.S., L.M. Mannuzzu, C.S. Gandhi, and E.Y. Isacoff. (1999). Spectroscopic mapping of voltage sensor movement in the Shaker potassium channel. Nature 402: 813-817.

Gobert, A., G. Park, A. Amtmann, D. Sanders, and F.J. Maathuis. (2006). Arabidopsis thaliana cyclic nucleotide gated channel 3 forms a non-selective ion transporter involved in germination and cation transport. J Exp Bot 57: 791-800.

Gofman Y., Shats S., Attali B., Haliloglu T. and Ben-Tal N. (2012). How does KCNE1 regulate the Kv7.1 potassium channel? Model-structure, mutations, and dynamics of the Kv7.1-KCNE1 complex. Structure. 20(8):1343-52.

Gofman, Y., C. Schärfe, D.S. Marks, T. Haliloglu, and N. Ben-Tal. (2014). Structure, dynamics and implied gating mechanism of a human cyclic nucleotide-gated channel. PLoS Comput Biol 10: e1003976.

Gohar, O. (2006). Ion Channel Modulation by G-protein Coupled Receptors. Modulators. 21:2-9.

Gomez-Lagunas, F. (2010). Quinidine interaction with Shab K+ channels: pore block and irreversible collapse of the K+ conductance. J. Physiol. 588: 2691-2706.

Gomez-Ospina, N., F. Tsuruta, O. Barreto-Chang, L. Hu, and R. Dolmetsch. (2006). The C terminus of the L-type voltage-gated calcium channel Ca(V)1.2 encodes a transcription factor. Cell 127: 591-606.

Gong, Q., M.A. Jones, and Z. Zhou. (2006). Mechanisms of pharmacological rescue of trafficking-defective hERG mutant channels in human long QT syndrome. J. Biol. Chem. 281: 4069-4074.

Gonzalez W., Riedelsberger J., Morales-Navarro SE., Caballero J., Alzate-Morales JH., Gonzalez-Nilo FD. and Dreyer I. (2012). The pH sensor of the plant K+-uptake channel KAT1 is built from a sensory cloud rather than from single key amino acids. Biochem J. 442(1):57-63.

Gonzalez W., Valdebenito B., Caballero J., Riadi G., Riedelsberger J., Martinez G., Ramirez D., Zuniga L., Sepulveda FV., Dreyer I., Janta M. and Becker D. (2015). K(2)p channels in plants and animals. Pflugers Arch. 467(5):1091-104.

Gonzalez, C., G.F. Contreras, A. Peyser, P. Larsson, A. Neely, and R. Latorre. (2012). Voltage sensor of ion channels and enzymes. Biophys Rev 4: 1-15.

González-Sanabria, N., F. Echeverría, I. Segura, R. Alvarado-Sánchez, and R. Latorre. (2021). BK in Double-Membrane Organelles: A Biophysical, Pharmacological, and Functional Survey. Front Physiol 12: 761474.

Goodchild, S.J., C. Lamy, V. Seutin, and N.V. Marrion. (2009). Inhibition of K(Ca)2.2 and K(Ca)2.3 channel currents by protonation of outer pore histidine residues. J Gen Physiol 134: 295-308.

Goral RO., Leipold E., Nematian-Ardestani E. and Heinemann SH. (2015). Heterologous expression of NaV1.9 chimeras in various cell systems. Pflugers Arch. 467(12):2423-35.

Gouas, L., C. Bellocq, M. Berthet, F. Potet, S. Demolombe, A. Forhan, R. Lescasse, F. Simon, B. Balkau, I. Denjoy, B. Hainque, I. Baró, P. Guicheney, and. (2004). New KCNQ1 mutations leading to haploinsufficiency in a general population; Defective trafficking of a KvLQT1 mutant. Cardiovasc Res 63: 60-68.

Goutierre, M., S. Al Awabdh, F. Donneger, E. François, D. Gomez-Dominguez, T. Irinopoulou, L. Menendez de la Prida, and J.C. Poncer. (2019). KCC2 Regulates Neuron.al Excitability and Hippocampal Activity via Interaction with Task-3 Channels. Cell Rep 28: 91-103.e7.

Grabe, M., H.C. Lai, M. Jain, Y. Nung Jan, and L. Yeh Jan. (2007). Structure prediction for the down state of a potassium channel voltage sensor. Nature 445: 550-553.

Grabner, M., R.T. Dirksen, N. Suda, and K.G. Beam. (1999). The II-III loop of the skeletal muscle dihydropyridine receptor is responsible for the bi-directional coupling with the ryanodine receptor. J. Biol. Chem. 274: 21913-21919.

Grahammer, F., R. Warth, J. Barhanin, M. Bleich, and M.J. Hug. (2001). The small conductance K+ channel, KCNQ1. Expression, function, and subunit composition in murine trachea. J. Biol. Chem. 276: 42268-42275.

Gravante, B., A. Barbuti, R. Milanesi, I. Zappi, C. Viscomi, and D. DiFrancesco. (2004). Interaction of the pacemaker channel HCN1 with filamin A. J. Biol. Chem. 279: 43847-43853.

Gray, R. and D. Johnston. (2021). Sodium sensitivity of K channels in mouse CA1 neurons. J Neurophysiol. [Epub: Ahead of Print]

Grefen, C., Z. Chen, A. Honsbein, N. Donald, A. Hills, and M.R. Blatt. (2010). A novel motif essential for SNARE interaction with the K+ channel KC1 and channel gating in Arabidopsis. Plant Cell 22: 3076-3092.

Greiner, T., A. Moroni, J.L. Van Etten, and G. Thiel. (2018). Genes for Membrane Transport Proteins: Not So Rare in Viruses. Viruses 10:.

Griguoli, M., A. Maul, C. Nguyen, A. Giorgetti, P. Carloni, and E. Cherubini. (2010). Nicotine blocks the hyperpolarization-activated current Ih and severely impairs the oscillatory behavior of oriens-lacunosum moleculare interneurons. J. Neurosci. 30: 10773-10783.

Groome JR., Lehmann-Horn F., Fan C., Wolf M., Winston V., Merlini L. and Jurkat-Rott K. (2014). NaV1.4 mutations cause hypokalaemic periodic paralysis by disrupting IIIS4 movement during recovery. Brain. 137(Pt 4):998-1008.

Grupe, A., K.H. Schröter, J.P. Ruppersberg, M. Stocker, T. Drewes, S. Beckh, and O. Pongs. (1990). Cloning and expression of a human voltage-gated potassium channel. A novel member of the RCK potassium channel family. EMBO. J. 9: 1749-1756.

Gu, R.X. and B.L. de Groot. (2020). Lipid-protein interactions modulate the conformational equilibrium of a potassium channel. Nat Commun 11: 2162.

Gu, Z., L.D. Plant, X.Y. Meng, J.M. Perez-Aguilar, Z. Wang, M. Dong, D.E. Logothetis, and R. Zhou. (2017). Exploring the Nanotoxicology of MoS2: A Study on the Interaction of MoS2 Nanoflakes and K+ Channels. ACS Nano. [Epub: Ahead of Print]

Gubitosi-Klug, R.A., D.J. Mancuso, and R.W. Gross. (2005). The human Kv1.1 channel is palmitoylated, modulating voltage sensing: Identification of a palmitoylation consensus sequence. Proc. Natl. Acad. Sci. USA 102: 5964-5968.

Gulbins, E., N. Sassi, H. Grassmè, M. Zoratti, and I. Szabò. (2010). Role of Kv1.3 mitochondrial potassium channel in apoptotic signalling in lymphocytes. Biochim. Biophys. Acta. 1797: 1251-1259.

Gulbis, J.M., M. Zhou, S. Mann, and R. MacKinnon. (2000). Structure ofthe cytoplasmic β subunit-T1 assembly of voltage-dependent K+ channels. Science 289: 123-127.

Gulbis, J.M., S. Mann, and R. MacKinnon. (1999). Structure of a voltage-dependent K+ channel beta subunit. Cell 97: 943-952.

Guo, J., W. Zeng, and Y. Jiang. (2017). Tuning the ion selectivity of two-pore channels. Proc. Natl. Acad. Sci. USA. [Epub: Ahead of Print]

Guo, J., W. Zeng, Q. Chen, C. Lee, L. Chen, Y. Yang, C. Cang, D. Ren, and Y. Jiang. (2015). Structure of the voltage-gated two-pore channel TPC1 from Arabidopsis thaliana. Nature. [Epub: Ahead of Print]

Gupta, R.K., D.K. Swain, V. Singh, M. Anand, S. Choudhury, S. Yadav, A. Saxena, and S.K. Garg. (2018). Molecular characterization of voltage-gated potassium channel (Kv) and its importance in functional dynamics in bull spermatozoa. Theriogenology 114: 229-236. [Epub: Ahead of Print]

Gurevitz, M. (2012). Mapping of scorpion toxin receptor sites at voltage-gated sodium channels. Toxicon 60: 502-511.

Haitin, Y. and B. Attali. (2008). The C-terminus of Kv7 channels: a multifunctional module. J. Physiol. 586: 1803-1810.

Hall, M.K., D.A. Weidner, S. Dayal, E. Pak, A.K. Murashov, and R.A. Schwalbe. (2017). Membrane Distribution and Activity of a Neuron.al Voltage-Gated K+ Channel is Modified by Replacement of Complex Type N-Glycans with Hybrid Type. J Glycobiol 6:.

Hamamoto, S., J. Marui, K. Matsuoka, K. Higashi, K. Igarashi, T. Nakagawa, T. Kuroda, Y. Mori, Y. Murata, Y. Nakanishi, M. Maeshima, I. Yabe, and N. Uozumi. (2008). Characterization of a tobacco TPK-type K+ channel as a novel tonoplast K+ channel using yeast tonoplasts. J. Biol. Chem. 283: 1911-1920.

Hamid, J., J.B. Peloquin, A. Monteil, and G.W. Zamponi. (2006). Determinants of the differential gating properties of Cav3.1 and Cav3.3 T-type channels: a role of domain IV? Neuroscience 143: 717-728.

Hamilton, K.L., Syme, C.A., and Devor, D.C. (2003). Molecular localization of the inhibitory arachidonic acid binding site to the pore of hIK1. J. Biol. Chem. 278: 16690-16697.

Han, C., Y. Yang, R.H. Te Morsche, J.P. Drenth, J.M. Politei, S.G. Waxman, and S.D. Dib-Hajj. (2016). Familial gain-of-function Nav1.9 mutation in a painful channelopathy. J Neurol Neurosurg Psychiatry. [Epub: Ahead of Print]

Han, W., S. Nattel, T. Noguchi, and A. Shrier. (2006). C-terminal domain of Kv4.2 and associated KChIP2 interactions regulate functional expression and gating of Kv4.2. J. Biol. Chem. 281: 27134-27144.

Hanlon, M.R. and B.A. Wallace. (2002). Structure and function of voltage-dependent ion channel regulatory β subunits. Biochemistry 41: 2886-2894.

Hantouche, C., B. Williamson, W.C. Valinsky, J. Solomon, A. Shrier, and J.C. Young. (2016). Bag1 Promotes TRC8-Dependent Degradation of Misfolded hERG Potassium Channels. J. Biol. Chem. [Epub: Ahead of Print]

Harkcom, W.T., M. Papanikolaou, V. Kanda, S.M. Crump, and G.W. Abbott. (2019). KCNQ1 rescues TMC1 plasma membrane expression but not mechanosensitive channel activity. J Cell Physiol. [Epub: Ahead of Print]

Hashimoto, K., M. Saito, H. Matsuoka, K. Iida, and H. Iida. (2004). Functional analysis of a rice putative voltage-dependent Ca2+ channel, OsTPC1, expressed in yeast cells lacking its homologous gene CCH1. Plant Cell Physiol. 45: 496-500.

Hayoz, S., P.B. Tiwari, G. Piszczek, A. Üren, and T.I. Brelidze. (2017). Investigating cyclic nucleotide and cyclic dinucleotide binding to HCN channels by surface plasmon resonance. PLoS One 12: e0185359.

He, C., S. Altshuler-Keylin, D. Daniel, N.D. L''Etoile, and D. O''Halloran. (2016). The cyclic nucleotide gated channel subunit CNG-1 instructs behavioral outputs in Caenorhabditis elegans by coincidence detection of nutritional status and olfactory input. Neurosci Lett 632: 71-78. [Epub: Ahead of Print]

He, W., G.T. Young, B. Zhang, P.J. Cox, L.T. Cho, S. John, S.A. Paciga, L.S. Wood, N. Danziger, S. Scollen, and C. Vangjeli. (2018). Functional confirmation that the R1488* variant in SCN9A results in complete loss-of-function of Na1.7. BMC Med Genet 19: 124.

Heath, G.R. and S. Scheuring. (2019). Advances in high-speed atomic force microscopy (HS-AFM) reveal dynamics of transmembrane channels and transporters. Curr. Opin. Struct. Biol. 57: 93-102.

Held, K., F. Gruss, V.D. Aloi, A. Janssens, C. Ulens, T. Voets, and J. Vriens. (2018). Mutations in the voltage-sensing domain affect the alternative ion permeation pathway in the TRPM3 channel. J. Physiol. [Epub: Ahead of Print]

Hellmer, J. and C. Zeilinger. (2003). MjK1, a K+ channel from M. jannaschii, mediates K+ uptake and K+ sensitivity in E. coli. FEBS Lett. 547: 165-169.

Hemara-Wahanui A., S. Berjukow, C.I. Hope, P.K. Dearden, S.B. Wu, J. Wilson-Wheeler, D.M. Sharp, P. Lundon-Treweek, G.M. Clover, J.C. Hoda, J. Striessnig, R. Marksteiner, S. Hering, M.A. Maw. (2005). A CACNA1F mutation identified in an X-linked retinal disorder shifts the voltage dependence of Cav1.4 channel activation. Proc. Natl. Acad. Sci. U.S.A. 102: 7553-7558.

Henrion, U., S. Zumhagen, K. Steinke, N. Strutz-Seebohm, B. Stallmeyer, F. Lang, E. Schulze-Bahr, and G. Seebohm. (2012). Overlapping Cardiac Phenotype Associated with a Familial Mutation in the Voltage Sensor of the KCNQ1 Channel. Cell Physiol Biochem 29: 809-818.

Hertel, B., S. Tayefeh, T. Kloss, J. Hewing, M. Gebhardt, D. Baumeister, A. Moroni, G. Thiel, and S.M. Kast. (2010). Salt bridges in the miniature viral channel Kcv are important for function. Eur Biophys. J. 39: 1057-1068.

Hille, B. (1992). Chapter 9: Structure of channel proteins; Chapter 20: Evolution and diversity. In: Ionic Channels of Excitable Membranes, 2nd Ed., Sinaur Assoc. Inc., Pubs., Sunderland, Massachusetts.

Hirano, M., Y. Onishi, T. Yanagida, and T. Ide. (2011). Role of the KcsA channel cytoplasmic domain in pH-dependent gating. Biophys. J. 101: 2157-2162.

Hirazawa, K., M. Tateyama, Y. Kubo, and T. Shimomura. (2021). Phosphoinositide regulates dynamic movement of the S4 voltage sensor in the second repeat in two-pore channel 3. J. Biol. Chem. 297: 101425.

Hite, R.K., P. Yuan, Z. Li, Y. Hsuing, T. Walz, and R. MacKinnon. (2015). Cryo-electron microscopy structure of the Slo2.2 Na+-activated K+ channel. Nature 527: 198-203.

Hofer, N.T., P. Tuluc, N.J. Ortner, Y.V. Nikonishyna, M.L. Fernándes-Quintero, K.R. Liedl, B.E. Flucher, H. Cox, and J. Striessnig. (2020). Biophysical classification of a de novo mutation as a high-risk mutation for a severe neurodevelopmental disorder. Mol Autism 11: 4.

Hoffgaard F., Kast SM., Moroni A., Thiel G. and Hamacher K. (2015). Tectonics of a K(+) channel: The importance of the N-terminus for channel gating. Biochim Biophys Acta. 1848(12):3197-204.

Holland, K.D., J.A. Kearney, T.A. Glauser, G. Buck, M. Keddache, J.R. Blankston, I.W. Glaaser, R.S. Kass, and M.H. Meisler. (2008). Mutation of sodium channel SCN3A in a patient with cryptogenic pediatric partial epilepsy. Neurosci Lett 433(1): 65-70.

Honsbein A., Sokolovski S., Grefen C., Campanoni P., Pratelli R., Paneque M., Chen Z., Johansson I. and Blatt MR. (2009). A tripartite SNARE-K+ channel complex mediates in channel-dependent K+ nutrition in Arabidopsis. Plant Cell. 21(9):2859-77.

Hoomann, T., N. Jahnke, A. Horner, S. Keller, and P. Pohl. (2013). Filter gate closure inhibits ion but not water transport through potassium channels. Proc. Natl. Acad. Sci. USA 110: 10842-10847.

Hooper, R., D. Churamani, E. Brailoiu, C.W. Taylor, and S. Patel. (2011). Membrane topology of NAADP-sensitive two-pore channels and their regulation by N-linked glycosylation. J. Biol. Chem. 286: 9141-9149.

Horn, R. (2000). Conversation between voltage sensors and gates of ion channels. Biochemistry 39: 15653-15658.

Horng, T.L., R.S. Eisenberg, C. Liu, and F. Bezanilla. (2018). Continuum Gating Current Models Computed with Consistent Interactions. Biophys. J. [Epub: Ahead of Print]

Hou, S., R. Xu, S.H. Heinemann, and T. Hoshi. (2008). The RCK1 high-affinity Ca2+ sensor confers carbon monoxide sensitivity to Slo1 BK channels. Proc. Natl. Acad. Sci. USA 105: 4039-4043.

Howarth, G.S. and A.E. McDermott. (2022). High-Resolution Magic Angle Spinning NMR of KcsA in Liposomes: The Highly Mobile C-Terminus. Biomolecules 12:.

Hu, W., R.B. Clark, W.R. Giles, E. Shibata, and H. Zhang. (2021). Physiological Roles of the Rapidly Activated Delayed Rectifier K Current in Adult Mouse Heart Primary Pacemaker Activity. Int J Mol Sci 22:.

Huang, D.T., N. Chi, S.C. Chen, T.Y. Lee, and K. Hsu. (2011). Background K(2P) channels KCNK3/9/15 limit the budding of cell membrane-derived vesicles. Cell Biochem Biophys 61: 585-594.

Huang, J., M. Estacion, P. Zhao, F.B. Dib-Hajj, B. Schulman, A. Abicht, I. Kurth, K. Brockmann, S.G. Waxman, and S.D. Dib-Hajj. (2019). A Novel Gain-of-Function Nav1.9 Mutation in a Child With Episodic Pain. Front Neurosci 13: 918.

Huang, M.H., P.Y. Liu, and S.N. Wu. (2019). Characterization of Perturbing Actions by Verteporfin, a Benzoporphyrin Photosensitizer, on Membrane Ionic Currents. Front Chem 7: 566.

Hug, L.A., B.J. Baker, K. Anantharaman, C.T. Brown, A.J. Probst, C.J. Castelle, C.N. Butterfield, A.W. Hernsdorf, Y. Amano, K. Ise, Y. Suzuki, N. Dudek, D.A. Relman, K.M. Finstad, R. Amundson, B.C. Thomas, and J.F. Banfield. (2016). A new view of the tree of life. Nat Microbiol 1: 16048.

Hull, J.M. and L.L. Isom. (2017). Voltage-gated sodium channel β subunits: The power outside the pore in brain development and disease. Neuropharmacology. [Epub: Ahead of Print]

Humphries, J., L. Xiong, J. Liu, A. Prindle, F. Yuan, H.A. Arjes, L. Tsimring, and G.M. Süel. (2017). Species-Independent Attraction to Biofilms through Electrical Signaling. Cell 168: 200-209.e12.

Idikuda, V., W. Gao, Z. Su, Q. Liu, and L. Zhou. (2018). cAMP binds to closed, inactivated, and open sea urchin HCN channels in a state-dependent manner. J Gen Physiol. [Epub: Ahead of Print]

Ikematsu, N., M.L. Dallas, F.A. Ross, R.W. Lewis, J.N. Rafferty, J.A. David, R. Suman, C. Peers, D.G. Hardie, and A.M. Evans. (2011). Phosphorylation of the voltage-gated potassium channel Kv2.1 by AMP-activated protein kinase regulates membrane excitability. Proc. Natl. Acad. Sci. USA 108: 18132-18137.

Ikrar, T., H. Hanawa, H. Watanabe, S. Okada, Y. Aizawa, M.M. Ramadan, S. Komura, F. Yamashita, M. Chinushi, and Y. Aizawa. (2008). A double-point mutation in the selectivity filter site of the KCNQ1 potassium channel results in a severe phenotype, LQT1, of long QT syndrome. J Cardiovasc Electrophysiol 19: 541-549.

Imbrici, P., A. Accogli, R. Blunck, C. Altamura, M. Iacomino, M.C. D''adamo, A. Allegri, M. Pedemonte, N. Brolatti, S. Vari, M. Cataldi, V. Capra, S. Gustincich, F. Zara, J.F. Desaphy, and C. Fiorillo. (2021). Musculoskeletal Features without Ataxia Associated with a Novel de novo Mutation in Impairing the Voltage Sensitivity of Kv1.1 Channel. Biomedicines 9:.

Infield, D.T., E.E.L. Lee, J.D. Galpin, G.D. Galles, F. Bezanilla, and C.A. Ahern. (2018). Replacing voltage sensor arginines with citrulline provides mechanistic insight into charge versus shape. J Gen Physiol 150: 1017-1024.

Infield, D.T., K. Matulef, J.D. Galpin, K. Lam, E. Tajkhorshid, C.A. Ahern, and F.I. Valiyaveetil. (2018). Main-chain mutagenesis reveals intrahelical coupling in an ion channel voltage-sensor. Nat Commun 9: 5055.

Iorio, J., C. Duranti, T. Lottini, E. Lastraioli, G. Bagni, A. Becchetti, and A. Arcangeli. (2020). K11.1 Potassium Channel and the Na/H Antiporter NHE1 Modulate Adhesion-Dependent Intracellular pH in Colorectal Cancer Cells. Front Pharmacol 11: 848.

Isbell, H.M., A.M. Kilpatrick, Z. Lin, R. Mahling, and M.A. Shea. (2018). Backbone resonance assignments of complexes of apo human calmodulin bound to IQ motif peptides of voltage-dependent sodium channels Na1.1, Na1.4 and Na1.7. Biomol NMR Assign. [Epub: Ahead of Print]

Ito, M., H. Xu, A.A. Guffanti, Y. Wei, L. Zvi, D.E. Clapham, and T.A. Krulwich. (2004). The voltage-gated Na+ channel NavBP has a role in motility, chemotaxis, and pH homeostasis of the alkaliphilic Bacillus. Proc. Natl. Acad. Sci. USA 101: 10566-10571.

Iwahashi, Y., Y. Toyama, S. Imai, H. Itoh, M. Osawa, M. Inoue, and I. Shimada. (2020). Conformational equilibrium shift underlies altered K channel gating as revealed by NMR. Nat Commun 11: 5168.

Iwamoto, M., H. Shimizu, F. Inoue, T. Konno, Y.C. Sasaki, and S. Oiki. (2006). Surface structure and its dynamic rearrangements of the KcsA potassium channel upon gating and tetrabutylammonium blocking. J. Biol. Chem. 281: 28379-28386.

Jacinto, J.G.P., I.M. Häfliger, E.E. Akyürek, R. Sacchetto, C. Benazzi, A. Gentile, and C. Drögemüller. (2021). -Related Syndromic Form of Congenital Neuromuscular Channelopathy in a Crossbred Calf. Genes (Basel) 12:.

Jalily Hasani, H., A. Ganesan, M. Ahmed, and K.H. Barakat. (2018). Effects of protein-protein interactions and ligand binding on the ion permeation in KCNQ1 potassium channel. PLoS One 13: e0191905.

Jalkanen, R., N.T. Bech-Hansen, R. Tobias, E.M. Sankila, M. Mäntyjärvi, H. Forsius, A. de la Chapelle, and T. Alitalo. (2007). A novel CACNA1F gene mutation causes Aland Island eye disease. Invest Ophthalmol Vis Sci 48: 2498-2502.

James, Z.M., A.J. Borst, Y. Haitin, B. Frenz, F. DiMaio, W.N. Zagotta, and D. Veesler. (2017). CryoEM structure of a prokaryotic cyclic nucleotide-gated ion channel. Proc. Natl. Acad. Sci. USA 114: 4430-4435.

Jan, L.Y. and Y.N. Jan. (1997). Cloned potassium channels from eukaryotes and prokaryotes. Annu. Rev. Neurosci. 20: 91-123.

Jaślan, D., T.D. Mueller, D. Becker, J. Schultz, T. Cuin, I. Marten, I. Dreyer, G. Schönknecht, and R. Hedrich. (2016). Gating of the two-pore cation channel AtTPC1 in the plant vacuole is based on a single voltage-sensing domain. Plant Biol (Stuttg). [Epub: Ahead of Print]

Jędrychowska, J. and V. Korzh. (2019). Kv2.1 voltage-gated potassium channel et al. in developmental perspective. Dev Dyn. [Epub: Ahead of Print]

Jegla, T. and L. Salkoff. (1995). A multigene family of novel K+ channels from Paramecium tetraurelia. Receptors Channels 3: 51-60.

Jensen H.S., K. Callo, T. Jespersen, B.S. Jensen, S.P. Olesen. (2005). The KCNQ5 potassium channel from mouse: a broadly expressed M-current like potassium channel modulated by zinc, pH, and volume changes. Brain Res. Mol. Brain Res. 139: 52-62.

Jensen, M.&.#.2.1.6.;., V. Jogini, D.W. Borhani, A.E. Leffler, R.O. Dror, and D.E. Shaw. (2012). Mechanism of voltage gating in potassium channels. Science 336: 229-233.

Jia, Z., M. Yazdani, G. Zhang, J. Cui, and J. Chen. (2018). Hydrophobic gating in BK channels. Nat Commun 9: 3408.

Jiang D., Du Y., Nomura Y., Wang X., Wu Y., Zhorov BS. and Dong K. (2015). Mutations in the transmembrane helix S6 of domain IV confer cockroach sodium channel resistance to sodium channel blocker insecticides and local anesthetics. Insect Biochem Mol Biol. 66:88-95.

Jiang, D., T.M. Gamal El-Din, C. Ing, P. Lu, R. Pomès, N. Zheng, and W.A. Catterall. (2018). Structural basis for gating pore current in periodic paralysis. Nature. [Epub: Ahead of Print]

Jiang, Q.X. (2021). High-Resolution Structures of K Channels. Handb Exp Pharmacol. [Epub: Ahead of Print]

Jiang, Y., A. Lee, J. Chen, M. Cadene, B.T. Chait, and R. MacKinnon. (2002). Crystal structure and mechanism of a calcium-gated potassium channel. Nature 417: 515-522.

Jiang, Y., A. Lee, J. Chen, V. Ruta, M. Cadene, B.T. Chait, and R. MacKinnon. (2003a). X-ray structure of a voltage-dependent K+ channel. Nature 423: 33-41.

Jiang, Y., V. Idikuda, S. Chowdhury, and B. Chanda. (2020). Activation of the archaeal ion channel MthK is exquisitely regulated by temperature. Elife 9:.

Jiang, Y., V. Ruta, J. Chen, A. Lee, and R. MacKinnon. (2003b). The principle of gating charge movement in a voltage-dependent K+ channel. Nature 423: 42-48.

Johansson, I., K. Wulfetange, F. Porée, E. Michard, P. Gajdanowicz, B. Lacombe, H. Sentenac, J.B. Thibaud, B. Mueller-Roeber, M.R. Blatt, and I. Dreyer. (2006). External K+ modulates the activity of the Arabidopsis potassium channel SKOR via an unusual mechanism. Plant J. 46: 269-281.

Jones, J.M., L. Dionne, J. Dell''Orco, R. Parent, J.N. Krueger, X. Cheng, S.D. Dib-Hajj, R.K. Bunton-Stasyshyn, L.M. Sharkey, J.J. Dowling, G.G. Murphy, V.G. Shakkottai, P. Shrager, and M.H. Meisler. (2016). Single amino acid deletion in transmembrane segment D4S6 of sodium channel Scn8a (Nav1.6) in a mouse mutant with a chronic movement disorder. Neurobiol Dis 89: 36-45.

Jospin, M., S. Watanabe, D. Joshi, S. Young, K. Hamming, C. Thacker, T.P. Snutch, E.M. Jorgensen, and K. Schuske. (2007). UNC-80 and the NCA ion channels contribute to endocytosis defects in synaptojanin mutants. Curr. Biol. 17: 1595-1600.

Jæger, K.H., A.G. Edwards, W.R. Giles, and A. Tveito. (2021). A computational method for identifying an optimal combination of existing drugs to repair the action potentials of SQT1 ventricular myocytes. PLoS Comput Biol 17: e1009233.

Kanellopoulos, A.H. and A. Matsuyama. (2016). Voltage-gated sodium channels and pain-related disorders. Clin Sci (Lond) 130: 2257-2265.

Kanellopoulos, A.H., J. Koenig, H. Huang, M. Pyrski, Q. Millet, S. Lolignier, T. Morohashi, S.J. Gossage, M. Jay, J.E. Linley, G. Baskozos, B.M. Kessler, J.J. Cox, A.C. Dolphin, F. Zufall, J.N. Wood, and J. Zhao. (2018). Mapping protein interactions of sodium channel Na1.7 using epitope-tagged gene-targeted mice. EMBO. J. 37: 427-445.

Kang, C., C.G. Vanoye, R.C. Welch, W.D. Van Horn, and C.R. Sanders. (2010). Functional delivery of a membrane protein into oocyte membranes using bicelles. Biochemistry 49: 653-655.

Kang, D., E. Mariash, and D. Kim. (2004). Functional expression of TRESK-2, a new member of the tandem-pore K+ channel family. J. Biol. Chem. 279: 28063-28070.

Kanzaki, M., M. Nagasawa, I. Kojima, C. Sato, K. Naruse, M. Sokabe, and H. Iida. (1999). Molecular identification of a eukaryotic, stretch-activated nonselective cation channel. Science 285: 882-886.

Kapplinger JD., Giudicessi JR., Ye D., Tester DJ., Callis TE., Valdivia CR., Makielski JC., Wilde AA. and Ackerman MJ. (2015). Enhanced Classification of Brugada Syndrome-Associated and Long-QT Syndrome-Associated Genetic Variants in the SCN5A-Encoded Nav1.5 Cardiac Sodium Channel. Circ Cardiovasc Genet. 8(4):582-95.

Kapplinger, J.D., D.J. Tester, M. Alders, B. Benito, M. Berthet, J. Brugada, P. Brugada, V. Fressart, A. Guerchicoff, C. Harris-Kerr, S. Kamakura, F. Kyndt, T.T. Koopmann, Y. Miyamoto, R. Pfeiffer, G.D. Pollevick, V. Probst, S. Zumhagen, M. Vatta, J.A. Towbin, W. Shimizu, E. Schulze-Bahr, C. Antzelevitch, B.A. Salisbury, P. Guicheney, A.A. Wilde, R. Brugada, J.J. Schott, and M.J. Ackerman. (2010). An international compendium of mutations in the SCN5A-encoded cardiac sodium channel in patients referred for Brugada syndrome genetic testing. Heart Rhythm 7: 33-46.

Karelina, T.V., Y.D. Stepanenko, P.A. Abushik, D.A. Sibarov, and S.M. Antonov. (2017). Downregulation of Purkinje Cell Activity by Modulators of Small Conductance Calcium-Activated Potassium Channels In Rat Cerebellum. Acta Naturae 8: 91-99.

Kariev, A.M. and M.E. Green. (2018). The Role of Proton Transport in Gating Current in a Voltage Gated Ion Channel, as Shown by Quantum Calculations. Sensors (Basel) 18:.

Kaupp, U.B. and R. Seifert. (2001). Molecular diversity of pacemaker ion channels. Annu. Rev. Physiol. 63: 235-257.

Kihira, Y., T.O. Hermanstyne, and H. Misonou. (2010). Formation of heteromeric Kv2 channels in mammalian brain neurons. J. Biol. Chem. 285: 15048-15055.

Kim, H., J.T. Pierce-Shimomura, H.J. Oh, B.E. Johnson, M.B. Goodman, and S.L. McIntire. (2009). The dystrophin complex controls bk channel localization and muscle activity in Caenorhabditis elegans. PLoS Genet 5: e1000780.

Kim, H.J., B.G. Kim, J.E. Park, C.S. Ki, J. Huh, J.B. Youm, J.S. Kang, and H. Cho. (2019). Characterization of a novel LQT3 variant with a selective efficacy of mexiletine treatment. Sci Rep 9: 12997.

Kim, H.J., D. Yang, S.H. Kim, B. Kim, H.D. Kim, J.S. Lee, J.R. Choi, S.T. Lee, and H.C. Kang. (2019). Genetic and clinical features of SCN8A developmental and epileptic encephalopathy. Epilepsy Res 158: 106222. [Epub: Ahead of Print]

Kim, H.J., P. Lv, C.R. Sihn, and E.N. Yamoah. (2011). Cellular and molecular mechanisms of autosomal dominant form of progressive hearing loss, DFNA2. J. Biol. Chem. 286: 1517-1527.

Kim, T., S. Kim, H.M. Yun, K.C. Chung, Y.S. Han, H.S. Shin, and H. Rhim. (2009). Modulation of Ca(v)3.1 T-type Ca2+ channels by the ran binding protein RanBPM. Biochem. Biophys. Res. Commun. 378: 15-20.

Kintzer, A.F. and R.M. Stroud. (2016). Structure, inhibition and regulation of two-pore channel TPC1 from Arabidopsis thaliana. Nature 531: 258-262.

Kintzer, A.F., E.M. Green, P.K. Dominik, M. Bridges, J.P. Armache, D. Deneka, S.S. Kim, W. Hubbell, A.A. Kossiakoff, Y. Cheng, and R.M. Stroud. (2018). Structural basis for activation of voltage sensor domains in an ion channel TPC1. Proc. Natl. Acad. Sci. USA. [Epub: Ahead of Print]

Kirichok, Y., B. Navarro, and D.E. Clapham. (2006). Whole-cell patch-clamp measurements of spermatozoa reveal an alkaline-activated Ca2+ channel. Nature 439: 737-740.

Kirsch, S.A., A. Kugemann, A. Carpaneto, R.A. Böckmann, and P. Dietrich. (2018). Phosphatidylinositol-3,5-bisphosphate lipid-binding-induced activation of the human two-pore channel 2. Cell Mol Life Sci. [Epub: Ahead of Print]

Kise, Y., G. Kasuya, H.H. Okamoto, D. Yamanouchi, K. Kobayashi, T. Kusakizako, T. Nishizawa, K. Nakajo, and O. Nureki. (2021). Structural basis of gating modulation of Kv4 channel complexes. Nature. [Epub: Ahead of Print]

Kleopa, K.A. (2011). Autoimmune channelopathies of the nervous system. Curr Neuropharmacol 9: 458-467.

Kluge, C., M. Pöhnl, and R.A. Böckmann. (2022). Spontaneous local membrane curvature induced by transmembrane proteins. Biophys. J. 121: 671-683.

Koishi, R., H. Xu, D. Ren, B. Navarro, B.W. Spiller, Q. Shi, and D.E. Clapham. (2004). A superfamily of voltage-gated sodium channels in bacteria. J. Biol. Chem. 279: 9532-9538.

Komiya, M., M. Kato, D. Tadaki, T. Ma, H. Yamamoto, R. Tero, Y. Tozawa, M. Niwano, and A. Hirano-Iwata. (2020). Advances in Artificial Cell Membrane Systems as a Platform for Reconstituting Ion Channels. Chem Rec. [Epub: Ahead of Print]

Kon, S., A. Takaku, F. Toyama, E. Takayama-Watanabe, and A. Watanabe. (2019). Acrosome reaction-inducing substance triggers two different pathways of sperm intracellular signaling in newt fertilization. Int J Dev Biol 63: 589-595.

Köpfer, D.A., C. Song, T. Gruene, G.M. Sheldrick, U. Zachariae, and B.L. de Groot. (2014). Ion permeation in K⁺ channels occurs by direct Coulomb knock-on. Science 346: 352-355.

Koulgi, S., V. Jani, V. Nair, J.S. Saini, S. Phukan, U. Sonavane, R. Joshi, R. Kamboj, and V. Palle. (2021). Molecular dynamics of hERG channel: insights into understanding the binding of small molecules for detuning cardiotoxicity. J Biomol Struct Dyn 1-17. [Epub: Ahead of Print]

Kourrich, S., T. Hayashi, J.Y. Chuang, S.Y. Tsai, T.P. Su, and A. Bonci. (2013). Dynamic interaction between sigma-1 receptor and Kv1.2 shapes neuronal and behavioral responses to cocaine. Cell 152: 236-247.

Kowal, J., M. Chami, P. Baumgartner, M. Arheit, P.L. Chiu, M. Rangl, S. Scheuring, G.F. Schröder, C.M. Nimigean, and H. Stahlberg. (2014). Ligand-induced structural changes in the cyclic nucleotide-modulated potassium channel MloK1. Nat Commun 5: 3106.

Kratochvil, H.T., J.K. Carr, K. Matulef, A.W. Annen, H. Li, M. Maj, J. Ostmeyer, A.L. Serrano, H. Raghuraman, S.D. Moran, J.L. Skinner, E. Perozo, B. Roux, F.I. Valiyaveetil, and M.T. Zanni. (2016). Instantaneous ion configurations in the K+ ion channel selectivity filter revealed by 2D IR spectroscopy. Science 353: 1040-1044.

Krishnamoorthy-Natarajan, G. and M. Koide. (2016). BK Channels in the Vascular System. Int Rev Neurobiol 128: 401-438.

Kuang Q., Purhonen P., Jegerschold C. and Hebert H. (2014). The projection structure of Kch, a putative potassium channel in Escherichia coli, by electron crystallography. Biochim Biophys Acta. 1838(1 Pt B):237-43.

Kuang, Q., P. Purhonen, C. Jegerschöld, P.J.B. Koeck, and H. Hebert. (2015). Free RCK arrangement in Kch, a putative escherichia coli potassium channel, as suggested by electron crystallography. Structure 23: 199-205.

Kubota, T., A.M. Correa, and F. Bezanilla. (2017). Mechanism of functional interaction between potassium channel Kv1.3 and sodium channel NavBeta1 subunit. Sci Rep 7: 45310.

Kubota, T., F. Wu, S. Vicart, M. Nakaza, D. Sternberg, D. Watanabe, M. Furuta, Y. Kokunai, T. Abe, N. Kokubun, B. Fontaine, S.C. Cannon, and M.P. Takahashi. (2020). Hypokalaemic periodic paralysis with a charge-retaining substitution in the voltage sensor. Brain Commun 2: fcaa103.

Kuenze, G., C.G. Vanoye, R.R. Desai, S. Adusumilli, K.R. Brewer, H. Woods, E.F. McDonald, C.R. Sanders, A.L. George, Jr, and J. Meiler. (2020). Allosteric mechanism for KCNE1 modulation of KCNQ1 potassium channel activation. Elife 9:.

Kugler, A., B. Köhler, K. Palme, P. Wolff, and P. Dietrich. (2009). Salt-dependent regulation of a CNG channel subfamily in Arabidopsis. BMC Plant Biol 9: 140.

Kukovetz, K., B. Hertel, C.R. Schvarcz, A. Saponaro, M. Manthey, U. Burk, T. Greiner, G.F. Steward, J.L. Van Etten, A. Moroni, G. Thiel, and O. Rauh. (2020). A Functional K Channel from Tetraselmis Virus 1, a Member of the. Viruses 12:.

Kullmann DM. and Waxman SG. (2010). Neurological channelopathies: new insights into disease mechanisms and ion channel function. J Physiol. 588(Pt 11):1823-7.

Kumar, P., D. Kumar, S.K. Jha, N.K. Jha, and R.K. Ambasta. (2016). Ion Channels in Neurological Disorders. Adv Protein Chem Struct Biol 103: 97-136.

Kunkel, M.T., D.B. Johnstone, J.H. Thomas, and L. Salkoff. (2000). Mutants of a temperature-sensitive two-P domain potassium channel. J. Neurosci. 20: 7517-7524.

Kuo, M.M., Y. Saimi, C. Kung, and S. Choe. (2007). Patch clamp and phenotypic analyses of a prokaryotic cyclic nucleotide-gated K+ channel using Escherichia coli as a host. J. Biol. Chem. 282: 24294-24301.

Kuo, M.M.-C., Y. Saimi, and C. Kung. (2003). Gain-of-function mutations indicate that Escherichia coli Kch forms a functional K+ conduit in vivo. EMBO J. 22: 4049-4058.

Kurusu, T., T. Yagala, A. Miyao, H. Hirochika, and K. Kuchitsu. (2005). Identification of a putative voltage-gated Ca2+ channel as a key regulator of elicitor-induced hypersensitive cell death and mitogen-activated protein kinase activation in rice. Plant J. 42: 798-809.

Kurusu, T., Y. Sakurai, A. Miyao, H. Hirochika, and K. Kuchitsu. (2004). Identification of a putative voltage-gated Ca2+ -permeable channel (OsTPC1) involved in Ca2+ influx and regulation of growth and development in rice. Plant Cell Physiol. 45: 693-702.

Kuum, M., V. Veksler, J. Liiv, R. Ventura-Clapier, and A. Kaasik. (2012). Endoplasmic reticulum potassium-hydrogen exchanger and small conductance calcium-activated potassium channel activities are essential for ER calcium uptake in neurons and cardiomyocytes. J Cell Sci 125: 625-633.

Labro, A.J., I.R. Boulet, F.S. Choveau, E. Mayeur, T. Bruyns, G. Loussouarn, A.L. Raes, and D.J. Snyders. (2011). The S4-S5 linker of KCNQ1 channels forms a structural scaffold with the S6 segment controlling gate closure. J. Biol. Chem. 286: 717-725.

Ladwig, F., R.I. Dahlke, N. Stührwohldt, J. Hartmann, K. Harter, and M. Sauter. (2015). Phytosulfokine Regulates Growth in Arabidopsis through a Response Module at the Plasma Membrane That Includes CYCLIC NUCLEOTIDE-GATED CHANNEL17, H+-ATPase, and BAK1. Plant Cell 27: 1718-1729.

Lamothe, S.M., A.E. Hogan-Cann, W. Li, J. Guo, T. Yang, J.N. Tschirhart, and S. Zhang. (2018). The N terminus and transmembrane segment S1 of Kv1.5 can coassemble with the rest of the channel independent of the S1-S2 linkage. J. Biol. Chem. [Epub: Ahead of Print]

Lampert, A., S.D. Dib-Hajj, L. Tyrrell, and S.G. Waxman. (2006). Size matters: Erythromelalgia mutation S241T in Nav1.7 alters channel gating. J. Biol. Chem. 281: 36029-36035.

Langan, P.S., V.G. Vandavasi, W. Kopec, B. Sullivan, P.V. Afonne, K.L. Weiss, B.L. de Groot, and L. Coates. (2020). The structure of a potassium-selective ion channel reveals a hydrophobic gate regulating ion permeation. IUCrJ 7: 835-843.

Larsson, J.E., D.J.A. Frampton, and S.I. Liin. (2020). Polyunsaturated Fatty Acids as Modulators of K7 Channels. Front Physiol 11: 641.

Latorre, R., K. Castillo, W. Carrasquel-Ursulaez, R.V. Sepulveda, F. Gonzalez-Nilo, C. Gonzalez, and O. Alvarez. (2017). Molecular Determinants of BK Channel Functional Diversity and Functioning. Physiol. Rev. 97: 39-87.

Latz, A., D. Becker, M. Hekman, T. Müller, D. Beyhl, I. Marten, C. Eing, A. Fischer, M. Dunkel, A. Bertl, U.R. Rapp, and R. Hedrich. (2007). TPK1, a Ca2+-regulated Arabidopsis vacuole two-pore K+ channel is activated by 14-3-3 proteins. Plant J. 52: 449-459.

Lazniewska, J. and N. Weiss. (2017). Glycosylation of voltage-gated calcium channels in health and disease. Biochim. Biophys. Acta. 1859: 662-668. [Epub: Ahead of Print]

Lazzari-Dean, J.R., A.M.M. Gest, and E.W. Miller. (2019). Optical estimation of absolute membrane potential using fluorescence lifetime imaging. Elife 8:. [Epub: Ahead of Print]

Lebaudy, A., F. Pascaud, A.A. Véry, C. Alcon, I. Dreyer, J.B. Thibaud, and B. Lacombe. (2010). Preferential KAT1-KAT2 heteromerization determines inward K+ current properties in Arabidopsis guard cells. J. Biol. Chem. 285: 6265-6274.

Lee H., Lin MC., Kornblum HI., Papazian DM. and Nelson SF. (2014). Exome sequencing identifies de novo gain of function missense mutation in KCND2 in identical twins with autism and seizures that slows potassium channel inactivation. Hum Mol Genet. 23(13):3481-9.

Lee, C.H. and R. MacKinnon. (2017). Structures of the Human HCN1 Hyperpolarization-Activated Channel. Cell 168: 111-120.e11.

Lee, C.H. and R. MacKinnon. (2018). Activation mechanism of a human SK-calmodulin channel complex elucidated by cryo-EM structures. Science 360: 508-513.

Lee, J.H., B.H. Lee, S.H. Choi, I.S. Yoon, T.J. Shin, M.K. Pyo, S.M. Lee, H.C. Kim, and S.Y. Nah. (2008). Involvement of batrachotoxin binding sites in ginsenoside-mediated voltage-gated Na+ channel regulation. Brain Res 1203: 61-67.

Lee, U.S., J. Shi, and J. Cui. (2010). Modulation of BK channel gating by the ß2 subunit involves both membrane-spanning and cytoplasmic domains of Slo1. J. Neurosci. 30: 16170-16179.

Leipold, E., F. Ullrich, M. Thiele, A.A. Tietze, H. Terlau, D. Imhof, and S.H. Heinemann. (2017). Subtype-specific block of voltage-gated K channels by μ-conopeptides. Biochem. Biophys. Res. Commun. 482: 1135-1140.

Leng Q., R.W. Mercier, B.G. Hua, H. Fromm, G.A. Berkowitz. (2002). Electrophysiological analysis of cloned cyclic nucleotide-gated ion channels. Plant Physiol. 128: 400-410.

Lengyel, M., G. Czirják, and P. Enyedi. (2018). TRESK background potassium channel is not gated at the helix bundle crossing near the cytoplasmic end of the pore. PLoS One 13: e0197622.

Lewis, A., Z.A. McCrossan, R.W. Manville, M.O. Popa, L.G. Cuello, and S.A.N. Goldstein. (2020). TOK channels use the two gates in classical K channels to achieve outward rectification. FASEB J. [Epub: Ahead of Print]

Li, F., X. Gong, L. Yuan, X. Pan, H. Jin, R. Lu, and S. Wu. (2022). Indoxacarb resistance-associated mutation of Liriomyza trifolii in Hainan, China. Pestic Biochem Physiol 183: 105054.

Li, H., X. Ding, H. Guan, and C. Xiong. (2009). Inhibition of human sperm function and mouse fertilization in vitro by an antibody against cation channel of sperm 1: the contraceptive potential of its transmembrane domains and pore region. Fertil Steril 92: 1141-1146.

Li, J., Y. Li, Y. Liu, H. Yu, N. Xu, D. Huang, Y. Xue, S. Li, H. Chen, J. Liu, Q. Li, Y. Zhao, R. Zhang, H. Xue, Y. Sun, M. Li, P. Li, M. Liu, Z. Zhang, X. Li, W. Du, N. Wang, and B. Yang. (2021). Fibroblast Growth Factor 21 Ameliorates Na1.5 and Kir2.1 Channel Dysregulation in Human AC16 Cardiomyocytes. Front Pharmacol 12: 715466.

Li, L., K. Liu, Y. Hu, D. Li, and S. Luan. (2008). Single mutations convert an outward K+ channel into an inward K+ channel. Proc. Natl. Acad. Sci. USA 105: 2871-2876.

Li, M., X. Zhou, S. Wang, I. Michailidis, Y. Gong, D. Su, H. Li, X. Li, and J. Yang. (2017). Structure of a eukaryotic cyclic-nucleotide-gated channel. Nature. [Epub: Ahead of Print]

Li, P., H. Liu, C. Lai, P. Sun, W. Zeng, F. Wu, L. Zhang, S. Wang, C. Tian, and J. Ding. (2014). Differential Modulations of KCNQ1 by Auxiliary Proteins KCNE1 and KCNE2. Sci Rep 4: 4973.

Li, Q., S. Wanderling, P. Sompornpisut, and E. Perozo. (2014). Structural basis of lipid-driven conformational transitions in the KvAP voltage-sensing domain. Nat Struct Mol Biol 21: 160-166.

Li, Q., X. Guan, K. Yen, J. Zhang, and J. Yan. (2016). The single transmembrane segment determines the modulatory function of the BK channel auxiliary γ subunit. J Gen Physiol 147: 337-351.

Li, S., B. Wu, and W. Han. (2019). Parametrization of MARTINI for Modeling Hinging Motions in Membrane Proteins. J Phys Chem B 123: 2254-2269.

Li, W. and R.W. Aldrich. (2011). Electrostatic influences of charged inner pore residues on the conductance and gating of small conductance Ca2+ activated K+ channels. Proc. Natl. Acad. Sci. USA 108: 5946-5953.

Liao, P., Y. Qiu, Y. Mo, J. Fu, Z. Song, L. Huang, S. Bai, Y. Wang, J.J. Zhu, F. Tian, Z. Chen, N. Pan, E.Y. Sun, L. Yang, X. Lan, Y. Chen, D. Huang, P. Sun, L. Zhao, D. Yang, W. Lu, T. Yang, J. Xiao, W.G. Li, Z. Gao, B. Shen, Q. Zhang, J. Liu, H. Jiang, R. Jiang, and H. Yang. (2019). Selective activation of TWIK-related acid-sensitive K 3 subunit-containing channels is analgesic in rodent models. Sci Transl Med 11:.

Liin, S.I., P.E. Lund, J.E. Larsson, J. Brask, B. Wallner, and F. Elinder. (2018). Biaryl sulfonamide motifs up- or down-regulate ion channel activity by activating voltage sensors. J Gen Physiol. [Epub: Ahead of Print]

Lim, H.H., B.J. Park, H.S. Choi, C.S. Park, S.H. Eom, and J. Ahnn. (1999). Identification and characterization of a putative C. elegans potassium channel gene (Ce-slo-2) distantly related to Ca2+-activated K+ channels. Gene 240: 35-43.

Lin, S., M. Ke, Y. Zhang, Z. Yan, and J. Wu. (2021). Structure of a mammalian sperm cation channel complex. Nature 595: 746-750.

Lin, Y., T. Zhao, S. He, J. Huang, Q. Liu, Z. Yang, J. Qin, N. Yu, H. Lu, and X. Lin. (2020). Compound and heterozygous mutations of KCNQ1 in long QT syndrome with familial history of unexplained sudden death: Identified by analysis of whole exome sequencing and predisposing genes. Ann Noninvasive Electrocardiol 25: e12694.

Ling, K.Y., B. Vaillant, W.J. Haynes, Y. Saimi, and C. Kung. (1998). A comparison of internal eliminated sequences in the genes that encode two K+-channel isoforms in Paramecium tetraurelia. J Eukaryot Microbiol 45: 459-465.

Liu J., J. Xia, K.H. Cho, D.E. Clapham, D. Ren. (2007). CatSperβ, a novel transmembrane protein in the CatSper channel complex. J. Biol. Chem. 282: 18945-18952.

Liu, H., H.G. Wang, G.S. Pitt, and Z.J. Liu. (2022). Direct Observation of Compartment-Specific Localization and Dynamics of Voltage-Gated Sodium Channels. J. Neurosci. [Epub: Ahead of Print]

Liu, J., A. Prindle, J. Humphries, M. Gabalda-Sagarra, M. Asally, D.Y. Lee, S. Ly, J. Garcia-Ojalvo, and G.M. Süel. (2015). Metabolic co-dependence gives rise to collective oscillations within biofilms. Nature 523: 550-554.

Liu, J., H. Tan, W. Yang, S. Yao, and L. Hong. (2019). The voltage-gated sodium channel Na1.7 associated with endometrial cancer. J Cancer 10: 4954-4960.

Liu, K., L. Li, and S. Luan. (2006). Intracellular K+ sensing of SKOR, a Shaker-type K+ channel from Arabidopsis. Plant J. 46: 260-268.

Liu, M. and A. Gelli. (2008). Elongation factor 3, EF3, associates with the calcium channel Cch1 and targets Cch1 to the plasma membrane in Cryptococcus neoformans. Eukaryot. Cell. 7: 1118-1126.

Liu, P., B. Chen, and Z.W. Wang. (2014). SLO-2 potassium channel is an important regulator of neurotransmitter release in Caenorhabditis elegans. Nat Commun 5: 5155.

Liu, P., Q. Ge, B. Chen, L. Salkoff, M.I. Kotlikoff, and Z.W. Wang. (2011). Genetic dissection of ion currents underlying all-or-none action potentials in C. elegans body-wall muscle cells. J. Physiol. 589: 101-117.

Liu, X., Y. Wu, and Y. Zhou. (2010). Intracellular linkers are involved in Mg2+-dependent modulation of the Eag potassium channel. Channels (Austin) 4: 311-318.

Liu, Z., L. Hu, Z. Zhang, L. Song, P. Zhang, Z. Cao, and J. Ma. (2021). Isoliensinine Eliminates Afterdepolarizations Through Inhibiting Late Sodium Current and L-Type Calcium Current. Cardiovasc Toxicol 21: 67-78.

Liu, Z., Y. Jia, L. Song, Y. Tian, P. Zhang, P. Zhang, Z. Cao, and J. Ma. (2020). Antiarrhythmic effect of crotonoside by regulating sodium and calcium channels in rabbit ventricular myocytes. Life Sci 244: 117333.

Locke E.G., M. Bonilla, L. Liang, Y. Takita, K.W. Cunningham. (2000). A homolog of voltage-gated Ca2+ channels stimulated by depletion of secretory Ca2+ in yeast. Mol. Cell Biol. 20: 6686-6694

Loganathan, K., S. Moriya, M. Sivalingam, K.W. Ng, and I.S. Parhar. (2017). Sequence and localization of kcnk10a in the brain of adult zebrafish (Danio rerio). J Chem Neuroanat 86: 92-99. [Epub: Ahead of Print]

Lolicato, M., P.M. Riegelhaupt, C. Arrigoni, K.A. Clark, and D.L. Minor, Jr. (2014). Transmembrane helix straightening and buckling underlies activation of mechanosensitive and thermosensitive K(2P) channels. Neuron. 84: 1198-1212.

Long, S.B., X. Tao, E.B. Campbell, and R. MacKinnon. (2007). Atomic structure of a voltage-dependent K+ channel in a lipid membrane-like environment. Nature 450: 376-382.

Lopez-Cayuqueo KI., Pena-Munzenmayer G., Niemeyer MI., Sepulveda FV. and Cid LP. (2015). TASK-2 K(2)p K(+) channel: thoughts about gating and its fitness to physiological function. Pflugers Arch. 467(5):1043-53.

Lorca, R.A., X. Ma, and S.K. England. (2017). The unique N-terminal sequence of the BKCa channel α-subunit determines its modulation by β-subunits. PLoS One 12: e0182068.

Lorincz, A. and Z. Nusser. (2010). Molecular identity of dendritic voltage-gated sodium channels. Science 328: 906-909.

Lörinczi, &.#.2.0.1.;., J.C. Gómez-Posada, P. de la Peña, A.P. Tomczak, J. Fernández-Trillo, U. Leipscher, W. Stühmer, F. Barros, and L.A. Pardo. (2015). Voltage-dependent gating of KCNH potassium channels lacking a covalent link between voltage-sensing and pore domains. Nat Commun 6: 6672.

Lowe, J.S., O. Palygin, N. Bhasin, T.J. Hund, P.A. Boyden, E. Shibata, M.E. Anderson, and P.J. Mohler. (2008). Voltage-gated Nav channel targeting in the heart requires an ankyrin-G dependent cellular pathway. J. Cell. Biol. 180: 173-186.

Lu, B., Y. Su, S. Das, J. Liu, J. Xia, and D. Ren. (2007). The neuronal channel NALCN contributes resting sodium permeability and is required for normal respiratory rhythm. Cell 129: 371-383.

Lu, S., S. Ma, Y. Wang, T. Huang, Z. Zhu, and G. Zhao. (2017). Mus musculus-microRNA-449a ameliorates neuropathic pain by decreasing the level of KCNMA1 and TRPA1, and increasing the level of TPTE. Mol Med Rep. [Epub: Ahead of Print]

Lundberg, M.E., E.C. Becker, and S. Choe. (2013). MstX and a putative potassium channel facilitate biofilm formation in Bacillus subtilis. PLoS One 8: e60993.

Lyashchenko, A.K., and G.R. Tibbs. (2008). Ion binding in the open HCN pacemaker channel pore: fast mechanisms to shape "slow" channels. J. Gen. Physiol. 131: 227-243.

Lyashchenko, A.K., K.J. Redd, P.A. Goldstein, and G.R. Tibbs. (2014). cAMP control of HCN2 channel Mg2+ block reveals loose coupling between the cyclic nucleotide-gating ring and the pore. PLoS One 9: e101236.

Männikkö, R., F. Elinder, and H.P. Larsson. (2002). Voltage-sensing mechanism is conserved among ion channels gated by opposite voltages. Nature 419: 837-841.

Ma, T., M. Sato, M. Komiya, K. Kanomata, T. Watanabe, X. Feng, R. Miyata, D. Tadaki, F. Hirose, Y. Tozawa, and A. Hirano-Iwata. (2021). Lateral voltage as a new input for artificial lipid bilayer systems. Faraday Discuss. [Epub: Ahead of Print]

Ma, Y., R. Sugiura, A. Koike, H. Ebina, S.O. Sio, and T. Kuno. (2011). Transient receptor potential (TRP) and Cch1-Yam8 channels play key roles in the regulation of cytoplasmic Ca2+ in fission yeast. PLoS One 6: e22421.

Mackieh, R., R. Abou-Nader, R. Wehbe, C. Mattei, C. Legros, Z. Fajloun, and J.M. Sabatier. (2021). Voltage-Gated Sodium Channels: A Prominent Target of Marine Toxins. Mar Drugs 19:.

MacKinnon, R. (1995). Pore loops: an emerging theme in ion channel structure. Neuron 14: 889-892.

Mahling, R., A.M. Kilpatrick, and M.A. Shea. (2017). Backbone resonance assignments of complexes of human voltage-dependent sodium channel NaV1.2 IQ motif peptide bound to apo calmodulin and to the C-domain fragment of apo calmodulin. Biomol NMR Assign. [Epub: Ahead of Print]

Maingret, F., A.J. Patel, F. Lesage, M. Lazdunski, and E. Honoré. (1999). Mechano- or acid stimulation, two interactive modes of activation of the TREK-1 potassium channel. J. Biol. Chem. 274: 26691-26696.

Maity, S., A. Marchesi, V. Torre, and M. Mazzolini. (2016). Structural Heterogeneity of CNGA1 Channels Revealed by Electrophysiology and Single-Molecule Force Spectroscopy. ACS Omega 1: 1205-1219.

Maity, S., M. Mazzolini, M. Arcangeletti, A. Valbuena, P. Fabris, M. Lazzarino, and V. Torre. (2015). Conformational rearrangements in the transmembrane domain of CNGA1 channels revealed by single-molecule force spectroscopy. Nat Commun 6: 7093.

Malak, O.A., F. Abderemane-Ali, Y. Wei, F.C. Coyan, G. Pontus, D. Shaya, C. Marionneau, and G. Loussouarn. (2020). Up-regulation of voltage-gated sodium channels by peptides mimicking S4-S5 linkers reveals a variation of the ligand-receptor mechanism. Sci Rep 10: 5852.

Maljevic, S., S. Vejzovic, M.K. Bernhard, A. Bertsche, S. Weise, M. Döcker, H. Lerche, J.R. Lemke, A. Merkenschlager, and S. Syrbe. (2016). Novel KCNQ3 Mutation in a Large Family with Benign Familial Neonatal Epilepsy: A Rare Cause of Neonatal Seizures. Mol Syndromol 7: 189-196.

Mallmann, R., K. Ondacova, L. Moravcikova, B. Jurkovicova-Tarabova, M. Pavlovicova, L. Lichvarova, V. Kominkova, N. Klugbauer, and L. Lacinova. (2019). Four novel interaction partners demonstrate diverse modulatory effects on voltage-gated Ca2.2 Ca channels. Pflugers Arch. [Epub: Ahead of Print]

Mallmann, R.T., T. Wilmes, L. Lichvarova, A. Bührer, B. Lohmüller, J. Castonguay, L. Lacinova, and N. Klugbauer. (2013). Tetraspanin-13 modulates voltage-gated CaV2.2 Ca2+ channels. Sci Rep 3: 1777.

Manville, R.W. and G.W. Abbott. (2018). Gabapentin Is a Potent Activator of KCNQ3 and KCNQ5 Potassium Channels. Mol Pharmacol 94: 1155-1163.

Manville, R.W. and G.W. Abbott. (2019). Cilantro leaf harbors a potent potassium channel-activating anticonvulsant. FASEB J. fj201900485R. [Epub: Ahead of Print]

Marcel D., Muller T., Hedrich R. and Geiger D. (2010). K+ transport characteristics of the plasma membrane tandem-pore channel TPK4 and pore chimeras with its vacuolar homologs. FEBS Lett. 584(11):2433-9.

Marchesi A., Mazzolini M. and Torre V. (2012). A ring of threonines in the inner vestibule of the pore of CNGA1 channels constitutes a binding site for permeating ions. J Physiol. 590(Pt 20):5075-90.

Marchesi, A., M. Arcangeletti, M. Mazzolini, and V. Torre. (2015). Proton transfer unlocks inactivation in cyclic nucleotide-gated A1 channels. J. Physiol. 593: 857-870.

Mari, S.A., J. Pessoa, S. Altieri, U. Hensen, L. Thomas, J.H. Morais-Cabral, and D.J. Müller. (2011). Gating of the MlotiK1 potassium channel involves large rearrangements of the cyclic nucleotide-binding domains. Proc. Natl. Acad. Sci. USA 108: 20802-20807.

Marini, C., A. Porro, A. Rastetter, C. Dalle, I. Rivolta, D. Bauer, R. Oegema, C. Nava, E. Parrini, D. Mei, C. Mercer, R. Dhamija, C. Chambers, C. Coubes, J. Thévenon, P. Kuentz, S. Julia, L. Pasquier, C. Dubourg, W. Carré, A. Rosati, F. Melani, T. Pisano, M. Giardino, A.M. Innes, Y. Alembik, S. Scheidecker, M. Santos, S. Figueiroa, C. Garrido, C. Fusco, D. Frattini, C. Spagnoli, A. Binda, T. Granata, F. Ragona, E. Freri, S. Franceschetti, L. Canafoglia, B. Castellotti, C. Gellera, R. Milanesi, M.M. Mancardi, D.R. Clark, F. Kok, K.L. Helbig, S. Ichikawa, L. Sadler, J. Neupauerová, P. Laššuthova, K. Šterbová, A. Laridon, E. Brilstra, B. Koeleman, J.R. Lemke, F. Zara, P. Striano, J. Soblet, G. Smits, N. Deconinck, A. Barbuti, D. DiFrancesco, E. LeGuern, R. Guerrini, B. Santoro, K. Hamacher, G. Thiel, A. Moroni, J.C. DiFrancesco, and C. Depienne. (2018). HCN1 mutation spectrum: from neonatal epileptic encephalopathy to benign generalized epilepsy and beyond. Brain 141: 3160-3178.

Marino, J., N. Bordag, S. Keller, and O. Zerbe. (2015). Mistic''s membrane association and its assistance in overexpression of a human GPCR are independent processes. Protein. Sci. 24: 38-48.

Marosi, M., M.N. Nenov, J. Di Re, N.M. Dvorak, M. Alshammari, and F. Laezza. (2022). Inhibition of the Akt/PKB Kinase Increases Na1.6-Mediated Currents and Neuron.al Excitability in CA1 Hippocampal Pyramidal Neuron.s. Int J Mol Sci 23:.

Martin, D.C., H. Kim, N.A. Mackin, L. Maldonado-Báez, C.C. Evangelista, Jr, V.G. Beaudry, D.D. Dudgeon, D.Q. Naiman, S.E. Erdman, and K.W. Cunningham. (2011). New regulators of a high affinity Ca2+ influx system revealed through a genome-wide screen in yeast. J. Biol. Chem. 286: 10744-10754.

Martinez-Moreno, R., E. Selga, H. Riuró, D. Carreras, M. Parnes, C. Srinivasan, M.F. Wangler, G.J. Pérez, F.S. Scornik, and R. Brugada. (2020). An Variant Affects Both Cardiac-Type (Na1.5) and Brain-Type (Na1.1) Sodium Currents and Contributes to Complex Concomitant Brain and Cardiac Disorders. Front Cell Dev Biol 8: 528742.

Mashanov, G.I., M. Nobles, S.C. Harmer, J.E. Molloy, and A. Tinker. (2010). Direct observation of individual KCNQ1 potassium channels reveals their distinctive diffusive behavior. J. Biol. Chem. 285: 3664-3675.

Matthies, D., C. Bae, G.E. Toombes, T. Fox, A. Bartesaghi, S. Subramaniam, and K.J. Swartz. (2018). Single-particle cryo-EM structure of a voltage-activated potassium channel in lipid nanodiscs. Elife 7:.

Mazzone, A., P.R. Strege, D.J. Tester, C.E. Bernard, G. Faulkner, R. De Giorgio, J.C. Makielski, V. Stanghellini, S.J. Gibbons, M.J. Ackerman, and G. Farrugia. (2008). A mutation in telethonin alters nav1.5 function. J. Biol. Chem. 283: 16537-16544.

McBride CM., Smith AM., Smith JL., Reloj AR., Velasco EJ., Powell J., Elayi CS., Bartos DC., Burgess DE. and Delisle BP. (2013). Mechanistic basis for type 2 long QT syndrome caused by KCNH2 mutations that disrupt conserved arginine residues in the voltage sensor. J Membr Biol. 246(5):355-64.

McClafferty, H., H. Runciman, and M.J. Shipston. (2020). Site specific deacylation by ABHD17a controls BK channel splice variant activity. J. Biol. Chem. [Epub: Ahead of Print]

McCoy JG., Rusinova R., Kim DM., Kowal J., Banerjee S., Jaramillo Cartagena A., Thompson AN., Kolmakova-Partensky L., Stahlberg H., Andersen OS. and Nimigean CM. (2014). A KcsA/MloK1 chimeric ion channel has lipid-dependent ligand-binding energetics. J Biol Chem. 289(14):9535-46.

McCusker, E.C., C. Bagnéris, C.E. Naylor, A.R. Cole, N. D'Avanzo, C.G. Nichols, and B.A. Wallace. (2012). Structure of a bacterial voltage-gated sodium channel pore reveals mechanisms of opening and closing. Nat Commun 3: 1102.

McCusker, E.C., N. D'Avanzo, C.G. Nichols, and B.A. Wallace. (2011). Simplified bacterial "pore" channel provides insight into the assembly, stability, and structure of sodium channels. J. Biol. Chem. 286: 16386-16391.

McDonough, A.A. and R.A. Fenton. (2022). Potassium homeostasis: sensors, mediators, and targets. Pflugers Arch. [Epub: Ahead of Print]

McNair, W.P., G. Sinagra, M.R. Taylor, A. Di Lenarda, D.A. Ferguson, E.E. Salcedo, D. Slavov, X. Zhu, J.H. Caldwell, L. Mestroni, and. (2011). SCN5A mutations associate with arrhythmic dilated cardiomyopathy and commonly localize to the voltage-sensing mechanism. J Am Coll Cardiol 57: 2160-2168.

Mederos Y Schnitzler, M., S. Rinné, L. Skrobek, V. Renigunta, G. Schlichthörl, C. Derst, T. Gudermann, J. Daut, and R. Preisig-Müller. (2009). Mutation of histidine 105 in the T1 domain of the potassium channel Kv2.1 disrupts heteromerization with Kv6.3 and Kv6.4. J. Biol. Chem. 284: 4695-4704.

Medovoy, D., E. Perozo, and B. Roux. (2016). Multi-ion free energy landscapes underscore the microscopic mechanism of ion selectivity in the KcsA channel. Biochim. Biophys. Acta. [Epub: Ahead of Print]

Meng, J.G., L. Liang, P.F. Jia, Y.C. Wang, H.J. Li, and W.C. Yang. (2020). Integration of ovular signals and exocytosis of a Ca channel by MLOs in pollen tube guidance. Nat Plants 6: 143-153.

Mezghrani, A., A. Monteil, K. Watschinger, M.J. Sinnegger-Brauns, C. Barrère, E. Bourinet, J. Nargeot, J. Striessnig, and P. Lory. (2008). A destructive interaction mechanism accounts for dominant-negative effects of misfolded mutants of voltage-gated calcium channels. J. Neurosci. 28: 4501-4511.

Miceli, F., L. Carotenuto, V. Barrese, M.V. Soldovieri, E.L. Heinzen, A.M. Mandel, N. Lippa, L. Bier, D.B. Goldstein, E.C. Cooper, M.R. Cilio, M. Taglialatela, and T.T. Sands. (2020). A Novel Kv7.3 Variant in the Voltage-Sensing S Segment in a Family With Benign Neonatal Epilepsy: Functional Characterization and Rescue by β-Hydroxybutyrate. Front Physiol 11: 1040.

Miceli, F., M.V. Soldovieri, P. Ambrosino, M. De Maria, L. Manocchio, A. Medoro, and M. Taglialatela. (2015). Molecular pathophysiology and pharmacology of the voltage-sensing module of neuronal ion channels. Front Cell Neurosci 9: 259.

Michalakis, S., J. Reisert, H. Geiger, C. Wetzel, X. Zong, J. Bradley, M. Spehr, S. Hüttl, A. Gerstner, A. Pfeifer, H. Hatt, K.W. Yau, and M. Biel. (2006). Loss of CNGB1 protein leads to olfactory dysfunction and subciliary cyclic nucleotide-gated channel trapping. J. Biol. Chem. 281: 35156-35166.

Miller, A.N. and S.B. Long. (2012). Crystal structure of the human two-pore domain potassium channel K2P1. Science 335: 432-436.

Miller, W.C., A.J. Miles, and B.A. Wallace. (2016). Structure of the C-terminal domain of the prokaryotic sodium channel orthologue NsvBa. Eur Biophys. J. [Epub: Ahead of Print]

Miloshevsky, G.V., and P.C. Jordan. (2007). Open-state conformation of the KcsA K+ channel: Monte Carlo normal mode following simulations. Structure 15: 1654-1662.

Minor, D.L., Jr and F. Findeisen. (2010). Progress in the structural understanding of voltage-gated calcium channel (CaV) function and modulation. Channels (Austin) 4: 459-474.

Mio, K., M. Mio, F. Arisaka, M. Sato, and C. Sato. (2010). The C-terminal coiled-coil of the bacterial voltage-gated sodium channel NaChBac is not essential for tetramer formation, but stabilizes subunit-to-subunit interactions. Prog Biophys Mol Biol 103: 111-121.

Mio, K., T. Ogura, and C. Sato. (2008). Structure of six-transmembrane cation channels revealed by single-particle analysis from electron microscopic images. J Synchrotron Radiat 15: 211-214.

Miranda, P., M. Holmgren, and T. Giraldez. (2018). Voltage-dependent dynamics of the BK channel cytosolic gating ring are coupled to the membrane-embedded voltage sensor. Elife 7:.

Mishima, E., Y. Sato, K. Nanatani, N. Hoshi, J.K. Lee, N. Schiller, G. von Heijne, M. Sakaguchi, and N. Uozumi. (2016). The topogenic function of S4 promotes membrane insertion of the voltage-sensor domain in the KvAP channel. Biochem. J. [Epub: Ahead of Print]

Mitchell, M.R. and S. Leibler. (2017). Elastic strain and twist analysis of protein structural data and allostery of the transmembrane channel KcsA. Phys Biol. [Epub: Ahead of Print]

Miyata, R., D. Tadaki, D. Yamaura, S. Araki, M. Sato, M. Komiya, T. Ma, H. Yamamoto, M. Niwano, and A. Hirano-Iwata. (2021). Parallel Recordings of Transmembrane hERG Channel Currents Based on Solvent-Free Lipid Bilayer Microarray. Micromachines (Basel) 12:.

Monteleone, S., A. Lieb, A. Pinggera, G. Negro, J.E. Fuchs, F. Hofer, J. Striessnig, P. Tuluc, and K.R. Liedl. (2017). Mechanisms Responsible for ω-Pore Currents in Cav Calcium Channel Voltage-Sensing Domains. Biophys. J. 113: 1485-1495.

Montini, G., J. Booker, A. Sula, and B.A. Wallace. (2018). Comparisons of voltage-gated sodium channel structures with open and closed gates and implications for state-dependent drug design. Biochem Soc Trans 46: 1567-1575.

Moran, Y. and H.H. Zakon. (2014). The evolution of the four subunits of voltage-gated calcium channels: ancient roots, increasing complexity, and multiple losses. Genome Biol Evol 6: 2210-2217.

Moran, Y., M.G. Barzilai, B.J. Liebeskind, and H.H. Zakon. (2015). Evolution of voltage-gated ion channels at the emergence of Metazoa. J Exp Biol 218: 515-525.

Moreau, A., P. Gosselin-Badaroudine, and M. Chahine. (2014). Biophysics, pathophysiology, and pharmacology of ion channel gating pores. Front Pharmacol 5: 53.

Moreau, A., P. Gosselin-Badaroudine, M. Boutjdir, and M. Chahine. (2015). Mutations in the Voltage Sensors of Domains I and II of Nav1.5 that are Associated with Arrhythmias and Dilated Cardiomyopathy Generate Gating Pore Currents. Front Pharmacol 6: 301.

Moreno, C., A. Oliveras, C. Bartolucci, C. Muñoz, A. de la Cruz, D.A. Peraza, J.R. Gimeno, M. Martín-Martínez, S. Severi, A. Felipe, P.D. Lambiase, T. Gonzalez, and C. Valenzuela. (2017). D242N, a KV7.1 LQTS mutation uncovers a key residue for IKs voltage dependence. J Mol. Cell Cardiol 110: 61-69. [Epub: Ahead of Print]

Morera FJ., Alioua A., Kundu P., Salazar M., Gonzalez C., Martinez AD., Stefani E., Toro L. and Latorre R. (2012). The first transmembrane domain (TM1) of beta2-subunit binds to the transmembrane domain S1 of alpha-subunit in BK potassium channels. FEBS Lett. 586(16):2287-93.

Morrill, J.A. and R. MacKinnon. (1999). Isolation of a single carboxyl proton binding site in the pore of a cyclic nucleotide-gated channel. J. Genet. Physiol. 114: 71-83.

Morton, M.J., A. Abohamed, A. Sivaprasadarao, and M. Hunter. (2005). pH sensing in the two-pore domain K+ channel, TASK2. Proc. Natl. Acad. Sci. USA 102: 16102-16106.

Mouline K., A.A. Very, F. Gaymard, J. Boucherez, G. Pilot, M. Devic, D. Bouchez, J.B. Thibaud, H. Sentenac. (2002). Pollen tube development and competitive ability are impaired by disruption of a Shaker K(+) channel in Arabidopsis. Genes Dev. 16:339-350.

Munsey, T.S., A. Mohindra, S.P. Yusaf, A. Grainge, M.H. Wang, D. Wray, and A. Sivaprasadarao. (2002). Functional properties of Kch, a prokaryotic homologue of eukaryotic potassium channels. Biochem. Biophys. Res. Commun. 297: 10-16.

Muona, M., S.F. Berkovic, L.M. Dibbens, K.L. Oliver, S. Maljevic, M.A. Bayly, T. Joensuu, L. Canafoglia, S. Franceschetti, R. Michelucci, S. Markkinen, S.E. Heron, M.S. Hildebrand, E. Andermann, F. Andermann, A. Gambardella, P. Tinuper, L. Licchetta, I.E. Scheffer, C. Criscuolo, A. Filla, E. Ferlazzo, J. Ahmad, A. Ahmad, B. Baykan, E. Said, M. Topcu, P. Riguzzi, M.D. King, C. Ozkara, D.M. Andrade, B.A. Engelsen, A. Crespel, M. Lindenau, E. Lohmann, V. Saletti, J. Massano, M. Privitera, A.J. Espay, B. Kauffmann, M. Duchowny, R.S. Møller, R. Straussberg, Z. Afawi, B. Ben-Zeev, K.E. Samocha, M.J. Daly, S. Petrou, H. Lerche, A. Palotie, and A.E. Lehesjoki. (2015). A recurrent de novo mutation in KCNC1 causes progressive myoclonus epilepsy. Nat. Genet. 47: 39-46.

Murry, C.R., I.V. Agarkova, J.S. Ghosh, F.C. Fitzgerald, R.M. Carlson, B. Hertel, K. Kukovetz, O. Rauh, G. Thiel, and J.L. Van Etten. (2020). Genetic Diversity of Potassium Ion Channel Proteins Encoded by Chloroviruses That Infect. Viruses 12:.

Nagaraja, S., L.F. Queme, M.C. Hofmann, S.G. Tewari, M.P. Jankowski, and J. Reifman. (2021). Identification of Key Factors Driving the Response of Muscle Sensory Neuron.s to Noxious Stimuli. Front Neurosci 15: 719735.

Nakagawa, H., T. Munakata, and A. Sunami. (2019). Mexiletine Block of Voltage-Gated Sodium Channels: Isoform- and State-Dependent Drug-Pore Interactions. Mol Pharmacol 95: 236-244.

Nakajo, K., M.H. Ulbrich, Y. Kubo, and E.Y. Isacoff. (2010). Stoichiometry of the KCNQ1 - KCNE1 ion channel complex. Proc. Natl. Acad. Sci. USA 107: 18862-18867.

Nakamura, K., M. Kato, H. Osaka, S. Yamashita, E. Nakagawa, K. Haginoya, J. Tohyama, M. Okuda, T. Wada, S. Shimakawa, K. Imai, S. Takeshita, H. Ishiwata, D. Lev, T. Lerman-Sagie, D.E. Cervantes-Barragán, C.E. Villarroel, M. Ohfu, K. Writzl, B. Gnidovec Strazisar, S. Hirabayashi, D. Chitayat, D. Myles Reid, K. Nishiyama, H. Kodera, M. Nakashima, Y. Tsurusaki, N. Miyake, K. Hayasaka, N. Matsumoto, and H. Saitsu. (2013). Clinical spectrum of SCN2A mutations expanding to Ohtahara syndrome. Neurology 81: 992-998.

Nakamura, R.L. and R.F. Gaber. (2009). Ion selectivity of the Kat1 K+ channel pore. Mol. Membr. Biol. 26: 293-308.

Nakao H., Ikeda K., Iwamoto M., Shimizu H., Oiki S., Ishihama Y. and Nakano M. (2015). pH-dependent promotion of phospholipid flip-flop by the KcsA potassium channel. Biochim Biophys Acta. 1848(1 Pt A):145-50.

Naso, A., I. Dreyer, L. Pedemonte, I. Testa, J.L. Gomez-Porras, C. Usai, B. Mueller-Rueber, A. Diaspro, F. Gambale, and C. Picco. (2009). The role of the C-terminus for functional heteromerization of the plant channel KDC1. Biophys. J. 96: 4063-4074.

Natale, A.M., P.E. Deal, and D.L. Minor, Jr. (2021). Structural insights into the mechanisms and pharmacology of K potassium channels. J. Mol. Biol. 166995. [Epub: Ahead of Print]

Nathan, S., S.B. Gabelli, J.B. Yoder, L. Srinivasan, R.W. Aldrich, G.F. Tomaselli, M. Ben-Johny, and L.M. Amzel. (2021). Structural basis of cytoplasmic NaV1.5 and NaV1.4 regulation. J Gen Physiol 153:.

Naula, C.M., F.M. Logan, P.E. Wong, M.P. Barrett, and R.J. Burchmore. (2010). A glucose transporter can mediate ribose uptake: definition of residues that confer substrate specificity in a sugar transporter. J. Biol. Chem. 285: 29721-29728.

Nelson, R.D., G. Kuan, M.H. Saier, Jr., and M. Montal. (1999). Modular assembly of voltage-gated channel proteins: a sequence analysis and phylogenetic study. J. Mol. Microbiol. Biotechnol. 2: 281-287.

Neupärtl, M., C. Meyer, I. Woll, F. Frohns, M. Kang, J.L. Van Etten, D. Kramer, B. Hertel, A. Moroni, and G. Thiel. (2008). Chlorella viruses evoke a rapid release of K+ from host cells during the early phase of infection. Virology 372(2): 340-348.

Nguyen, H.M., C.A. Galea, G. Schmunk, B.J. Smith, R.A. Edwards, R.S. Norton, and K.G. Chandy. (2013). Intracellular Trafficking of the KV1.3 Potassium Channel Is Regulated by the Prodomain of a Matrix Metalloprotease. J. Biol. Chem. 288: 6451-6464.

Niemeyer, M.I., L.P. Cid, L.F. Barros, and F.V. Sepúlveda. (2001). Modulation of the two-pore domain acid-sensitive K+ channel TASK-2 (KCNK5) by changes in cell volume. J. Biol. Chem. 276: 43166-43174.

Nieves-Cordones, M. and I. Gaillard. (2014). Involvement of the S4-S5 linker and the C-linker domain regions to voltage-gating in plant Shaker channels: comparison with animal HCN and Kv channels. Plant Signal Behav 9: e972892.

Nieves-Cordones, M., A. Chavanieu, L. Jeanguenin, C. Alcon, W. Szponarski, S. Estaran, I. Chérel, S. Zimmermann, H. Sentenac, and I. Gaillard. (2014). Distinct amino acids in the C-linker domain of the Arabidopsis K+ channel KAT2 determine its subcellular localization and activity at the plasma membrane. Plant Physiol. 164: 1415-1429.

Nieves-Cordones, M., F. Alemán, V. Martínez, and F. Rubio. (2014). K+ uptake in plant roots. The systems involved, their regulation and parallels in other organisms. J Plant Physiol. 171: 688-695.

Niitsu, A., A. Egawa, K. Ikeda, K. Tachibana, and T. Fujiwara. (2018). Veratridine binding to a transmembrane helix of sodium channel Na1.4 determined by solid-state NMR. Bioorg Med Chem 26: 5644-5653.

Niu, X., Y. Yang, Y. Chen, M. Cheng, M. Liu, C. Ding, X. Tian, Z. Yang, Y. Jiang, and Y. Zhang. (2022). Genotype-phenotype correlation of CACNA1A variants in children with epilepsy. Dev Med Child Neurol 64: 105-111.

Núñez, E., A. Muguruza-Montero, and A. Villarroel. (2020). Atomistic Insights of Calmodulin Gating of Complete Ion Channels. Int J Mol Sci 21:.

Nurani, G., M. Radford, K. Charalambous, A.O. O'Reilly, N.B. Cronin, S. Haque, and B.A. Wallace. (2008). Tetrameric bacterial sodium channels: characterization of structure, stability, and drug binding. Biochemistry 47: 8114-8121.

O''Halloran, D.M., S. Altshuler-Keylin, X.D. Zhang, C. He, C. Morales-Phan, Y. Yu, J.A. Kaye, C. Brueggemann, T.Y. Chen, and N.D. L''Etoile. (2017). Contribution of the cyclic nucleotide gated channel subunit, CNG-3, to olfactory plasticity in Caenorhabditis elegans. Sci Rep 7: 169.

O''Reilly, A.O., A. Lattrell, A.J. Miles, A.B. Klinger, C. Nau, B.A. Wallace, and A. Lampert. (2017). Mutagenesis of the NaChBac sodium channel discloses a functional role for a conserved S6 asparagine. Eur Biophys. J. [Epub: Ahead of Print]

O'Brien, J.E. and M.H. Meisler. (2013). Sodium channel SCN8A (Nav1.6): properties and de novo mutations in epileptic encephalopathy and intellectual disability. Front Genet 4: 213.

O'Brien, J.E., L.M. Sharkey, C.N. Vallianatos, C. Han, J.C. Blossom, T. Yu, S.G. Waxman, S.D. Dib-Hajj, and M.H. Meisler. (2012). Interaction of Voltage-gated Sodium Channel Nav1.6 (SCN8A) with Microtubule-associated Protein Map1b. J. Biol. Chem. 287: 18459-18466.

Oliver, K.L., S. Franceschetti, C.J. Milligan, M. Muona, S.A. Mandelstam, L. Canafoglia, A.M. Boguszewska-Chachulska, A.D. Korczyn, F. Bisulli, C. Di Bonaventura, F. Ragona, R. Michelucci, B. Ben-Zeev, R. Straussberg, F. Panzica, J. Massano, D. Friedman, A. Crespel, B.A. Engelsen, F. Andermann, E. Andermann, K. Spodar, A. Lasek-Bal, P. Riguzzi, E. Pasini, P. Tinuper, L. Licchetta, E. Gardella, M. Lindenau, A. Wulf, R.S. Møller, F. Benninger, Z. Afawi, G. Rubboli, C.A. Reid, S. Maljevic, H. Lerche, A.E. Lehesjoki, S. Petrou, and S.F. Berkovic. (2017). Myoclonus epilepsy and ataxia due to KCNC1 mutation: Analysis of 20 cases and K+ channel properties. Ann Neurol 81: 677-689.

Olson, T.M., A.E. Alekseev, X.K. Liu, S. Park, L.V. Zingman, M. Bienengraeber, S. Sattiraju, J.D. Ballew, A. Jahangir, and A. Terzic. (2006). Kv1.5 channelopathy due to KCNA5 loss-of-function mutation causes human atrial fibrillation. Hum Mol Genet 15: 2185-2191.

Ooi, L., S. Gigout, L. Pettinger, and N. Gamper. (2013). Triple Cysteine Module within M-Type K+ Channels Mediates Reciprocal Channel Modulation by Nitric Oxide and Reactive Oxygen Species. J. Neurosci. 33: 6041-6046.

Orias, M., H. Velázquez, F. Tung, G. Lee, and G.V. Desir. (1997). Cloning and localization of a double-pore K channel, KCNK1: exclusive expression in distal nephron segments. Am. J. Physiol. Renal Physiol 273: F663-F666.

Ostacolo, C., F. Miceli, V. Di Sarno, P. Nappi, N. Iraci, M.V. Soldovieri, T. Ciaglia, P. Ambrosino, V. Vestuto, A. Lauritano, S. Musella, G. Pepe, M.G. Basilicata, M. Manfra, D.R. Perinelli, E. Novellino, A. Bertamino, I.M. Gomez-Monterrey, P. Campiglia, and M. Taglialatela. (2020). Synthesis and Pharmacological Characterization of Conformationally Restricted Retigabine Analogues as Novel Neuron.al Kv7 Channel Activators. J Med Chem 63: 163-185.

Osterbur ML., Zheng R., Marion R., Walsh C. and McDonald TV. (2015). An Interdomain KCNH2 Mutation Produces an Intermediate Long QT Syndrome. Hum Mutat. 36(8):764-73.

Ottschytsch, N., A.L. Raes, J.P. Timmermans, and D.J. Snyders. (2005). Domain analysis of Kv6.3, an electrically silent channel. J. Physiol. 568: 737-747.

Ouyang, Q., M. Goeritz, and R.M. Harris-Warrick. (2007). Panulirus interruptus Ih-channel gene PIIH: modification of channel properties by alternative splicing and role in rhythmic activity. J Neurophysiol 97: 3880-3892.

Page, D.A., K.E.A. Magee, J. Li, M. Jung, and E.C. Young. (2020). Cytoplasmic Autoinhibition in HCN Channels is Regulated by the Transmembrane Region. J. Membr. Biol. [Epub: Ahead of Print]

Paidhungat, M., and S. Garrett. (1997). A homolog of mammalian, voltage-gated calcium channels mediates yeast pheromone-stimulated Ca2+ uptake and exacerbates the cdc1(Ts) growth defect. Mol. Cell Biol. 17: 6339-6347.

Paldi, T. and M. Gurevitz. (2010). Coupling between residues on S4 and S1 defines the voltage-sensor resting conformation in NaChBac. Biophys. J. 99: 456-463.

Palomba, N.P., K. Martinello, G. Cocozza, S. Casciato, A. Mascia, G. Di Gennaro, R. Morace, V. Esposito, H. Wulff, C. Limatola, and S. Fucile. (2021). ATP-evoked intracellular Ca transients shape the ionic permeability of human microglia from epileptic temporal cortex. J Neuroinflammation 18: 44.

Pan, X., Z. Li, Q. Zhou, H. Shen, K. Wu, X. Huang, J. Chen, J. Zhang, X. Zhu, J. Lei, W. Xiong, H. Gong, B. Xiao, and N. Yan. (2018). Structure of the human voltage-gated sodium channel Na1.4 in complex with β1. Science 362:.

Pan, Y. and T.R. Cummins. (2020). Distinct functional alterations in SCN8A epilepsy mutant channels. J. Physiol. 598: 381-401.

Pandey, A., J. P, S. Tripathi, and C. Gopi Mohan. (2012). Harnessing Human N-type Ca2+ Channel Receptor by Identifying the Atomic Hotspot Regions for Its Structure-Based Blocker Design. Mol Inform 31: 643-657.

Papanatsiou, M., J. Petersen, L. Henderson, Y. Wang, J.M. Christie, and M.R. Blatt. (2019). Optogenetic manipulation of stomatal kinetics improves carbon assimilation, water use, and growth. Science 363: 1456-1459.

Pappa, A.M., H.Y. Liu, W. Traberg-Christensen, Q. Thiburce, A. Savva, A. Pavia, A. Salleo, S. Daniel, and R.M. Owens. (2020). Optical and Electronic Ion Channel Monitoring from Native Human Membranes. ACS Nano. [Epub: Ahead of Print]

Parfenova, L.V., Crane, B.M., and Rothberg, B.S. (2006). Modulation of MthK potassium channel activity at the intracellular entrance to the pore. J. Biol. Chem. 281: 21131-21138.

Parfenova, L.V., K. Abarca-Heidemann, B.M. Crane, and B.S. Rothberg. (2007). Molecular architecture and divalent cation activation of TvoK, a prokaryotic potassium channel. J. Biol. Chem. 282: 24302-24309.

Park, C.Y., A. Shcheglovitov, and R. Dolmetsch. (2010). The CRAC channel activator STIM1 binds and inhibits L-type voltage-gated calcium channels. Science 330: 101-105.

Parrasia, S., A. Mattarei, A. Furlan, M. Zoratti, and L. Biasutto. (2019). Small-Molecule Modulators of Mitochondrial Channels as Chemotherapeutic Agents. Cell Physiol Biochem 53: 11-43.

Pascual-Caro, C., M. Berrocal, A.M. Lopez-Guerrero, A. Alvarez-Barrientos, E. Pozo-Guisado, C. Gutierrez-Merino, A.M. Mata, and F.J. Martin-Romero. (2018). STIM1 deficiency is linked to Alzheimer''s disease and triggers cell death in SH-SY5Y cells by upregulation of L-type voltage-operated Ca entry. J Mol Med (Berl) 96: 1061-1079.

Patel A.J., F. Maingret, V. Magnone, M. Fosset, M. Lazdunski, E. Honoré. (2000). TWIK-2, an inactivating 2P domain K+ channel. J Biol Chem. 275:28722-30.

Patel, N.H., J. Johannesen, K. Shah, S.K. Goswami, N.J. Patel, D. Ponnalagu, A.R. Kohut, and H. Singh. (2018). Inhibition of BK negatively alters cardiovascular function. Physiol Rep 6: e13748.

Patel, S., D. Churamani, and E. Brailoiu. (2017). NAADP-evoked Ca2+ signals through two-pore channel-1 require arginine residues in the first S4-S5 linker. Cell Calcium 68: 1-4.

Pau, V.P., F.J. Smith, A.B. Taylor, L.V. Parfenova, E. Samakai, M.M. Callaghan, K. Abarca-Heidemann, P.J. Hart, and B.S. Rothberg. (2011). Structure and function of multiple Ca2+-binding sites in a K+ channel regulator of K+ conductance (RCK) domain. Proc. Natl. Acad. Sci. USA 108: 17684-17689.

Pau, V.P., Y. Zhu, Z. Yuchi, Q.Q. Hoang, and D.S. Yang. (2007). Characterization of the C-terminal domain of a potassium channel from Streptomyces lividans (KcsA). J. Biol. Chem. 282: 29163-29169.

Paul, A., Mubashra, and S. Singh. (2021). Identification of a novel calcium activated potassium channel from Leishmania donovani and in silico predictions of its antigenic features. Acta Trop 105922. [Epub: Ahead of Print]

Paulhus, K., L. Ammerman, and E. Glasscock. (2020). Clinical Spectrum of Mutations: New Insights into Episodic Ataxia and Epilepsy Comorbidity. Int J Mol Sci 21:.

Payandeh, J., T. Scheuer, N. Zheng, and W.A. Catterall. (2011). The crystal structure of a voltage-gated sodium channel. Nature 475: 353-358.

Pearlstein, R.A., C.J. Dickson, and V. Hornak. (2016). Contributions of the membrane dipole potential to the function of voltage-gated cation channels and modulation by small molecule potentiators. Biochim. Biophys. Acta. 1859: 177-194. [Epub: Ahead of Print]

Pedarzani, P., J.E. McCutcheon, G. Rogge, B.S. Jensen, P. Christophersen, C. Hougaard, D. Strobaek, and M. Stocker. (2005). Specific enhancement of SK channel activity selectively potentiates the afterhyperpolarizing current IAHP and modulates the firing properties of hippocampal pyrimidal neurons.

Peiter, E., M. Fischer, K. Sidaway, S.K. Roberts, and D. Sanders. (2005). The Saccharomyces cerevisiae Ca2+ channel Cch1pMid1p is essential for tolerance to cold stress and iron toxicity. FEBS Lett. 579: 5697-5703.

Peloquin, J.B., R. Rehak, C.J. Doering, and J.E. McRory. (2007). Functional analysis of congenital stationary night blindness type-2 CACNA1F mutations F742C, G1007R, and R1049W. Neuroscience. 150(2):335-345.

Peretz, A., L. Pell, Y. Gofman, Y. Haitin, L. Shamgar, E. Patrich, P. Kornilov, O. Gourgy-Hacohen, N. Ben-Tal, and B. Attali. (2010). Targeting the voltage sensor of Kv7.2 voltage-gated K+ channels with a new gating-modifier. Proc. Natl. Acad. Sci. USA 107: 15637-15642.

Pérez-Verdaguer, M., J. Capera, R. Martínez-Mármol, M. Camps, N. Comes, M.M. Tamkun, and A. Felipe. (2016). Caveolin interaction governs Kv1.3 lipid raft targeting. Sci Rep 6: 22453.

Perissinotti, L.L., P.M. De Biase, J. Guo, P.C. Yang, M.C. Lee, C.E. Clancy, H.J. Duff, and S.Y. Noskov. (2018). Determinants of Isoform-Specific Gating Kinetics of hERG1 Channel: Combined Experimental and Simulation Study. Front Physiol 9: 207.

Peroz, D., N. Rodriguez, F. Choveau, I. Baró, J. Mérot, and G. Loussouarn. (2008). Kv7.1 (KCNQ1) properties and channelopathies. J. Physiol. 586(7): 1785-1789.

Perry, M.D., S. Wong, C.A. Ng, and J.I. Vandenberg. (2013). Hydrophobic interactions between the voltage sensor and pore mediate inactivation in Kv11.1 channels. J Gen Physiol 142: 275-288.

Peschel, A., F.C. Cardoso, A.A. Walker, T. Durek, M.R.L. Stone, N. Braga Emidio, P.E. Dawson, M. Muttenthaler, and G.F. King. (2020). Two for the Price of One: Heterobivalent Ligand Design Targeting Two Binding Sites on Voltage-Gated Sodium Channels Slows Ligand Dissociation and Enhances Potency. J Med Chem. [Epub: Ahead of Print]

Peters, C.J., M. Vaid, A.J. Horne, D. Fedida, and E.A. Accili. (2009). The molecular basis for the actions of KVbeta1.2 on the opening and closing of the KV1.2 delayed rectifier channel. Channels (Austin) 3: 314-322.

Peters, S., B.A. Thompson, M. Perrin, P. James, D. Zentner, J.M. Kalman, J.I. Vandenberg, and D. Fatkin. (2021). Arrhythmic Phenotypes Are a Defining Feature of Dilated Cardiomyopathy-Associated Variants: A Systematic Review. Circ Genom Precis Med CIRCGEN121003432. [Epub: Ahead of Print]

Phan, K., C.A. Ng, E. David, D. Shishmarev, P.W. Kuchel, J.I. Vandenberg, and M.D. Perry. (2017). The S1 Helix Critically Regulates the Finely-tuned Gating of Kv11.1 Channels. J. Biol. Chem. [Epub: Ahead of Print]

Phartiyal, P., E.M. Jones, and G.A. Robertson. (2007). Heteromeric assembly of human ether-à-go-go-related gene (hERG) 1a/1b channels occurs cotranslationally via N-terminal interactions. J. Biol. Chem. 282: 9874-9882.

Philippar, K., K. Büchsenschütz, M. Abshagen, I. Fuchs, D. Geiger, B. Lacombe, and R. Hedrich. (2003). The K+ channel KZM1 mediates potassium uptake into the phloem and guard cells of the C4 grass Zea mays. J. Biol. Chem. 278: 16973-16981.

Pinilla, E., S. Comerma-Steffensen, J. Prat-Duran, L. Rivera, V.V. Matchkov, N.H. Buus, and U. Simonsen. (2021). Transglutaminase 2 Inhibitor LDN 27219 Age-Dependently Lowers Blood Pressure and Improves Endothelium-Dependent Vasodilation in Resistance Arteries. Hypertension 77: 216-227.

Platoshyn, O., C.V. Remillard, I. Fantozzi, M. Mandegar, T.T. Sison, S. Zhang, E. Burg, and J.X. Yuan. (2004). Diversity of voltage-dependent K+ channels in human pulmonary artery smooth muscle cells. Am. J. Physiol. Lung Cell Mol Physiol 287: L226-238.

Plugge, B., S. Gazzarrini, M. Nelson, R. Cerana, J.L. Van Etten, C. Derst, D. DiFrancesco, A. Moroni, and G. Thiel. (2000). A potassium channel protein encoded by Chlorella virus PBCV-1. Science 287: 1641.

Po, S., S. Roberds, D.J. Snyders, M.M. Tamkun, and P.B. Bennett. (1993). Heteromultimeric assembly of human potassium channels. Molecular basis of a transient outward current? Circ Res 72: 1326-1336.

Poirier, K., G. Viot, L. Lombardi, C. Jauny, P. Billuart, and T. Bienvenu. (2017). Loss of Function of KCNC1 is associated with intellectual disability without seizures. Eur J Hum Genet 25: 560-564.

Pope, L., C. Arrigoni, H. Lou, C. Bryant, A. Gallardo-Godoy, A.R. Renslo, and D.L. Minor, Jr. (2018). Protein and Chemical Determinants of BL-1249 Action and Selectivity for K Channels. ACS Chem Neurosci. [Epub: Ahead of Print]

Porro, A., G. Thiel, A. Moroni, and A. Saponaro. (2020). cyclic AMP Regulation and Its Command in the Pacemaker Channel HCN4. Front Physiol 11: 771.

Powl, A.M., A.J. Miles, and B.A. Wallace. (2012). Transmembrane and extramembrane contributions to membrane protein thermal stability: studies with the NaChBac sodium channel. Biochim. Biophys. Acta. 1818: 889-895.

Pozdnyakov, I., O. Matantseva, and S. Skarlato. (2018). Diversity and evolution of four-domain voltage-gated cation channels of eukaryotes and their ancestral functional determinants. Sci Rep 8: 3539.

Prindle, A., J. Liu, M. Asally, S. Ly, J. Garcia-Ojalvo, and G.M. Süel. (2015). Ion channels enable electrical communication in bacterial communities. Nature 527: 59-63.

Prontera, P., P. Sarchielli, S. Caproni, C. Bedetti, L.M. Cupini, P. Calabresi, and C. Costa. (2018). Epilepsy in hemiplegic migraine: Genetic mutations and clinical implications. Cephalalgia 38: 361-373.

Ptak, C.P., L.G. Cuello, and E. Perozo. (2005). Electrostatic interaction of a K+ channel RCK domain with charged membrane surfaces. Biochemistry 44: 62-71.

Púa-Torrejón, R.C., E. González-Alguacil, V. Soto-Insuga, T. Moreno-Cantero, N.V. Ortiz-Cabrera, M.S. Pérez-Poyato, M.L. Ruiz Falcó-Rojas, and J.J. García-Peñas. (2021). [Variability of the clinical expression of KCNB1 encephalopathy]. Rev Neurol 73: 403-408.

Pyo, Y.J., M. Gierth, J.I. Schroeder, and M.H. Cho. (2010). High-affinity K+ transport in Arabidopsis: AtHAK5 and AKT1 are vital for seedling establishment and postgermination growth under low-potassium conditions. Plant Physiol. 153: 863-875.

Qureshi, S.F., A. Ali, P. John, A.P. Jadhav, A. Venkateshwari, H. Rao, M.P. Jayakrishnan, C. Narasimhan, J. Shenthar, K. Thangaraj, and P. Nallari. (2015). Mutational analysis of SCN5A gene in long QT syndrome. Meta Gene 6: 26-35.

Qureshi, S.F., A. Ali, V. Ananthapur, M.P. Jayakrishnan, N. Calambur, K. Thangaraj, and P. Nallari. (2013). Novel mutations of KCNQ1 in Long QT syndrome. Indian Heart J 65: 552-560.

Radhakrishnan, K., M.A. Kamp, S.A. Siapich, J. Hescheler, M. Lüke, and T. Schneider. (2011). Ca(v)2.3 Ca2+ channel interacts with the G1-subunit of V-ATPase. Cell Physiol Biochem 27: 421-432.

Radicke, S., T. Riedel, D. Cotella, K. Turnow, U. Ravens, M. Schaefer, and E. Wettwer. (2013). Accessory subunits alter the temperature sensitivity of Kv4.3 channel complexes. J Mol. Cell Cardiol 56: 8-18.

Raisch, T., A. Brockmann, U. Ebbinghaus-Kintscher, J. Freigang, O. Gutbrod, J. Kubicek, B. Maertens, O. Hofnagel, and S. Raunser. (2021). Small molecule modulation of the Drosophila Slo channel elucidated by cryo-EM. Nat Commun 12: 7164.

Raja, M., N.K. Olrichs, E. Vales, and H. Schrempf. (2012). Transferring knowledge towards understanding the pore stabilizing variations in K+ channels: pore stability in K+ channels. J. Bioenerg. Biomembr. 44: 199-205.

Rajabian, A., F. Rajabian, F. Babaei, M. Mirzababaei, M. Nassiri-Asl, and H. Hosseinzadeh. (2022). Interaction of Medicinal Plants and Their Active Constituents With Potassium Ion Channels: A Systematic Review. Front Pharmacol 13: 831963.

Ramaswami, M., M. Gautam, A. Kamb, B. Rudy, M.A. Tanouye, and M.K. Mathew. (1990). Human potassium channel genes: Molecular cloning and functional expression. Mol. Cell Neurosci 1: 214-223.

Ramos Gomes F., Romaniello V., Sanchez A., Weber C., Narayanan P., Psol M. and Pardo LA. (2015). Alternatively Spliced Isoforms of KV10.1 Potassium Channels Modulate Channel Properties and Can Activate Cyclin-dependent Kinase in Xenopus Oocytes. J Biol Chem. 290(51):30351-65.

Randich, A.M., L.G. Cuello, S.S. Wanderling, and E. Perozo. (2014). Biochemical and structural analysis of the hyperpolarization-activated K+ channel MVP. Biochemistry 53: 1627-1636.

Rash, J.E., K.G. Vanderpool, T. Yasumura, J. Hickman, J.T. Beatty, and J.I. Nagy. (2016). KV1 channels identified in rodent myelinated axons, linked to Cx29 in innermost myelin: support for electrically active myelin in mammalian saltatory conduction. J Neurophysiol 115: 1836-1859.

Rasmussen, T. (2016). How do mechanosensitive channels sense membrane tension? Biochem Soc Trans 44: 1019-1025.

Rauh, O., M. Urban, L.M. Henkes, T. Winterstein, T. Greiner, J.L. Van Etten, A. Moroni, S.M. Kast, G. Thiel, and I. Schroeder. (2017). Identification of Intrahelical Bifurcated H-Bonds as a New Type of Gate in K+ Channels. J. Am. Chem. Soc. [Epub: Ahead of Print]

Raybaud, A., Y. Dodier, P. Bissonnette, M. Simoes, D.G. Bichet, R. Sauvé, and L. Parent. (2006). The role of the GX9GX3G motif in the gating of high voltage-activated Ca2+ channels. J. Biol. Chem. 281: 39424-39436.

Reed, A.P., G. Bucci, F. Abd-Wahab, and S.J. Tucker. (2016). Dominant-Negative Effect of a Missense Variant in the TASK-2 (KCNK5) K+ Channel Associated with Balkan Endemic Nephropathy. PLoS One 11: e0156456.

Rehak, R., T.M. Bartoletti, J.D. Engbers, G. Berecki, R.W. Turner, and G.W. Zamponi. (2013). Low Voltage Activation of KCa1.1 Current by Cav3-KCa1.1 Complexes. PLoS One 8: e61844.

Reher, T.A., Z. Wang, C.H. Hsueh, P.C. Chang, Z. Pan, M. Kumar, J. Patel, J. Tan, C. Shen, Z. Chen, M.C. Fishbein, M. Rubart, P. Boyden, and P.S. Chen. (2017). Small-Conductance Calcium-Activated Potassium Current in Normal Rabbit Cardiac Purkinje Cells. J Am Heart Assoc 6:.

Reimão, J.Q., F.A. Colombo, V.L. Pereira-Chioccola, and A.G. Tempone. (2011). In vitro and experimental therapeutic studies of the calcium channel blocker bepridil: detection of viable Leishmania (L.) chagasi by real-time PCR. Exp Parasitol 128: 111-115.

Reinson, K., E. Õiglane-Shlik, I. Talvik, U. Vaher, A. Õunapuu, M. Ennok, R. Teek, S. Pajusalu, &.#.2.2.0.;. Murumets, T. Tomberg, S. Puusepp, A. Piirsoo, T. Reimand, and K. Õunap. (2016). Biallelic CACNA1A mutations cause early onset epileptic encephalopathy with progressive cerebral, cerebellar, and optic nerve atrophy. Am J Med Genet A. [Epub: Ahead of Print]

Rems, L., M.A. Kasimova, I. Testa, and L. Delemotte. (2020). Pulsed Electric Fields Can Create Pores in the Voltage Sensors of Voltage-Gated Ion Channels. Biophys. J. [Epub: Ahead of Print]

Ren, D., B. Navarro, H. Xu, L. Yue, Q. Shi, and D.E. Clapham. (2001). A prokaryotic voltage-gated sodium channel. Science 294: 2372-2375.

Renart, M.L., F.N. Barrera, M.L. Molina, J.A. Encinar, J.A. Poveda, A.M. Fernandez, J. Gomez, and J.M. Gonzalez-Ros. (2006). Effects of conducting and blocking ions on the structure and stability of the potassium channel KcsA. J. Biol . Chem. 281: 29905-29915.

Rice, K.L., S.E. Webb, and A.L. Miller. (2022). Localized TPC1-mediated Ca2+ release from endolysosomes contributes to myoseptal junction development in zebrafish. J Cell Sci. [Epub: Ahead of Print]

Rickert, V., D. Kramer, A.L. Schubert, C. Sommer, E. Wischmeyer, and N. Üçeyler. (2019). Globotriaosylceramide-induced reduction of K1.1 channel activity and activation of the Notch1 signaling pathway in skin fibroblasts of male Fabry patients with pain. Exp Neurol 324: 113134. [Epub: Ahead of Print]

Rivera-Torres, I.O., T.B. Jin, M. Cadene, B.T. Chait, and S.F. Poget. (2016). Discovery and characterisation of a novel toxin from Dendroaspis angusticeps, named Tx7335, that activates the potassium channel KcsA. Sci Rep 6: 23904.

Rizzi, S., C. Schwarzer, L. Kremser, H.H. Lindner, and H.G. Knaus. (2015). Identification of potential novel interaction partners of the sodium-activated potassium channels Slick and Slack in mouse brain. Biochem Biophys Rep 4: 291-298.

Robertson, G.A. and J.H. Morais-Cabral. (2019). hERG Function in Light of Structure. Biophys. J. [Epub: Ahead of Print]

Rocheleau, J.M., and W.R. Kobertz. (2007). KCNE Peptides Differently Affect Voltage Sensor Equilibrium and Equilibration Rates in KCNQ1 K+ Channels. J. Gen. Physiol. 131: 59-68.

Rödström, K.E.J., A.K. Kiper, W. Zhang, S. Rinné, A.C.W. Pike, M. Goldstein, L.J. Conrad, M. Delbeck, M.G. Hahn, H. Meier, M. Platzk, A. Quigley, D. Speedman, L. Shrestha, S.M.M. Mukhopadhyay, N.A. Burgess-Brown, S.J. Tucker, T. Müller, N. Decher, and E.P. Carpenter. (2020). A lower X-gate in TASK channels traps inhibitors within the vestibule. Nature. [Epub: Ahead of Print]

Roller, A., G. Natura, H. Bihler, C.L. Slayman, and A. Bertl. (2008). Functional consequences of leucine and tyrosine mutations in the dual pore motifs of the yeast K+ channel, Tok1p. Pflugers Arch 456: 883-896.

Romanenko, V., T. Nakamoto, A. Srivastava, J.E. Melvin, and T. Begenisich. (2006). Molecular identification and physiological roles of parotid acinar cell maxi-K channels. J. Biol. Chem. 281: 27964-27972.

Roosild, T.P., J. Greenwald, M. Vega, S. Castronovo, R. Riek, and S. Choe. (2005). NMR structure of Mistic, a membrane-integrating protein for membrane protein expression. Science 307: 1317-1321.

Rosendo-Pineda, M.J., C.M. Moreno, and L. Vaca. (2020). Role of ion channels during cell division. Cell Calcium 91: 102258. [Epub: Ahead of Print]

Roux, B. and R. MacKinnon. (1999). The cavity and pore helices in the KcsA K+ channel: electrostatic stabilization of monovalent cations. Science 285: 100-102.

Rowe, A.H., Y. Xiao, M.P. Rowe, T.R. Cummins, and H.H. Zakon. (2013). Voltage-gated sodium channel in grasshopper mice defends against bark scorpion toxin. Science 342: 441-446.

Rusconi, R., P. Scalmani, R.R. Cassulini, G. Giunti, A. Gambardella, S. Franceschetti, G. Annesi, E. Wanke, and M. Mantegazza. (2007). Modulatory Proteins Can Rescue a Trafficking Defective Epileptogenic Nav1.1 Na+ Channel Mutant. J. Neurosci. 27(41):11037-11036.

Ruta, V., J. Chen, and R. MacKinnon. (2005). Calibrated measurement of gating-charge arginine displacement in the KvAP voltage-dependent K+ channel. Cell 123: 463-475.

Ruta, V., Y. Jiang, A. Lee, J. Chan, and R. MacKinnon. (2003). Functional analysis of an archaebacterial voltage-dependent K+ channel. Nature 422: 180-185.

Saavedra-Rodriguez, K., L. Urdaneta-Marquez, S. Rajatileka, M. Moulton, A.E. Flores, I. Fernandez-Salas, J. Bisset, M. Rodriguez, P.J. McCall, M.J. Donnelly, H. Ranson, J. Hemingway, and W.C. Black, 4th. (2007). A mutation in the voltage-gated sodium channel gene associated with pyrethroid resistance in Latin American Aedes aegypti. Insect Mol Biol 16: 785-798.

Saha, J., K. Giri, and S. Roy. (2020). Identification and characterization of differentially expressed genes in the rice root following exogenous application of spermidine during salt stress. Genomics 112: 4125-4136.

Sahoo, N., R. Schönherr, T. Hoshi, and S.H. Heinemann. (2012). Cysteines control the N- and C-linker-dependent gating of KCNH1 potassium channels. Biochim. Biophys. Acta. 1818: 1187-1195.

Sahu, I.D., G. Dixit, W.D. Reynolds, R. Kaplevatsky, B.D. Harding, C.K. Jaycox, R.M. McCarrick, and G.A. Lorigan. (2020). Characterization of the Human KCNQ1 Voltage Sensing Domain (VSD) in Lipodisq Nanoparticles for Electron Paramagnetic Resonance (EPR) Spectroscopic Studies of Membrane Proteins. J Phys Chem B 124: 2331-2342.

Sait, L.G., A. Sula, M.R. Ghovanloo, D. Hollingworth, P.C. Ruben, and B.A. Wallace. (2020). Cannabidiol interactions with voltage-gated sodium channels. Elife 9:.

Saito, S., N. Hoshi, L. Zulkifli, S. Widyastuti, S. Goshima, I. Dreyer, and N. Uozumi. (2017). Identification of regions responsible for the function of the plant K+ channels KAT1 and AKT2 in Saccharomyces cerevisiae and Xenopus laevis oocytes. Channels (Austin) 1-7. [Epub: Ahead of Print]

Sajman, J., M. Trus, D. Atlas, and E. Sherman. (2017). The L-type Voltage-Gated Calcium Channel co-localizes with Syntaxin 1A in nano-clusters at the plasma membrane. Sci Rep 7: 11350.

Sakurai, Y., A.A. Kolokoltsov, C.C. Chen, M.W. Tidwell, W.E. Bauta, N. Klugbauer, C. Grimm, C. Wahl-Schott, M. Biel, and R.A. Davey. (2015). Ebola virus. Two-pore channels control Ebola virus host cell entry and are drug targets for disease treatment. Science 347: 995-998.

Salkoff, L. and T. Jegla. (1995). Surfing the DNA databases for K+ channels nets yet more diversity. Neuron 15: 489-492.

Sanchez-Sandoval, A.L., Z. Herrera Carrillo, C.E. Díaz Velásquez, D.M. Delgadillo, H.M. Rivera, and J.C. Gomora. (2018). Contribution of S4 segments and S4-S5 linkers to the low-voltage activation properties of T-type CaV3.3 channels. PLoS One 13: e0193490.

Sánchez-Solano, A., A.A. Islas, T. Scior, B. Paiz-Candia, L. Millan-PerezPeña, and E.M. Salinas-Stefanon. (2016). Characterization of specific allosteric effects of the Na+ channel β1 subunit on the Nav1.4 isoform. Eur Biophys. J. [Epub: Ahead of Print]

Sansom, M.S. (1998). Ion channels: a first view of K+ channels in atomic glory. Curr. Biol. 8: R450-452.

Santi, C.M., A. Yuan, G. Fawcett, Z.W. Wang, A. Butler, M.L. Nonet, A. Wei, P. Rojas, and L. Salkoff. (2003). Dissection of K+ currents in Caenorhabditis elegans muscle cells by genetics and RNA interference. Proc. Natl. Acad. Sci. USA 100: 14391-14396.

Santos, J.S., S.M. Grigoriev, and M. Montal. (2008). Molecular template for a voltage sensor in a novel K+ channel. III. Functional reconstitution of a sensorless pore module from a prokaryotic Kv channel. J Gen Physiol 132: 651-666.

Saponaro, A., D. Bauer, M.H. Giese, P. Swuec, A. Porro, F. Gasparri, A.S. Sharifzadeh, A. Chaves-Sanjuan, L. Alberio, G. Parisi, G. Cerutti, O.B. Clarke, K. Hamacher, H.M. Colecraft, F. Mancia, W.A. Hendrickson, S.A. Siegelbaum, D. DiFrancesco, M. Bolognesi, G. Thiel, B. Santoro, and A. Moroni. (2021). Gating movements and ion permeation in HCN4 pacemaker channels. Mol. Cell 81: 2929-2943.e6.

Savalli N., Pantazis A., Yusifov T., Sigg D. and Olcese R. (2012). The contribution of RCK domains to human BK channel allosteric activation. J Biol Chem. 287(26):21741-50.

Scherer, S., M. Arheit, J. Kowal, X. Zeng, and H. Stahlberg. (2014). Single particle 3D reconstruction for 2D crystal images of membrane proteins. J Struct Biol 185: 267-277.

Schiffer, C., S. Rieger, C. Brenker, S. Young, H. Hamzeh, D. Wachten, F. Tüttelmann, A. Röpke, U.B. Kaupp, T. Wang, A. Wagner, C. Krallmann, S. Kliesch, C. Fallnich, and T. Strünker. (2020). Rotational motion and rheotaxis of human sperm do not require functional CatSper channels and transmembrane Ca signaling. EMBO. J. 39: e102363.

Schmidt, D., Q.X. Jiang, and R. MacKinnon. (2006). Phospholipids and the origin of cationic gating charges in voltage sensors. Nature 444: 775-779.

Schmidt, R.S., J.P. Macêdo, M.E. Steinmann, A.G. Salgado, P. Bütikofer, E. Sigel, D. Rentsch, and P. Mäser. (2018). Transporters of Trypanosoma brucei-phylogeny, physiology, pharmacology. FEBS J. 285: 1012-1023.

Schroeder, J.I. (2003). Knockout of the guard cell K+ out channel and stomatal movements. Proc. Natl. Acad. Sci. USA 100: 4976-4977.

Schünke, S., M. Stoldt, J. Lecher, U.B. Kaupp, and D. Willbold. (2011). Structural insights into conformational changes of a cyclic nucleotide-binding domain in solution from Mesorhizobium loti K1 channel. Proc. Natl. Acad. Sci. USA 108: 6121-6126.

Schwarzer, S., L. Kolacna, H. Lichtenberg-Fraté, H. Sychrova, and J. Ludwig. (2008). Functional expression of the voltage-gated neuronal mammalian potassium channel rat ether à go-go1 in yeast. FEMS Yeast Res 8(3): 405-413.

Schwenk, J., G. Zolles, N.G. Kandias, I. Neubauer, H. Kalbacher, M. Covarrubias, B. Fakler, and D. Bentrop. (2008). NMR analysis of KChIP4a reveals structural basis for control of surface expression of Kv4 channel complexes. J. Biol. Chem. 283: 18937-18946.

Scicchitano, P., S. Carbonara, G. Ricci, C. Mandurino, M. Locorotondo, G. Bulzis, M. Gesualdo, A. Zito, R. Carbonara, I. Dentamaro, G. Riccioni, and M.M. Ciccone. (2012). HCN Channels and Heart Rate. Molecules 17: 4225-4235.

Seebohm, G., P. Westenskow, F. Lang, and M.C. Sanguinetti. (2005). Mutation of colocalized residues of the pore helix and transmembrane segments S5 and S6 disrupt deactivation and modify inactivation of KCNQ1 K+ channels. J. Physiol. 563: 359-368.

Seeger, H.M., L. Aldrovandi, A. Alessandrini, and P. Facci. (2010). Changes in single K+ channel behavior induced by a lipid phase transition. Biophys. J. 99: 3675-3683.

Seikel, E. and J.S. Trimmer. (2009). Convergent modulation of Kv4.2 channel alpha subunits by structurally distinct DPPX and KChIP auxiliary subunits. Biochemistry 48: 5721-5730.

Selvakumar, D., M.J. Drescher, J.R. Dowdall, K.M. Khan, J.S. Hatfield, N.A. Ramakrishnan, and D.G. Drescher. (2012). CNGA3 is expressed in inner ear hair cells and binds to an intracellular C-terminus domain of EMILIN1. Biochem. J. 443: 463-476.

Senatore A. and Spafford JD. (2013). A uniquely adaptable pore is consistent with NALCN being an ion sensor. Channels (Austin). 7(2):60-8.

Shakkottai, V.G., I. Regaya, H. Wulff, Z. Fajloun, H. Tomita, M. Fathallah, M.D. Cahalan, J.J. Gargus, J.-M. Sabatier, and K.G. Chandy. (2001). Design and characterization of a highly selective peptide inhibitor of the small conductance calcium-activated K+ channel, SkCa2. J. Biol. Chem. 276: 43145-43151.

Sharmin, N. and W.J. Gallin. (2016). Intramolecular interactions that control voltage sensitivity in the jShak1 potassium channel from Polyorchis penicillatus. J Exp Biol. [Epub: Ahead of Print]

Shaya, D., M. Kreir, R.A. Robbins, S. Wong, J. Hammon, A. Brüggemann, and D.L. Minor, Jr. (2011). Voltage-gated sodium channel (NaV) protein dissection creates a set of functional pore-only proteins. Proc. Natl. Acad. Sci. USA 108: 12313-12318.

She, J., J. Guo, and Y. Jiang. (2022). Structure and Function of Plant and Mammalian TPC Channels. Handb Exp Pharmacol. [Epub: Ahead of Print]

She, J., J. Guo, Q. Chen, W. Zeng, Y. Jiang, and X.C. Bai. (2018). Structural insights into the voltage and phospholipid activation of the mammalian TPC1 channel. Nature. [Epub: Ahead of Print]

Sheikh, A.S. and K. Ranjan. (2014). Brugada syndrome: a review of the literature. Clin Med 14: 482-489.

Shen, H., Q. Zhou, X. Pan, Z. Li, J. Wu, and N. Yan. (2017). Structure of a eukaryotic voltage-gated sodium channel at near-atomic resolution. Science 355:.

Shen, H., Z. Li, Y. Jiang, X. Pan, J. Wu, B. Cristofori-Armstrong, J.J. Smith, Y.K.Y. Chin, J. Lei, Q. Zhou, G.F. King, and N. Yan. (2018). Structural basis for the modulation of voltage-gated sodium channels by animal toxins. Science 362:.

Shepard A.R., Rae J.L.. (1999). Electrically silent potassium channel subunits from human lens epithelium. Am. J. Physiol. 277: C412-424

Shi W., R.S. Wymore, H.S. Wang, Z. Pan, I.S. Cohen, D. McKinnon, J.E. Dixon. (1997). Identification of two nervous system-specific members of the erg potassium channel gene family. J. Neurosci. 17: 9423-9432

Shi, J., G. Krishnamoorthy, Y. Yang, L. Hu, N. Chaturvedi, D. Harilal, J. Qin, and J. Cui. (2002). Mechanism of magnesium activation of calcium-activated potassium channels. Nature 418: 876-880.

Shi, N., S. Ye, A. Alam, L. Chen, and Y. Jiang. (2006). Atomic structure of a Na+- and K+-conducting channel. Nature 440: 570-574.

Shimizu, H., M. Iwamoto, T. Konno, A. Nihei, Y.C. Sasaki, and S. Oiki. (2008). Global twisting motion of single molecular KcsA potassium channel upon gating. Cell 132: 67-78.

Shimomura, T., K. Irie, H. Nagura, T. Imai, and Y. Fujiyoshi. (2011). Arrangement and mobility of the voltage sensor domain in prokaryotic voltage-gated sodium channels. J. Biol. Chem. 286: 7409-7417.

Shishmarev, D. (2020). Excitation-contraction coupling in skeletal muscle: recent progress and unanswered questions. Biophys Rev. [Epub: Ahead of Print]

Sigworth, F.J. (1993). Voltage gating of ion channels. Quart. Rev. Biophys. 27: 1-40.

Silverå Ejneby, M., A. Gromova, N.E. Ottosson, S. Borg, A. Estrada-Mondragón, S. Yazdi, P. Apostolakis, F. Elinder, and L. Delemotte. (2021). Resin-acid derivatives bind to multiple sites on the voltage-sensor domain of the Shaker potassium channel. J Gen Physiol 153:.

Silverman, W.R., and L. Heginbotham. (2007). The MlotiK1 channel transports ions along the canonical conduction pore. FEBS Lett. 581: 5024-5028.

Silverman, W.R., J.P. Bannister, and D.M. Papazian. (2004). Binding site in eag voltage sensor accommodates a variety of ions and is accessible in closed channel. Biophys. J. 87: 3110-3121.

Singh, A., M. Gebhart, R. Fritsch, M.J. Sinnegger-Brauns, C. Poggiani, J.C. Hoda, J. Engel, C. Romanin, J. Striessnig, and A. Koschak. (2008). Modulation of voltage- and Ca2+-dependent gating of CaV1.3 L-type calcium channels by alternative splicing of a C-terminal regulatory domain. J. Biol. Chem. 283: 20733-20744.

Siotto, F., C. Martin, O. Rauh, J.L. Van Etten, I. Schroeder, A. Moroni, and G. Thiel. (2014). Viruses infecting marine picoplancton encode functional potassium ion channels. Virology 466-467: 103-111.

Skerritt, M.R. and D.L. Campbell. (2007). Role of S4 positively charged residues in the regulation of Kv4.3 inactivation and recovery. Am. J. Physiol. Cell Physiol. 293: C906-914.

Sklodowski, K., J. Riedelsberger, N. Raddatz, G. Riadi, J. Caballero, I. Chérel, W. Schulze, A. Graf, and I. Dreyer. (2017). The receptor-like pseudokinase MRH1 interacts with the voltage-gated potassium channel AKT2. Sci Rep 7: 44611.

Smith, J.J., T.R. Cummins, S. Alphy, and K.M. Blumenthal. (2007). Molecular interactions of the gating modifier toxin ProTx-II with NaV 1.5: implied existence of a novel toxin binding site coupled to activation. J. Biol. Chem. 282: 12687-12697.

Soh, H. and S.A. Goldstein. (2008). I SA channel complexes include four subunits each of DPP6 and Kv4.2. J. Biol. Chem. 283: 15072-15077.

Sojo, L.E., R. Kwan, C. Dang, M. Tung, and J. Li. (2019). On the Feasibility of Quantifying Sodium Channel Na 1.6 Protein in Mouse Brain using targeted UHPLC-ESI- MRM Mass Spectrometry. Rapid Commun Mass Spectrom. [Epub: Ahead of Print]

Sokolov, S., T. Scheuer, and W.A. Catterall. (2007). Gating pore current in an inherited ion channelopathy. Nature 446: 76-78.

Sokolov, S., T. Scheuer, and W.A. Catterall. (2010). Ion permeation and block of the gating pore in the voltage sensor of NaV1.4 channels with hypokalemic periodic paralysis mutations. J Gen Physiol 136: 225-236.

Soldovieri, M.V., Castaldo, P., Iodice, L., Miceli, F., Barrese, V., Bellini, G., Miraglia del Giudice, E., Pascotto, A., Bonatti, S., Annunziato, L., and Taglialatela M. (2006). Decreased subunit stability as a novel mechanism for potassium current impairment by a KCNQ2 C terminus mutation causing benign familial neonatal convulsions. J. Biol. Chem. 281: 418-428.

Soldovieri, M.V., P. Ambrosino, I. Mosca, F. Miceli, C. Franco, L.M.T. Canzoniero, B. Kline-Fath, E.C. Cooper, C. Venkatesan, and M. Taglialatela. (2019). Epileptic Encephalopathy In A Patient With A Novel Variant In The Kv7.2 S2 Transmembrane Segment: Clinical, Genetic, and Functional Features. Int J Mol Sci 20:.

Song, K.C., A.V. Molina, R. Chen, I.A. Gagnon, Y.H. Koh, B. Roux, and T.R. Sosnick. (2021). Folding and misfolding of potassium channel monomers during assembly and tetramerization. Proc. Natl. Acad. Sci. USA 118:.

Song, L., Z.F. Zhang, L.K. Hu, P.H. Zhang, Z.Z. Cao, Z.P. Liu, P.P. Zhang, and J.H. Ma. (2020). Curcumin, a Multi-Ion Channel Blocker That Preferentially Blocks Late Na Current and Prevents I/R-Induced Arrhythmias. Front Physiol 11: 978.

Sonkusare, S.K., A.D. Bonev, J. Ledoux, W. Liedtke, M.I. Kotlikoff, T.J. Heppner, D.C. Hill-Eubanks, and M.T. Nelson. (2012). Elementary Ca2+ signals through endothelial TRPV4 channels regulate vascular function. Science 336: 597-601.

Sottocornola, B., S. Visconti, S. Orsi, S. Gazzarrini, S. Giacometti, C. Olivari, L. Camoni, P. Aducci, M. Marra, A. Abenavoli, G. Thiel, and A. Moroni. (2006). The potassium channel KAT1 is activated by plant and animal 14-3-3 proteins. J. Biol. Chem. 281: 35735-35741.

Splawski, I., Yoo, D.S., Stotz, S.C., Cherry, A., Clapham, D.E., and Keating, M.T. (2006). CACNA1H mutations in autism spectrum disorders. J. Biol. Chem. 281: 22085-22091.

Spork, S., J.A. Hiss, K. Mandel, M. Sommer, T.W. Kooij, T. Chu, G. Schneider, U.G. Maier, and J.M. Przyborski. (2009). An unusual ERAD-like complex is targeted to the apicoplast of Plasmodium falciparum. Eukaryot. Cell. 8: 1134-1145.

Starace, D.M. and F. Bezanilla. (2004). A proton pore in a potassium channel voltage sensor reveals a focused electric field. Nature 427: 548-553.

Stingl, K., S. Brandt, E.M. Uhlemann, R. Schmid, K. Altendorf, C. Zeilinger, C. Ecobichon, A. Labigne, E.P. Bakker, and H. de Reuse. (2007). Channel-mediated potassium uptake in Helicobacter pylori is essential for gastric colonization. EMBO. J. 26: 232-241.

Struyk, A.F. and S.C. Cannon. (2007). A Na+ channel mutation linked to hypokalemic periodic paralysis exposes a proton-selective gating pore. J Gen Physiol 130: 11-20.

Su, K., H. Kyaw, P. Fan, Z. Zeng, B.K. Shell, K.C. Carter, and Y. Li. (1997). Isolation, characterization, and mapping of two human potassium channels. Biochem. Biophys. Res. Commun. 241: 675-681.

Suh, B.C., K. Leal, and B. Hille. (2010). Modulation of high-voltage activated Ca2+ channels by membrane phosphatidylinositol 4,5-bisphosphate. Neuron. 67: 224-238.

Sun, A.X., Q. Yuan, M. Fukuda, W. Yu, H. Yan, G.G.Y. Lim, M.H. Nai, G.A. D''Agostino, H.D. Tran, Y. Itahana, D. Wang, H. Lokman, K. Itahana, S.W.L. Lim, J. Tang, Y.Y. Chang, M. Zhang, S.A. Cook, O.J.L. Rackham, C.T. Lim, E.K. Tan, H.H. Ng, K.L. Lim, Y.H. Jiang, and H.S. Je. (2019). Potassium channel dysfunction in human neuronal models of Angelman syndrome. Science 366: 1486-1492.

Sun, J., S. Luo, K.J. Suetterlin, J. Song, J. Huang, W. Zhu, J. Xi, L. Zhou, J. Lu, J. Lu, C. Zhao, M.G. Hanna, R. Männikkö, E. Matthews, and K. Qiao. (2021). Clinical and genetic spectrum of a Chinese cohort with SCN4A gene mutations. Neuromuscul Disord. [Epub: Ahead of Print]

Suzuki, T. and K. Takimoto. (2004). Selective expression of HERG and Kv2 channels influences proliferation of uterine cancer cells. Int J Oncol 25: 153-159.

Suzuki, T., A. Hansen, and M.C. Sanguinetti. (2016). Hydrophobic interactions between the S5 segment and the pore helix stabilizes the closed state of Slo2.1 potassium channels. Biochim. Biophys. Acta. 1858: 783-792.

Swayne, L.A., A. Mezghrani, P. Lory, J. Nargeot, and A. Monteil. (2010). The NALCN ion channel is a new actor in pancreatic β-cell physiology. Islets 2: 54-56.

Sweet, T.B. and D.H. Cox. (2008). Measurements of the BKCa channel's high-affinity Ca2+ binding constants: effects of membrane voltage. J Gen Physiol 132: 491-505.

Szabó, G., V. Farkas, M. Grunnet, A. Mohácsi, and P.P. Nánási. (2011). Enhanced repolarization capacity: new potential antiarrhythmic strategy based on HERG channel activation. Curr. Med. Chem. 18: 3607-3621.

Szabò, I., J. Bock, A. Jekle, M. Soddemann, C. Adams, F. Lang, M. Zoratti, and E. Gulbins. (2005). A novel potassium channel in lymphocyte mitochondria. J. Biol. Chem. 280: 12790-12798.

Tada, Y., K. Kume, Y. Matsuda, T. Kurashige, Y. Kanaya, R. Ohsawa, H. Morino, H. Tabu, S. Kaneko, T. Suenaga, A. Kakizuka, and H. Kawakami. (2020). Genetic screening for potassium channel mutations in Japanese autosomal dominant spinocerebellar ataxia. J Hum Genet. [Epub: Ahead of Print]

Takahashi, S., K. Inamura, J. Yarimizu, M. Yamazaki, N. Murai, and K. Ni. (2017). Neurochemical and neuropharmacological characterization of ASP2905, a novel potent selective inhibitor of the potassium channel KCNH3. Eur J Pharmacol 810: 26-35.

Tang, C., X. Zhou, P.T. Nguyen, Y. Zhang, Z. Hu, C. Zhang, V. Yarov-Yarovoy, P.G. DeCaen, S. Liang, and Z. Liu. (2017). A novel tarantula toxin stabilizes the deactivated voltage sensor of bacterial sodium channel. FASEB J. 31: 3167-3178.

Tang, X.D., R. Xu, M.F. Reynolds, M.L. Garcia, S.H. Heinemann, and T. Hoshi. (2003). Haem can bind to and inhibit mammalian calcium-dependent Slo1 BK channels. Nature 425: 531-535.

Tao, X. and R. MacKinnon. (2019). Molecular structures of the human Slo1 K channel in complex with β4. Elife 8:.

Tao, X., A. Lee, W. Limapichat, D.A. Dougherty, and R. MacKinnon. (2010). A gating charge transfer center in voltage sensors. Science 328: 67-73.

Tariq, K., A. Ali, T.G.E. Davies, E. Naz, L. Naz, S. Sohail, M. Hou, and F. Ullah. (2019). RNA interference-mediated knockdown of voltage-gated sodium channel (MpNa) gene causes mortality in peach-potato aphid, Myzus persicae. Sci Rep 9: 5291.

Tavassoli, T., A. Kolevzon, A.T. Wang, J. Curchack-Lichtin, D. Halpern, L. Schwartz, S. Soffes, L. Bush, D. Grodberg, G. Cai, and J.D. Buxbaum. (2014). De novo SCN2A splice site mutation in a boy with Autism spectrum disorder. BMC Med Genet 15: 35.

Taylor, K.C. and C.R. Sanders. (2016). Regulation of KCNQ/Kv7 family voltage-gated K+ channels by lipids. Biochim. Biophys. Acta. [Epub: Ahead of Print]

Telezhkin V., Thomas AM., Harmer SC., Tinker A. and Brown DA. (2013). A basic residue in the proximal C-terminus is necessary for efficient activation of the M-channel subunit Kv7.2 by PI(4,5)P(2). Pflugers Arch. 465(7):945-53.

Tempone, A.G., N.N. Taniwaki, and J.Q. Reimão. (2009). Antileishmanial activity and ultrastructural alterations of Leishmania (L.) chagasi treated with the calcium channel blocker nimodipine. Parasitol Res 105: 499-505.

Terlau, H. and W. Stühmer. (1998). Structure and function of voltage-gated ion channels. Naturwissenschaften 85: 437-444.

Thiel G., Baumeister D., Schroeder I., Kast SM., Van Etten JL. and Moroni A. (2011). Minimal art: or why small viral K(+) channels are good tools for understanding basic structure and function relations. Biochim Biophys Acta. 1808(2):580-8.

Thomas, D., L.D. Plant, C.M. Wilkens, Z.A. McCrossan, and S.A. Goldstein. (2008). Alternative translation initiation in rat brain yields K2P2.1 potassium channels permeable to sodium. Neuron. 58: 859-870.

Thomson, A.S. and B.S. Rothberg. (2010). Voltage-dependent inactivation gating at the selectivity filter of the MthK K+ channel. J Gen Physiol 136: 569-579.

Tian, F., Y. Qiu, X. Lan, M. Li, H. Yang, and Z. Gao. (2019). A Small-Molecule Compound Selectively Activates K2P Channel TASK-3 by Acting at Two Distant Clusters of Residues. Mol Pharmacol 96: 26-35.

Tian, L., H. McClafferty, L. Chen, and M.J. Shipston. (2008). Reversible tyrosine protein phosphorylation regulates large conductance voltage- and calcium-activated potassium channels via cortactin. J. Biol. Chem. 283: 3067-3076.

Tian, L., O. Jeffries, H. McClafferty, A. Molyvdas, I.C. Rowe, F. Saleem, L. Chen, J. Greaves, L.H. Chamberlain, H.G. Knaus, P. Ruth, and M.J. Shipston. (2008). Palmitoylation gates phosphorylation-dependent regulation of BK potassium channels. Proc. Natl. Acad. Sci. USA 105: 21006-21011.

Tian, Y., S.H. Heinemann, and T. Hoshi. (2019). Large-conductance Ca- and voltage-gated K channels form and break interactions with membrane lipids during each gating cycle. Proc. Natl. Acad. Sci. USA 116: 8591-8596.

Tikhonov, D.B. and B.S. Zhorov. (2017). Conservation and Variability of the Pore-Lining Helices in P-Loop Channels. Channels (Austin) 0. [Epub: Ahead of Print]

Tipparaju, S.M., X.P. Li, P.J. Kilfoil, B. Xue, V.N. Uversky, A. Bhatnagar, and O.A. Barski. (2012). Interactions between the C-terminus of Kv1.5 and Kvβ regulate pyridine nucleotide-dependent changes in channel gating. Pflugers Arch 463: 799-818.

Tippens, A.L. and A. Lee. (2007). Caldendrin, a neuron-specific modulator of Cav1.2 (L-type) Ca2+ channels. J. Biol. Chem. 282: 8464-8473.

Tombola, F., M.M. Pathak, and E.Y. Isacoff. (2005). Voltage-sensing arginines in a potassium channel permeate and occlude cation-selective pores. Neuron. 45: 379-388.

Tombola, F., M.M. Pathak, P. Gorostiza, and E.Y. Isacoff. (2007). The twisted ion-permeation pathway of a resting voltage-sensing domain. Nature 445: 546-549.

Tomczak, A.P., J. Fernández-Trillo, S. Bharill, F. Papp, G. Panyi, W. Stühmer, E.Y. Isacoff, and L.A. Pardo. (2017). A new mechanism of voltage-dependent gating exposed by KV10.1 channels interrupted between voltage sensor and pore. J Gen Physiol. [Epub: Ahead of Print]

Tonggu, L. and L. Wang. (2022). Structure of the Human BK Ion Channel in Lipid Environment. Membranes (Basel) 12:.

Toro L., Li M., Zhang Z., Singh H., Wu Y. and Stefani E. (2014). MaxiK channel and cell signalling. Pflugers Arch. 466(5):875-86.

Triano, I., F.N. Barrera, M.L. Renart, M.L. Molina, G. Fernández-Ballester, J.A. Poveda, A.M. Fernández, J.A. Encinar, A.V. Ferrer-Montiel, D. Otzen, and J.M. González-Ros. (2010). Occupancy of nonannular lipid binding sites on KcsA greatly increases the stability of the tetrameric protein. Biochemistry 49: 5397-5404.

Tronin, A.Y., L.J. Maciunas, K.C. Grasty, P.J. Loll, H.A. Ambaye, A.A. Parizzi, V. Lauter, A.D. Geragotelis, J.A. Freites, D.J. Tobias, and J.K. Blasie. (2019). Voltage-Dependent Profile Structures of a Kv-Channel via Time-Resolved Neutron Interferometry. Biophys. J. [Epub: Ahead of Print]

Tsai, C.J., K. Tani, K. Irie, Y. Hiroaki, T. Shimomura, D.G. McMillan, G.M. Cook, G.F. Schertler, Y. Fujiyoshi, and X.D. Li. (2013). Two alternative conformations of a voltage-gated sodium channel. J. Mol. Biol. 425: 4074-4088.

Tsai, S.Y., C.C. Huang, P.H. Chen, A. Tripathi, Y.R. Wang, Y.L. Wang, and J.C. Chen. (2021). Rapid Drug-Screening Platform Using Field-Effect Transistor-Based Biosensors: A Study of Extracellular Drug Effects on Transmembrane Potentials. Anal Chem. [Epub: Ahead of Print]

Tsai, W.H., C. Grauffel, M.Y. Huang, S. Postić, M.S. Rupnik, C. Lim, and S.B. Yang. (2022). Allosteric coupling between transmembrane segment 4 and the selectivity filter of TALK1 potassium channels regulates their gating by extracellular pH. J. Biol. Chem. 101998. [Epub: Ahead of Print]

Tsorin, I.B., I.Y. Teplov, V.P. Zinchenko, M.B. Vititnova, E.M. Tsyrlina, M.S. Yunusov, and S.A. Kryzhanovskii. (2022). Analysis of Electrophysiological Mechanisms of N-Deacetyllapaconitine Monochlorhydrate, the Main Metabolite of Lappaconitine Hydrobromide. Bull Exp Biol Med 173: 219-223.

Tu, L. and C. Deutsch. (2017). Determinants of Helix Formation for a Kv1.3 Transmembrane Segment inside the Ribosome Exit Tunnel. J. Mol. Biol. [Epub: Ahead of Print]

Tuluc, P., B. Benedetti, P. Coste de Bagneaux, M. Grabner, and B.E. Flucher. (2016). Two distinct voltage-sensing domains control voltage sensitivity and kinetics of current activation in CaV1.1 calcium channels. J Gen Physiol 147: 437-449.

Turner, R.W., H. Asmara, J.D. Engbers, J. Miclat, A.P. Rizwan, G. Sahu, and G.W. Zamponi. (2016). Assessing the role of IKCa channels in generating the sAHP of CA1 hippocampal pyramidal cells. Channels (Austin) 0. [Epub: Ahead of Print]

Twiner, M.J., G.J. Doucette, A. Rasky, X.P. Huang, B.L. Roth, and M.C. Sanguinetti. (2012). Marine algal toxin azaspiracid is an open-state blocker of HERG potassium channels. Chem Res Toxicol 25: 1975-1984.

Uehara, A., Y. Nakamura, T. Shioya, S. Hirose, M. Yasukochi, and K. Uehara. (2008). Altered KCNQ3 Potassium Channel Function Caused by the W309R Pore-Helix Mutation Found in Human Epilepsy. J. Membr Biol. 222: 55-63.

Ulmschneider, M.B., C. Bagnéris, E.C. McCusker, P.G. Decaen, M. Delling, D.E. Clapham, J.P. Ulmschneider, and B.A. Wallace. (2013). Molecular dynamics of ion transport through the open conformation of a bacterial voltage-gated sodium channel. Proc. Natl. Acad. Sci. USA 110: 6364-6369.

Ungar, D., A. Barth, W. Haase, A. Kaunzinger, E. Lewitzki, T. Ruiz, H. Reiländer, and H. Michel. (2001). Analysis of a putative voltage-gated prokaryotic potassium channel. Eur. J. Biochem. 268: 5386-5396.

Vega-Saenz de Miera, E.C. (2004). Modification of Kv2.1 K+ currents by the silent Kv10 subunits. Brain Res Mol Brain Res 123: 91-103.

Vemana, S., S. Pandey, and H.P. Larsson. (2004). S4 movement in a mammalian HCN channel. J Gen Physiol 123: 21-32.

Verma, R., C. Malik, S. Azmi, S. Srivastava, S. Ghosh, and J.K. Ghosh. (2011). A synthetic S6 segment derived from KvAP channel self-assembles, permeabilizes lipid vesicles, and exhibits ion channel activity in bilayer lipid membrane. J. Biol. Chem. 286: 24828-24841.

Vicente, R., A. Escalada, N. Villalonga, L. Texido, M. Roura-Ferrer, M. Martin-Satue, C. Lopez-Iglesias, C. Soler, C. Solsona, M.M. Tamkun, and A. Felipe. (2006). Association of Kv1.5 and Kv1.3 contributes to the major voltage-dependent K+ channel in macrophages. J. Biol. Chem. 281: 37675-37685.

Vicente-Carrillo, A., M. Álvarez-Rodríguez, and H. Rodríguez-Martínez. (2017). The CatSper channel modulates boar sperm motility during capacitation. Reprod Biol. [Epub: Ahead of Print]

Vijayaragavan, K., M. Boutjdir, and M. Chahine. (2004). Modulation of Nav1.7 and Nav1.8 peripheral nerve sodium channels by protein kinase A and protein kinase C. J Neurophysiol 91: 1556-1569.

Vinekar, R.S. and R. Sowdhamini. (2016). Three-dimensional modelling of the voltage-gated sodium ion channel from Anopheles gambiae reveals spatial clustering of evolutionarily conserved acidic residues at the extracellular sites. Curr Neuropharmacol. [Epub: Ahead of Print]

Wagnon, J.L., B.S. Barker, M. Ottolini, Y. Park, A. Volkheimer, P. Valdez, M.E.M. Swinkels, M.K. Patel, and M.H. Meisler. (2017). Loss-of-function variants of in intellectual disability without seizures. Neurol Genet 3: e170.

Wan, J., M. Chen, Z. Wang, T.H. Everett, 4th, M. Rubart-von der Lohe, C. Shen, Z. Qu, J.N. Weiss, P.A. Boyden, and P.S. Chen. (2019). Small-conductance calcium-activated potassium current modulates the ventricular escape rhythm in normal rabbit hearts. Heart Rhythm 16: 615-623.

Wang, A.W., R. Yang, and H.T. Kurata. (2016). Sequence determinants of subtype-specific actions of KCNQ channel openers. J. Physiol. [Epub: Ahead of Print]

Wang, C., Y.F. Chen, X.Q. Quan, H. Wang, R. Zhang, J.H. Xiao, J.L. Wang, C.T. Zhang, J.Z. Xiang, and Q. Tang. (2015). Effects of neferine on Kv4.3 channels expressed in HEK293 cells and ex vivo electrophysiology of rabbit hearts. Acta Pharmacol Sin 36: 1451-1461.

Wang, G. and M. Covarrubias. (2006). Voltage-dependent gating rearrangements in the intracellular T1-T1 interface of a K+ channel. J Gen Physiol 127: 391-400.

Wang, G.K., C. Russell, and S.Y. Wang. (2004). State-dependent block of voltage-gated Na+ channels by amitriptyline via the local anesthetic receptor and its implication for neuropathic pain. Pain 110: 166-174.

Wang, H., Y. Yan, Q. Liu, Y. Huang, Y. Shen, L. Chen, Y. Chen, Q. Yang, Q. Hao, K. Wang, and J. Chai. (2007). Structural basis for modulation of Kv4 K+ channels by auxiliary KChIP subunits. Nat Neurosci 10: 32-39.

Wang, L., X. Meng, Z. Yuchi, Z. Zhao, D. Xu, D. Fedida, Z. Wang, and C. Huang. (2015). De Novo Mutation in the SCN5A Gene Associated with Brugada Syndrome. Cell Physiol Biochem 36: 2250-2262.

Wang, T., S. Young, H. Krenz, F. Tüttelmann, A. Röpke, C. Krallmann, S. Kliesch, X.H. Zeng, C. Brenker, and T. Strünker. (2020). The Ca2+ channel CatSper is not activated by cAMP/PKA signaling but directly affected by chemicals used to probe the action of cAMP and PKA. J. Biol. Chem. [Epub: Ahead of Print]

Wang, X., X. Zhang, X.P. Dong, M. Samie, X. Li, X. Cheng, A. Goschka, D. Shen, Y. Zhou, J. Harlow, M.X. Zhu, D.E. Clapham, D. Ren, and H. Xu. (2012). TPC Proteins Are Phosphoinositide- Activated Sodium-Selective Ion Channels in Endosomes and Lysosomes. Cell 151: 372-383.

Wang, Y. and F. Sesti. (2007). Molecular mechanisms underlying KVS-1-MPS-1 complex assembly. Biophys. J. 93: 3083-3091.

Wang, Y., S. Tang, K.E. Harvey, A.E. Salyer, T.A. Li, E.K. Rantz, M.A. Lill, and G.H. Hockerman. (2018). Molecular determinants of the differential modulation of Cav1.2 and Cav1.3 by nifedipine and FPL 64176. Mol Pharmacol. [Epub: Ahead of Print]

Wang, Z.J., I. Blanco, S. Hayoz, and T.I. Brelidze. (2020). The HCN domain is required for HCN channel cell-surface expression and couples voltage- and cAMP-dependent gating mechanisms. J. Biol. Chem. [Epub: Ahead of Print]

Welch, M.A., L.A. Forster, S.I. Atlas, and D.J. Baro. (2019). SUMOylating Two Distinct Sites on the A-type Potassium Channel, Kv4.2, Increases Surface Expression and Decreases Current Amplitude. Front Mol Neurosci 12: 144.

Wheeler, G.L. and C. Brownlee. (2008). Ca2+ signalling in plants and green algae--changing channels. Trends Plant Sci. 13: 506-514.

Whicher, J.R. and R. MacKinnon. (2016). Structure of the voltage-gated K⁺ channel Eag1 reveals an alternative voltage sensing mechanism. Science 353: 664-669.

Whicher, J.R. and R. MacKinnon. (2019). Regulation of Eag1 gating by its intracellular domains. Elife 8:.

Williams, B.S., J.P. Felix, B.T. Priest, R.M. Brochu, K. Dai, S.B. Hoyt, C. London, Y.S. Tang, J.L. Duffy, W.H. Parsons, G.J. Kaczorowski, and M.L. Garcia. (2007). Characterization of a new class of potent inhibitors of the voltage-gated sodium channel Nav1.7. Biochemistry. 46: 14693-14703.

Williams, S.E., S.P. Brazier, N. Baban, V. Telezhkin, C.T. Müller, D. Riccardi, and P.J. Kemp. (2008). A structural motif in the C-terminal tail of slo1 confers carbon monoxide sensitivity to human BK(Ca) channels. Pflugers Arch 456(3): 561-572.

Winterstein, L.M., K. Kukovetz, U.P. Hansen, I. Schroeder, J.L. Van Etten, A. Moroni, G. Thiel, and O. Rauh. (2021). Distinct lipid bilayer compositions have general and protein-specific effects on K+ channel function. J Gen Physiol 153:.

Wiriyasermkul, P., S. Moriyama, and S. Nagamori. (2020). Membrane transport proteins in melanosomes: Regulation of ions for pigmentation. Biochim. Biophys. Acta. Biomembr 1862: 183318.

Wisedchaisri, G., L. Tonggu, E. McCord, T.M. Gamal El-Din, L. Wang, N. Zheng, and W.A. Catterall. (2019). Resting-State Structure and Gating Mechanism of a Voltage-Gated Sodium Channel. Cell. [Epub: Ahead of Print]

Wittekindt, O.H., T. Dreker, D.J. Morris-Rosendahl, F. Lehmann-Horn, and S. Grissmer. (2004). A novel non-neuronal hSK3 isoform with a dominant-negative effect on hSK3 currents. Cell Physiol Biochem 14: 23-30.

Wojtovich, A.P., T.A. Sherman, S.M. Nadtochiy, W.R. Urciuoli, P.S. Brookes, and K. Nehrke. (2011). SLO-2 is cytoprotective and contributes to mitochondrial potassium transport. PLoS One 6: e28287.

Wojtyniak, M., A.G. Brear, D.M. O'Halloran, and P. Sengupta. (2013). Cell- and subunit-specific mechanisms of CNG channel ciliary trafficking and localization in C. elegans. J Cell Sci 126: 4381-4395.

Wolters, M., M. Madeja, A.M. Farrell, and O. Pongs. (1999). Bacillus stearothermophilus lctB gene gives rise to functional K+ channels in Escherichia coli and in Xenopus oocytes. Receptors Channels 6: 477-491.

Woo, D.H., K.S. Han, J.W. Shim, B.E. Yoon, E. Kim, J.Y. Bae, S.J. Oh, E.M. Hwang, A.D. Marmorstein, Y.C. Bae, J.Y. Park, and C.J. Lee. (2012). TREK-1 and Best1 channels mediate fast and slow glutamate release in astrocytes upon GPCR activation. Cell 151: 25-40.

Wright, P.D., E.L. Veale, D. McCoull, D.C. Tickle, J.M. Large, E. Ococks, G. Gothard, C. Kettleborough, A. Mathie, and J. Jerman. (2017). Terbinafine is a novel and selective activator of the two-pore domain potassium channel TASK3. Biochem. Biophys. Res. Commun. 493: 444-450.

Wright, P.D., G. Weir, J. Cartland, D. Tickle, C. Kettleborough, M.Z. Cader, and J. Jerman. (2013). Cloxyquin (5-chloroquinolin-8-ol) is an activator of the two-pore domain potassium channel TRESK. Biochem. Biophys. Res. Commun. 441: 463-468.

Wu, F., M. Quinonez, and S.C. Cannon. (2021). Gating pore currents occur in CaV1.1 domain III mutants associated with HypoPP. J Gen Physiol 153:.

Wu, L., S.L. Yong, C. Fan, Y. Ni, S. Yoo, T. Zhang, X. Zhang, C.A. Obejero-Paz, H.J. Rho, T. Ke, P. Szafranski, S.W. Jones, Q. Chen, and Q.K. Wang. (2008). Identification of a new co-factor, MOG1, required for the full function of cardiac sodium channel Nav 1.5. J. Biol. Chem. 283(11): 6968-6978.

Wu, R.S., G. Liu, S.I. Zakharov, N. Chudasama, H. Motoike, A. Karlin, and S.O. Marx. (2013). Positions of β2 and β3 subunits in the large-conductance calcium- and voltage-activated BK potassium channel. J Gen Physiol 141: 105-117.

Wu, X., R. Ramentol, M.E. Perez, S.Y. Noskov, and H.P. Larsson. (2021). A second S4 movement opens hyperpolarization-activated HCN channels. Proc. Natl. Acad. Sci. USA 118:.

Wu, Y., Y. Yang, S. Ye, and Y. Jiang. (2010). Structure of the gating ring from the human large-conductance Ca2+-gated K+ channel. Nature 466: 393-397.

Wunderlich, J. (2022). Updated List of Transport Proteins in. Front Cell Infect Microbiol 12: 926541.

Xia, J., N. Yamaji, T. Kasai, and J.F. Ma. (2010). Plasma membrane-localized transporter for aluminum in rice. Proc. Natl. Acad. Sci. USA 107: 18381-18385.

Xia, X.-M., X. Zeng, and C.J. Lingle. (2002). Multiple regulatory sites in large-conductance calcium-activated potassium channels. Nature 418: 880-884.

Xia, X.M., X. Zhang, and C.J. Lingle. (2004). Ligand-dependent activation of Slo family channels is defined by interchangeable cytosolic domains. J. Neurosci. 24: 5585-5591.

Xia, Z., X. Huang, K. Chen, H. Wang, J. Xiao, K. He, R. Huang, X. Duan, H. Liu, J. Zhang, and G. Xiang. (2016). Proapoptotic Role of Potassium Ions in Liver Cells. Biomed Res Int 2016: 1729135.

Xiao, K., Z. Sun, X. Jin, W. Ma, Y. Song, S. Lai, Q. Chen, M. Fan, J. Zhang, W. Yue, and Z. Huang. (2018). ERG3 potassium channel-mediated suppression of neuronal intrinsic excitability and prevention of seizure generation in mice. J. Physiol. 596: 4729-4752.

Xicluna, J., B. Lacombe, I. Dreyer, C. Alcon, L. Jeanguenin, H. Sentenac, J.B. Thibaud, and I. Cherel. (2007). Increased functional diversity of plant K+ channels by preferential heteromerization of the shaker-like subunits AKT2 and KAT2. J. Biol. Chem. 282: 486-494.

Xie, L., S. Dolai, Y. Kang, T. Liang, H. Xie, T. Qin, L. Yang, L. Chen, and H.Y. Gaisano. (2016). Syntaxin-3 Binds and Regulates Both R- and L-Type Calcium Channels in Insulin-Secreting INS-1 832/13 Cells. PLoS One 11: e0147862.

Xiong, H., X. Bai, Z. Quan, D. Yu, H. Zhang, C. Zhang, L. Liang, Y. Yao, Q. Yang, Z. Wang, L. Wang, Y. Huang, H. Li, X. Ren, X. Tu, T. Ke, C. Xu, and Q.K. Wang. (2021). Mechanistic insights into the interaction of cardiac sodium channel Na1.5 with MOG1 and a new molecular mechanism for Brugada syndrome. Heart Rhythm. [Epub: Ahead of Print]

Xiong, P., G. Yao, H. Zhang, and M. He. (2022). Molecular cloning and functional characterization of KCNQ1 in shell biomineralisation of pearl oyster Pinctada fucata martensii. Gene 821: 146285.

Xu H., Abuhatzira L., Carmona GN., Vadrevu S., Satin LS. and Notkins AL. (2015). The Ia-2beta intronic miRNA, miR-153, is a negative regulator of insulin and dopamine secretion through its effect on the Cacna1c gene in mice. Diabetologia. 58(10):2298-306.

Xu Y., Ramu Y., Shin HG., Yamakaze J. and Lu Z. (2013). Energetic role of the paddle motif in voltage gating of Shaker K(+) channels. Nat Struct Mol Biol. 20(5):574-81.

Xu, D., D. Su, S. Nusinowitz, and D. Sarraf. (2017). CENTRAL ELLIPSOID LOSS ASSOCIATED WITH CONE DYSTROPHY AND KCNV2 MUTATION. Retin Cases Brief Rep. [Epub: Ahead of Print]

Xu, F., X. Wu, L.H. Jiang, H. Zhao, and J. Pan. (2016). An organelle K+ channel is required for osmoregulation in Chlamydomonas reinhardtii. J Cell Sci. [Epub: Ahead of Print]

Xu, L., X. Ding, T. Wang, S. Mou, H. Sun, and T. Hou. (2019). Voltage-gated sodium channels: structures, functions, and molecular modeling. Drug Discov Today 24: 1389-1397.

Xu, P., K. Shimomura, C. Lee, X. Gao, E.H. Simpson, G. Huang, C.M. Joseph, V. Kumar, W.P. Ge, K.S. Pawlowski, M.D. Frye, S. Kourrich, E.R. Kandel, and J.S. Takahashi. (2022). A missense mutation in causes hippocampal learning deficits in mice. Proc. Natl. Acad. Sci. USA 119: e2204901119.

Xu, P., X. Mo, R. Xia, L. Jiang, C. Zhang, H. Xu, Q. Sun, G. Zhou, Y. Zhang, Y. Wang, and H. Xia. (2021). KCNN4 promotes the progression of lung adenocarcinoma by activating the AKT and ERK signaling pathways. Cancer Biomark. [Epub: Ahead of Print]

Xu, T., L. Nie, Y. Zhang, J. Mo, W. Feng, D. Wei, E. Petrov, L.E. Calisto, B. Kachar, K.W. Beisel, A.E. Vazquez, and E.N. Yamoah. (2007). Roles of alternative splicing in the functional properties of inner ear-specific KCNQ4 channels. J. Biol. Chem. 282: 23899-23909.

Xu, Y.Y., W.P. Wan, S. Zhao, and Z.G. Ma. (2020). L-type Calcium Channels are Involved in Iron-induced Neurotoxicity in Primary Cultured Ventral Mesencephalon Neuron.s of Rats. Neurosci Bull 36: 165-173.

Yagi, N., H. Itoh, T. Hisamatsu, Y. Tomita, H. Kimura, Y. Fujii, T. Makiyama, M. Horie, and S. Ohno. (2018). A challenge for mutation specific risk stratification in long QT syndrome type 1. J Cardiol 72: 56-65.

Yamagata, K., T. Senokuchi, M. Lu, M. Takemoto, M. Fazlul Karim, C. Go, Y. Sato, M. Hatta, T. Yoshizawa, E. Araki, J. Miyazaki, and W.J. Song. (2011). Voltage-gated K+ channel KCNQ1 regulates insulin secretion in MIN6 β-cell line. Biochem. Biophys. Res. Commun. 407: 620-625.

Yan, Z., Q. Zhou, L. Wang, J. Wu, Y. Zhao, G. Huang, W. Peng, H. Shen, J. Lei, and N. Yan. (2017). Structure of the Nav1.4-β1 Complex from Electric Eel. Cell 170: 470-482.e11.

Yang, H., L. Hu, J. Shi, K. Delaloye, F.T. Horrigan, and J. Cui. (2007). Mg2+ mediates interaction between the voltage sensor and cytosolic domain to activate BK channels. Proc. Natl. Acad. Sci. U.S.A. 104: 18270-18275.

Yang, J., G. Krishnamoorthy, A. Saxena, G. Zhang, J. Shi, H. Yang, K. Delaloye, D. Sept, and J. Cui. (2010). An epilepsy/dyskinesia-associated mutation enhances BK channel activation by potentiating Ca2+ sensing. Neuron. 66: 871-883.

Yang, J.K., J. Lu, S.S. Yuan, Asan, X. Cao, H.Y. Qiu, T.T. Shi, F.Y. Yang, Q. Li, C.P. Liu, Q. Wu, Y.H. Wang, H.X. Huang, A. Kayoumu, J.P. Feng, R.R. Xie, X.R. Zhu, C. Liu, G.R. Yang, M.R. Zhang, C.L. Xie, C. Chen, B. Zhang, G. Liu, X.Q. Zhang, and A. Xu. (2018). From Hyper- to Hypoinsulinemia and Diabetes: Effect of KCNH6 on Insulin Secretion. Cell Rep 25: 3800-3810.e6.

Yang, L., A. Katchman, J.P. Morrow, D. Doshi, and S.O. Marx. (2011). Cardiac L-type calcium channel (Cav1.2) associates with gamma subunits. FASEB J. 25: 928-936.

Yazdani, M., G. Zhang, Z. Jia, J. Shi, J. Cui, and J. Chen. (2020). Aromatic interactions with membrane modulate human BK channel activation. Elife 9:.

Yazdani, M., Z. Jia, and J. Chen. (2020). Hydrophobic dewetting in gating and regulation of transmembrane protein ion channels. J Chem Phys 153: 110901.

Ye, B. and J.M. Nerbonne. (2009). Proteolytic processing of HCN2 and co-assembly with HCN4 in the generation of cardiac pacemaker channels. J. Biol. Chem. 284: 25553-25559.

Yellen, G. (2002). The voltage-gated potassium channels and their relatives. Nature 419: 35-42.

Yellen, G. (1998). The moving parts of voltage-gated ion channels. Quat. Rev. Biophys. 31: 239-295.

Yu, R., X.F. Fan, C. Chen, and Z.H. Liu. (2017). Whole‑exome sequencing identifies a novel mutation (R367G) in SCN5A to be associated with familial cardiac conduction disease. Mol Med Rep 16: 410-414.

Yuan, A., C.M. Santi, A. Wei, Z.W. Wang, K. Pollak, M. Nonet, L. Kaczmarek, C.M. Crowder, and L. Salkoff. (2003). The sodium-activated potassium channel is encoded by a member of the Slo gene family. Neuron. 37: 765-773.

Yuan, A., M. Dourado, A. Butler, N. Walton, A. Wei, and L. Salkoff. (2000). SLO-2, a K+ channel with an unusual Cl- dependence. Nat Neurosci 3: 771-779.

Yuan, F.F., X. Gu, X. Huang, Y.W. Hou, Y. Zhong, J. Lin, and J. Wu. (2017). Attention-deficit/hyperactivity disorder associated with KChIP1 rs1541665 in Kv channels accessory proteins. PLoS One 12: e0188678.

Yuan, H., H. Yuan, Q. Wang, W. Ye, R. Yao, W. Xu, and Y. Liu. (2020). Two novel KCNA1 variants identified in two unrelated Chinese families affected by episodic ataxia type 1 and neurodevelopmental disorders. Mol Genet Genomic Med e1434. [Epub: Ahead of Print]

Yuan, P., M.D. Leonetti, Y. Hsiung, and R. MacKinnon. (2012). Open structure of the Ca2+ gating ring in the high-conductance Ca2+-activated K+ channel. Nature 481: 94-97.

Yuchi, Z., V.P. Pau, and D.S. Yang. (2008). GCN4 enhances the stability of the pore domain of potassium channel KcsA. FEBS J. 275: 6228-6236.

Yusifov, T., N. Savalli, C.S. Gandhi, M. Ottolia, and R. Olcese. (2008). The RCK2 domain of the human BKCa channel is a calcium sensor. Proc. Natl. Acad. Sci. U.S.A. 105: 376-381.

Zaman, T., K.L. Helbig, J. Clatot, C.H. Thompson, S.K. Kang, K. Stouffs, A.E. Jansen, L. Verstraete, A. Jacquinet, E. Parrini, R. Guerrini, Y. Fujiwara, S. Miyatake, B. Ben-Zeev, H. Bassan, O. Reish, D. Marom, N. Hauser, T.A. Vu, S. Ackermann, C.E. Spencer, N. Lippa, S. Srinivasan, A. Charzewska, D. Hoffman-Zacharska, D. Fitzpatrick, V. Harrison, P. Vasudevan, S. Joss, D.T. Pilz, K.A. Fawcett, I. Helbig, N. Matsumoto, J.A. Kearney, A.E. Fry, and E.M. Goldberg. (2020). SCN3A-related neurodevelopmental disorder: A spectrum of epilepsy and brain malformation. Ann Neurol. [Epub: Ahead of Print]

Zaydman MA., Silva JR., Delaloye K., Li Y., Liang H., Larsson HP., Shi J. and Cui J. (2013). Kv7.1 ion channels require a lipid to couple voltage sensing to pore opening. Proc Natl Acad Sci U S A. 110(32):13180-5.

Zaytseva, A.K., A.M. Kiselev, A.S. Boitsov, Y.V. Fomicheva, G.S. Pavlov, B.S. Zhorov, and A.A. Kostareva. (2022). Characterization of the novel heterozygous genetic variant Y739D associated with Brugada syndrome. Biochem Biophys Rep 30: 101249.

Zelman, A.K., A. Dawe, C. Gehring, and G.A. Berkowitz. (2012). Evolutionary and structural perspectives of plant cyclic nucleotide-gated cation channels. Front Plant Sci 3: 95.

Zeng, Q., Y. Yang, J. Duan, X. Niu, Y. Chen, D. Wang, J. Zhang, J. Chen, X. Yang, J. Li, Z. Yang, Y. Jiang, J. Liao, and Y. Zhang. (2022). -Related Epilepsy: The Phenotypic Spectrum, Treatment and Prognosis. Front Mol Neurosci 15: 809951.

Zhan, H., R. Stanciauskas, C. Stigloher, K.K. Dizon, M. Jospin, J.L. Bessereau, and F. Pinaud. (2014). In vivo single-molecule imaging identifies altered dynamics of calcium channels in dystrophin-mutant C. elegans. Nat Commun 5: 4974.

Zhang, D., L. Sun, S. Li, W. Wang, Y. Ding, S.A. Swarm, L. Li, X. Wang, X. Tang, Z. Zhang, Z. Tian, P.J. Brown, C. Cai, R.L. Nelson, and J. Ma. (2018). Elevation of soybean seed oil content through selection for seed coat shininess. Nat Plants. [Epub: Ahead of Print]

Zhang, F., Y. Liu, F. Tang, B. Liang, H. Chen, H. Zhang, and K. Wang. (2019). Electrophysiological and pharmacological characterization of a novel and potent neuronal Kv7 channel opener SCR2682 for antiepilepsy. FASEB J. fj201802848RR. [Epub: Ahead of Print]

Zhang, G., S.Y. Huang, J. Yang, J. Shi, X. Yang, A. Moller, X. Zou, and J. Cui. (2010). Ion sensing in the RCK1 domain of BK channels. Proc. Natl. Acad. Sci. USA 107: 18700-18705.

Zhang, J., D. Luo, F. Li, Z. Li, X. Gao, J. Qiao, L. Wu, and M. Li. (2021). Ginsenoside Rg3 Alleviates Antithyroid Cancer Drug Vandetanib-Induced QT Interval Prolongation. Oxid Med Cell Longev 2021: 3520034.

Zhang, J., X. Qu, M. Covarrubias, and M.W. Germann. (2013). Insight into the modulation of Shaw2 Kv channels by general anesthetics: structural and functional studies of S4-S5 linker and S6 C-terminal peptides in micelles by NMR. Biochim. Biophys. Acta. 1828: 595-601.

Zhang, L., Y. Wen, Q. Zhang, Y. Chen, J. Wang, K. Shi, L. Du, and X. Bao. (2020). Gene Variants in Eight Chinese Patients With a Wide Range of Phenotypes. Front Pediatr 8: 577544.

Zhang, X., F. Bertaso, J.W. Yoo, K. Baumgärtel, S.M. Clancy, V. Lee, C. Cienfuegos, C. Wilmot, J. Avis, T. Hunyh, C. Daguia, C. Schmedt, J. Noebels, and T. Jegla. (2010). Deletion of the potassium channel Kv12.2 causes hippocampal hyperexcitability and epilepsy. Nat Neurosci 13: 1056-1058.

Zhang, Y., Y. Zhao, H. Liu, W. Yu, F. Yang, W. Li, Z. Cao, and Y. Wu. (2018). Mouse β-Defensin 3, A Defensin Inhibitor of Both Its Endogenous and Exogenous Potassium Channels. Molecules 23:.

Zhang, Y., Z. Wang, L. Zhang, Y. Cao, D. Huang, and K. Tang. (2006). Molecular cloning and stress-dependent regulation of potassium channel gene in Chinese cabbage (Brassica rapa ssp. Pekinensis). J Plant Physiol. 163: 968-978.

Zhang, Z., H.A. Ledford, S. Park, W. Wang, S. Rafizadeh, H.J. Kim, W. Xu, L. Lu, V.C. Lau, A.A. Knowlton, X.D. Zhang, E.N. Yamoah, and N. Chiamvimonvat. (2016). Distinct subcellular mechanisms for the enhancement of the surface membrane expression of SK2 channel by its interacting proteins, α-actinin2 and filamin A. J. Physiol. [Epub: Ahead of Print]

Zhao, C., Y. Tang, J. Wang, Y. Zeng, H. Sun, Z. Zheng, R. Su, K. Schneeberger, J.E. Parker, and H. Cui. (2021). A mis-regulated cyclic nucleotide-gated channel mediates cytosolic calcium elevation and activates immunity in Arabidopsis. New Phytol. [Epub: Ahead of Print]

Zhao, F., J.L. Wang, H.Y. Ming, Y.N. Zhang, Y.Q. Dun, J.H. Zhang, and Y.B. Song. (2019). Insights into the binding mode and functional components of the analgesic-antitumour peptide from Karsch to human voltage-gated sodium channel 1.7 based on dynamic simulation analysis. J Biomol Struct Dyn 1-12. [Epub: Ahead of Print]

Zhao, G., Z.P. Neeb, M.D. Leo, J. Pachuau, A. Adebiyi, K. Ouyang, J. Chen, and J.H. Jaggar. (2010). Type 1 IP3 receptors activate BKCa channels via local molecular coupling in arterial smooth muscle cells. J Gen Physiol 136: 283-291.

Zhao, J. and R. Blunck. (2016). The isolated voltage sensing domain of the Shaker potassium channel forms a voltage-gated cation channel. Elife 5:. [Epub: Ahead of Print]

Zhao, Y., T. Scheuer, and W.A. Catterall. (2004). Reversed voltage-dependent gating of a bacterial sodium channel with proline substitutions in the S6 transmembrane segment. Proc. Natl. Acad. Sci. USA 101: 17873-17878.

Zheng, H., X. Yan, G. Li, H. Lin, S. Deng, W. Zhuang, F. Yao, Y. Lu, X. Xia, H. Yuan, L. Jin, and Z. Yan. (2022). Proactive functional classification of all possible missense single-nucleotide variants in. Genome Res. [Epub: Ahead of Print]

Zheng, Z., H. Chen, P. Xie, C.A. Dickerson, J.A.C. King, M.F. Alexeyev, H.S. Shin, and S. Wu. (2019). α1G T-type Calcium Channel Determines the Angiogenic Potential of Pulmonary Microvascular Endothelial Cells. Am. J. Physiol. Cell Physiol. [Epub: Ahead of Print]

Zhong, H., L.L. Molday, R.S. Molday, and K.-W. Yau. (2002). The heteromeric cyclic nucleotide-gated channel adopts a 3A:1B stoichiometry. Nature 420: 193-198.

Zhong, T., X. Pan, J. Wang, B. Yang, and L. Ding. (2019). The regulatory roles of calcium channels in tumors. Biochem Pharmacol 169: 113603. [Epub: Ahead of Print]

Zhou, Y., S.M. Assmann, and T. Jegla. (2021). External Cd2+ and protons activate the hyperpolarization-gated K+ channel KAT1 at the voltage sensor. J Gen Physiol 153:.

Zhu, L., K. Ploessl, and H.F. Kung. (2013). Chemistry. Expanding the scope of fluorine tags for PET imaging. Science 342: 429-430.

Zhuo, R.G., P. Peng, J.Q. Zheng, Y.L. Zhang, L. Wen, X.L. Wei, and X.Y. Ma. (2017). The glycine hinge of transmembrane segment 2 modulates the subcellular localization and gating properties in TREK channels. Biochem. Biophys. Res. Commun. 490: 1125-1131.

Zhuo, R.G., P. Peng, X.Y. Liu, H.T. Yan, J.P. Xu, J.Q. Zheng, X.L. Wei, and X.Y. Ma. (2016). Allosteric coupling between proximal C-terminus and selectivity filter is facilitated by the movement of transmembrane segment 4 in TREK-2 channel. Sci Rep 6: 21248.

Zimmermann, K., A. Leffler, A. Babes, C.M. Cendan, R.W. Carr, J. Kobayashi, C. Nau, J.N. Wood, and P.W. Reeh. (2007). Sensory neuron sodium channel Nav1.8 is essential for pain at low temperatures. Nature. 447: 855-888.


TC#NameOrganismal TypeExample

Two TMS K+ and water channel (conducts K+ (KD = 8 mM); blocked by Na+ (190 mM) (Renart et al., 2006) and tetrabutylammonium (Iwamoto et al., 2006)). Ion permeation occurs by ion-ion contacts in single file fashion through the selectivity filter (Köpfer et al. 2014). A narrow pore lined with four arrays of carbonyl groups is responsible for ion selectivity, whereas a conformational change of the four inner transmembrane helices (TMS2) is involved in gating (Baker et al. 2007). Two gates have been identified; one is located at the inner bundle crossing and is activated by H+ while the second gate is in the selectivity filter (Rauh et al. 2017). The C-terminal domain mediates pH modulation (Hirano et al., 2011Pau et al., 2007). KcsA exhibits a global twisting motion upon gating (Shimizu et al., 2008).  Activity is influenced by the phase of the lipid bilayer (Seeger et al. 2010), and occupancy of nonannular lipid binding sites increases the stability of the tetrameric complex (Triano et al. 2010).  The open conformation of KcsA can disturb the bilayer integrity and catalyze the flipping of phospholipids (Nakao et al. 2014).  This protein is identical to the KcsA orthologue (P0A333) in Streptomyces coelicolor.  The stability of the pre domain in KcsA is stabilized by GCN4 (Yuchi et al. 2008).  The potential role of pore hydration in channel gating has been evaluated (Blasic et al. 2015).  Having multiple K+ ions bound simultaneously is required for selective K+ conduction, and a reduction in the number of bound K+ ions destroys the multi-ion selectivity mechanism utilized by K+ channels (Medovoy et al. 2016).  The channel accomodates K+ and H2O molecules alternately in a K+-H2O-K+-H2O  series through the channel (Kratochvil et al. 2016). Insertion of KcsA is spontaneous and directional as the cytosolic part of the protein does not translocate across the membrane barrier. Charged residues, not hydrophobic residues, are crucial for insertion of the unfolded protein into the membrane via electrostatic interactions between membrane and protein.  A two-step mechanism was proposed. An initial electrostatic attraction between membrane and protein represents the first step prior to insertion of hydrophobic residues into the hydrocarbon core of the membrane (Altrichter et al. 2016). Bend, splay, and twist distinguish KcsA gate opening, filter opening, and filter-gate coupling, respectively (Mitchell and Leibler 2017). Details of the water permeability have been presented. Water flow through KcsA is halved by 200 mM K+ in the aqueous solution, which indicates an effective K+ dissociation constant in that range for a singly occupied channel. (Hoomann et al. 2013). A parameterized MARTINI program can be used to predict the hinging motions of the protein (Li et al. 2019). Activation of KcsA is initiated by proton binding to the pH gate upon an intracellular drop in pH which prompts a conformational switch, leading to a loss of affinity for potassium ions at the selectivity filter and therefore to channel inactivation (Rivera-Torres et al. 2016). An alteration in the conformational equilibrium of the intracellular K+-gate is one of the fundamental mechanisms underlying the dysfunctions of K+ channels caused by disease-related mutations (Iwahashi et al. 2020). Folding and misfolding of KcsA monomers during assembly and tetramerization has been examined (Song et al. 2021). The flexible C-terminus stabilizes KcsA tetramers at a neutral pH with decreased stabilization at acidic pH (Howarth and McDermott 2022).

Gram-positive bacteria

Skc1 (KcsA) of Streptomyces lividans


TC#NameOrganismal TypeExample

Voltage-sensitive Na+ channel, NaV1.7 (Cox et al., 2006). The human orthologue, SCN3A or Nav1.3, when mutated causes cryptogenic pediatric partial epilepsy (Holland et al., 2008; Zaman et al. 2020). Batrachotoxin (BTX) is a steroidal alkaloid neurotoxin that activates NaV channels through interacting with transmembrane domain-I-segment 6 (IS6) of these channels. Ginsenoside inhibits BTX binding (Lee et al. 2008). VGSCs are heterotrimeric complexes consisting of a single pore-forming alpha subunit joined by two beta subunits, a noncovalently linked beta1 or beta3 and a covalently linked beta2 or beta4 subunit (Hull and Isom 2017).  The binding mode and functional components of the analgesic-antitumour peptide from Buthus martensii Karsch to human voltage-gated sodium channel 1.7 have been characterized (Zhao et al. 2019). Dvorak et al. 2021 developed allosteric modulators of ion channels by targeting their PPI interfaces, particularly in the C-terminal domain of the Nav, with auxiliary proteins. Fenestrations are key functional regions of Nav that modulate drug binding, lipid binding, and influence gating behaviors (Gamal El-Din and Lenaeus 2022). Compartment-specific localizations and trafficking mechanisms for VGSCs are regulated separately to modulate membrane excitability in the brain (Liu et al. 2022).


Voltage-sensitive Na+ channel of Rattus norvegicus


The insect (cockroach) Na+ channel. Batrachotoxin, pyrethroids, and BTG 502 share overlapping binding sites (Du et al., 2011).  Insecticides tagetting Na+ channels include indoxacarb and metaflumizone (Casida and Durkin 2013). They preferably bind to and trap sodium channels in the slow-inactivated non-conducting state, a mode of action similar to that of local anesthetics (Jiang et al. 2015).  Asp802 is involved in gating and action, but not binding, of pyrethroid insecticides (Du et al. 2010).

Animals (Insects)

Na+ channel of Blattella germanica (O01307)


Sodium channel of 2215 aas, VmNa.  An L925V mutation in the channel domain renders the honey bee mites resistant to pyrethroids such as tau- fluvalinate and flumethrin (González-Cabrera et al. 2013).


Animals (Insects)

VmNa of Varroa destructor


Type 2 Na+ channel, SCN2A or NaV1.2, of 2,005 aas and 24 TMSs.  Mutations give rise to epileptic encephalophathy, Ohtahara syndrome (Nakamura et al. 2013). They may also give rise to autism (ASD) (Tavassoli et al. 2014). This protein is orthologous to the rat Na+ channel, TC# 1.A.1.10.1 and very similar to the type 1 Na+ channel (1.A.1.10.7). NaV1.2 has a single pore-forming alpha-subunit and two transmembrane beta-subunits. Expressed primarily in the brain, NaV1.2 is critical for initiation and propagation of action potentials. Milliseconds after the pore opens, sodium influx is terminated by inactivation processes mediated by regulatory proteins including calmodulin (CaM). Both calcium-free (apo) CaM and calcium-saturated CaM bind tightly to an IQ motif in the C-terminal tail of the alpha-subunit. Thermodynamic studies and solution structure (2KXW) of a C-domain fragment of apo 13C,15N- CaM (CaMC) bound to an unlabeled peptide with the sequence of the rat NaV1.2 IQ motif showed that apo CaMC (a) was necessary and sufficient for binding, and (b) bound more favorably than calcium-saturated CaMC. CaMN  apparently does not influence apo CaM binding to NaV1.2IQp (Mahling et al. 2017). The phenotypic spectrum of SCN2A-related epilepsy is broad, ranging from benign epilepsy in neonate and infancy to severe epileptic encephalopathy. Oxcarbazepine and valproate are the most effective drugs in epilepsy patients with SCN2A variants. Sodium channel blockers often worsen seizures in patients with seizure onset beyond 1 year of age. Abnormal brain MRI findings and de novo variations are often related to poor prognosis. Most SCN2A variants located in transmembrane regions were related to patients with developmental delay (Zeng et al. 2022).


SCN2A of Homo sapiens


Voltage-sensitive Na+ channel of 2821 aas and 24 TMSs (Cohen et al. 2009). Pyrethroid, an insecticide, binds to insect Na+ channels at two sites called pyrethroid,receptors, PyR1 (initial) and PyR2, located in the domain interfaces II/III and I/II, respectively, and binding residues have been identified (Du et al. 2015).


Na+ channel of Drosophila melanogaster


The voltage-gated Ca2+ channel (VDCC; CAV2), α-subunit of 2027 aas and 24 TMSs in four domains, each with six transmembrane segments and EEEE loci in the ion-selective filter, typical of VDCCs in vertebrates. CAV2 primarily localizes in the distal part of flagella and is transported toward the flagellar tip via intraflagellar transport (IFT) although CAV2 accumulates near the flagellar base when IFT is blocked. Thus, Ca2+ influx into Chlamydomonas flagella is mediated by the VDCC, CAV2, whose distribution is biased to the distal region of the flagellum, and this is required for flagellar waveform conversion (Fujiu et al. 2009).

Plants (Algae)

CAV2 of Chlamydomonas reinhardtii (Chlamydomonas smithii)


The sodium channel of 1989 aas and 24 TMSs.  80% identical to the characterized channel of the crayfish (Astacus leptodactylus (Turkish narrow-clawed crayfish) (Pontastacus leptodactylus)) in which functional regions responsible for the selectivity filter, inactivation gate, voltage sensor, and phosphorylation have been identified (Coskun and Purali 2016).

Na+ channel of Cancer borealis (Jonah crab)


The voltage-gated sodium channel of 2147 aas and 24 TMSs.  Several mutations in the structural gene give rise to pyrethroid resistance (kdr) (Saavedra-Rodriguez et al. 2007).

Na+ channel of Aedes aegypti (Yellowfever mosquito) (Culex aegypti), the most prevalent vector of dengue and yellow fever viruses.


Voltage-gated Na+ Channel protein of 2,139 aas and 24 TMSs.  Mediates voltage-dependent sodium ion permeability of excitable membranes.  3-d modeling revealed spacial clustering of evolutionarily conserved acidic residues at extracellular sites (Vinekar and Sowdhamini 2016).

PARA sodium channel of Anopheles gambiae (African malaria mosquito)


Sodium channel protein, α-subunit, FPC1, of 2050 aas and 24 TMSs.  The 3-d structure has been solved by cryoEM to 3.8 Å resolution (Shen et al. 2017). One residue at the corresponding selectivity filter (SF) locus in each repeat, Asp/Glu/Lys/Ala (DEKA), determines Na+ selectivity. The S1 to S4 segments in each repeat form a voltage-sensing domain (VSD), wherein S4 carries repetitively occurring positive residues essential for voltage sensing. There are seven extracellular glycosylation sites (Shen et al. 2017).

FPC1 of Periplaneta americana (American cockroach) (Blatta americana)


Sodium channel Nav1.4-beta complex of 1820 and 209 aas, respectively.  Voltage-gated sodium (Nav) channels initiate and propagate action potentials. Yan et al. 2017 presented the cryo-EM structure of EeNav1.4, the Nav channel from electric eel, in complex with the beta1 subunit at 4.0 Å resolution. The immunoglobulin domain of beta1 docks onto the extracellular L5I and L6IV loops of EeNav1.4 via extensive polar interactions, and the single transmembrane helix interacts with the third voltage-sensing domain (VSDIII). The VSDs exhibit ""up"" conformations, while the intracellular gate of the pore domain is kept open by a digitonin-like molecule. Structural comparison with closed NavPaS shows that the outward transfer of gating charges is coupled to the iris-like pore domain dilation through intricate force transmissions involving multiple channel segments. The IFM fast inactivation motif on the III-IV linker is plugged into the corner enclosed by the outer S4-S5 and inner S6 segments in repeats III and IV, suggesting a potential allosteric blocking mechanism for fast inactivation (Yan et al. 2017). The PDB# for the complex is 5XSY, and that for the two subunits are 5XSY_A and 5XSY_B. Domain 4 TMS 6 of Nav1.4 plays a key role in channel gating regulation, and is targeted by the neurotoxin, veratridine (VTD) (Niitsu et al. 2018).

Nav1.4-beta subunits of Electrophorus electricus (Electric eel) (Gymnotus electricus)

1.A.1.10.2Na+ channel, α-subunit, SCAP1 MetazoaSCAP1 from Aplysia californica (P90670)

Voltage-gated sodium channel of 1836 aas and 24 TMSs, PaFPC1. The 3-d structure has been determined (Shen et al. 2017).  It mediates the voltage-dependent sodium ion permeability in excitable membranes.


PaFPC1 of Periplaneta americana (American cockroach) (Blatta americana)


Putative two component voltage-gated Na+ channel, subunit 1 of 1149 aas and subunit 2 of 958 aas.  Decreased expression of these genes, encoding this system, gives rise to mortality of the peach-potato aphid, Myzus persicae (Tariq et al. 2019).

NaV of Myzus persicae.


Ca2+-regulated heart Na+ channel, Nav1.5, SCN5A or INa channel of 2016 aas. The COOH terminus functions in the control of channel inactivation and in pathologies caused by inherited mutations that disrupt it (Glaaser et al., 2006); regulated by ProTx-II Toxin (Smith et al. 2007), telethonin, the titin cap protein (167aas; secreted protein; O15273) (Mazzone et al., 2008), and the Mog1 protein, a central component of the channel complex (Wu et al., 2008). Nav1.5, the principal Na+ channel in the heart, possesses an ankyrin binding site, and direct interaction with ankyrin-G is required for the expression of Nav1.5 at the cardiomyocyte cell surface (Bennett and Healy, 2008; Lowe et al., 2008). Mutations cause type 3 long QT syndrome and type 1 Brugada syndrome, two distinct heritable arrhythmia syndromes (Mazzone et al., 2008; Kapplinger et al. 2010; Wang et al. 2015). SCN5A mutations causing arrhythmic dilated cardiomyopathy, commonly localized to the voltage-sensing mechanism, and giving rise to gating pore currents (currents that go through the voltage sensor) have been identified (McNair et al., 2011; Moreau et al., 2014).  Patients with Brugada syndrome are prone to develop ventricular tachyarrhythmias that may lead to syncope, cardiac arrest or sudden cardiac death (Sheikh and Ranjan 2014) and (Kapplinger et al. 2015). Mutations causing disease have been identified (Qureshi et al. 2015). These give rise to arrhythias and cardiomyopathies (Moreau et al. 2015).  Mutations that cause relative resistance to slow inactivation have been identified (Chancey et al. 2007).  Green tea catechins are potential anti-arrhythmics because of the significant effect of Epigallocatechin-3-Gallate (E3G) on  cardiac sodium channelopathies that display a hyperexcitability phenotype (Boukhabza et al. 2016). A mutatioin, R367G, causes the familial cardiac conductioin disease (Yu et al. 2017). The C-terminal domain of calmodulin (CaM) binds to an IQ motif in the C-terminal tail of the alpha-subunit of all NaV isoforms, and contributes to calcium-dependent pore-gating in some (Isbell et al. 2018). Ventricular fibrillation in patients with Brugada syndrome (BrS) is often initiated by premature ventricular contractions, and the presence of SCN5A mutations increases the risk upon exposure to sodium channel blockers in patients with or without baseline type-1 ECG (Amin et al. 2018). A mutation (R367G) is associated with familial cardiac conduction disease (Yu et al. 2017). Among ranolazine, flecainide, and mexiletine, only mexiletine restored inactivation kinetics of the currents of the mutant protein, A1656D (Kim et al. 2019).  Epigallocatechin-3-gallate (EGCG) is protective against cardiovascular disorders due in part to its action on multiple molecular pathways and transmembrane proteins, including the cardiac Nav1.5 channels (Amarouch et al. 2020). An SCN1B variant affects both cardiac-type (NaV1.5) and brain-type (NaV1.1) sodium currents and contributes to complex concomitant brain and cardiac disorders (Martinez-Moreno et al. 2020). Mice null for Scn1b, which encodes NaV beta1 and beta1b subunits, have defects in neuronal development and excitability, spontaneous generalized seizures, cardiac arrhythmias, and early mortality (Martinez-Moreno et al., 2020; Martinez-Moreno et al. 2020). The structural basis of cytoplasmic NaV1.5 and NaV1.4 regulation has been reviewed (Nathan et al. 2021). Fibroblast growth factor 21 ameliorates NaV1.5 and Kir2.1 channel dysregulation in human AC16 cardiomyocytes (Li et al. 2021). The interaction of Nav1.5 with MOG1 (RANGRF), a Ran guanine nucleotide release factor and chaparone, provides a possible molecular mechanism for Brugada syndrome (Xiong et al. 2021). Arrhythmic phenotypes are a defining feature of dilated cardiomyopathy-associated SCN5A variants (Peters et al. 2021). A SCN5A genetic variant, Y739D, is associated with Brugada syndrome (Zaytseva et al. 2022). Melatonin treatment causes an increase of conduction via enhancement of sodium channel protein expression and increases of sodium current in the ventricular myocytes (Durkina et al. 2022). Quantification of Nav1.5 expression has been published (Adams et al. 2022).





Nav1.5 of Homo sapiens (Q14524)


The skeletal muscle Na+ channel, NaV1.4 of 1836 aas and 24 TMSs. Mutations in charged residues in the S4 segment cause hypokalemic periodic paralysis (HypoPP)) due to sustained sarcolemmal depolarization (Struyk and Cannon 2007; Sokolov et al., 2007; Groome et al. 2014). Also causes myotonia; regulated by calmodulin which binds to the C-terminus of Nav1.4 (Biswas et al., 2008). NaV1.4 gating pores are permeable to guanidine as well as Na+ and H+ (Sokolov et al., 2010). The R669H mutation allows transmembrane permeation of protons, but not larger cations, similar to the conductance displayed by histidine substitution at Shaker K+ channel S4 sites (Struyk and Cannon 2007).  The mechanism of inactivation involves transient interactions between intracellular domains resulting in direct pore occlusion by the IFM motif and concomitant extracellular interactions with the beta1 subunit (Sánchez-Solano et al. 2016). Potassium-sensitive hypokalaemic and normokalaemic periodic paralysis are inherited skeletal muscle diseases in humans, characterized by episodes of flaccid muscle weakness. They are caused by single mutations in positively charged residues ('gating charges') in the S4 transmembrane segment of the voltage sensor of the voltage-gated sodium channel Nav1.4 or the calcium channel Cav1.1. Mutations of the outermost gating charges (R1 and R2) cause hypokalaemic periodic paralysis by creating a pathogenic gating pore in the voltage sensor through which cations leak in the resting state. Mutations of the third gating charge (R3) cause normokalaemic periodic paralysis owing to cation leak in both activated and inactivated states (Jiang et al. 2018). The neurotoxic cone snail peptide μ-GIIIA specifically blocks skeletal muscle voltage-gated sodium (NaV1.4) channels (Leipold et al. 2017). the cryo-electron microscopy structure of the human Nav1.4-β1 complex at 3.2-Å resolution. Accurate model building was made for the pore domain, the voltage-sensing domains, and the β1 subunit (Pan et al. 2018) provided insight into the molecular basis for Na+ permeation and kinetic asymmetry of the four repeats. Structural analysis of reported functional residues and disease mutations corroborates an allosteric blocking mechanism for fast inactivation of Nav channels. the S4-S5L of the DI, DII and DIII domains allosterically modulate the activation gate and stabilize its open state (Malak et al. 2020). The structural basis of cytoplasmic NaV1.5 and NaV1.4 regulation has been reviewed (Nathan et al. 2021). Mutations in SCN4A give rise to a variety of pathological conditions (Sun et al. 2021).




NaV1.4 of Homo sapiens (P35499)


Voltage-sensitive Na+ channel, type 9, α-subunit, Nav1.7 or SCN9A (orthologous to 1.A.1.10.1). Loss of function, resulting from point mutations, results in a channelopathy called Congenital Insensitivity to Pain (CIP) (He et al. 2018), that causes the congenital inability to experience pain (Cregg et al., 2010; Kleopa, 2011). An S241T mutation causes inherited erythromelalgia IEM; erythermalgia, an autosomal dominant neuropathy characterized by burning pain in the extremities in response to mild warmth (due to altered gating) (Lampert et al., 2006; Drenth and Waxman, 2007). Gain-of-function mutations in the Na(v)1.7 channel lead to DRG neuron hyperexcitability associated with severe pain, whereas loss of the Na(v)1.7 channel in patients leads to indifference to pain (Dib-Hajj et al., 2007). Blocked by 1-benzazepin-2-one (Kd = 1.6 nM) (Williams et al., 2007). Mutations in the Nav1.7 Na channel α-subunit give rise to familial pain syndromes called chronic non-paoxysmal neuropathic pain (Catterall et al., 2008; Fischer and Waxman, 2010; Dabby et al. 2011 ). It interacts with the sodium channel beta3 (Scn3b), rather than the beta1 subunit, as well as the collapsing-response mediator protein (Crmp2) through which the analgesic drug lacosamide regulates Nav1.7 current (Kanellopoulos et al. 2018). The R1488 variant is totally inactive (He et al. 2018). Nav1.7 is inhibited by knottins (see TC# 8.B.19.2) (Agwa et al. 2018). Nav1.7 interacts with the following proteins: syn3b (TC# 8.a.17.1.2; the β3 subunit), Crmp2, Syt2 (Q8N9I0) and Tmed10 (P49755), and it also regulates opioid receptor efficacy (Kanellopoulos et al. 2018). Mutations in TRPA1 and Nav1.7 to  insensitivity to pain-promoting algogens such as capsaicin, acid, and allyl isothiocyanate (AITC), have been documented (Eigenbrod et al. 2019). Nav1.7 is associated with endometrial cancer (Liu et al. 2019) and fever-associated seizures or epilepsy (FASE) (Ding et al. 2019). Nav1.7 and Nav1.8 peripheral nerve sodium channels are modulated by protein kinases A and C (Vijayaragavan et al. 2004).


Nav1.7 of Homo sapiens (Q15858)


Tetrodotoxin-resistant voltage-gated Na+ channel of dorsal ganglion sensory neurons, Nav1.8 (Akopian et al., 1996). Essential for pain at low temperatures (Zimmermann et al., 2007). Nav1.8 is the sole electrical impulse generator in a nociceptor that transmits information to the central nervous system.  Bark scorpion venom induces pain in many mammals (house mice, rats, humans) by activating Nav1.7 but has no effect on Nav1.8. Grasshopper mice Nav1.8 has amino acid variants that bind bark scorpion toxins and inhibit Na+ currents, blocking action potential propagation and inducing analgesia.  These mice thereby can use scorpions as a food source (Zhu et al. 2013; Rowe et al. 2013). Nav1.8 is involved in bull spermatozoa dynamics including motility, membrane integrity, acrosome integrity, capacitation and mitochondrial transmembrane potential (Chauhan et al. 2017).


Nav1.8 of Rattus norvegicus


Voltage-sensitive Na+ channel, Nav1.1 or SCN1A (causes epilepsy when mutated) (Rusconi et al., 2007).  Mutations are associated with a wide range of mild to severe epileptic syndromes with phenotypes ranging from the relatively mild generalized epilepsy with febrile seizures to other severe epileptic encephalopathies (Colosimo et al. 2007), including myoclonic epilepsy in infancy (SMEI), cryptogenic focal epilepsy (CFE), cryptogenic generalized epilepsy (CGE) and a distinctive subgroup termed as severe infantile multifocal epilepsy (SIMFE) (Ben Mahmoud et al. 2015). Mutations can give rise to familial sporadic hemiplegic migranes (Prontera et al. 2018). An SCN1B variant affects both cardiac-type (NaV1.5) and brain-type (NaV1.1) sodium currents and contributes to complex concomitant brain and cardiac disorders (Martinez-Moreno et al. 2020). Mice null for Scn1b, which encodes NaV beta1 and beta1b subunits, have defects in neuronal development and excitability, spontaneous generalized seizures, cardiac arrhythmias, and early mortality (Martinez-Moreno et al. 2020).


Nav1.1 of Homo sapiens (P35498)


The Voltage-gated Na+ channel α-subunit, Nav1.6, encoded by the Scn8a gene which when defective gives rise to the ENU-induced neurological mutant ataxia3 which gives rise to ataxia, tremors, and juvenile lethality.   75% identical to 1.A.1.10.7. Nav1.6 is the dendritic, voltage-gated sodium channel (responsible for dendritic excitability (Lorincz and Nusser, 2010)). Nav1.6 (SCN8A) interacts with microtubule-associated protein (O'Brien et al., 2012). Scorpion alpha toxins bind at receptor site-3 and inhibit channel inactivation, whereas beta toxins bind at receptor site-4 and shift the voltage-dependent activation toward more hyperpolarizing potentials (Gurevitz, 2012).  Mutations give rise to epileptic encephalopathy and intellectual disability (O'Brien and Meisler 2013).  A gain-of-function mutation gave rise to increased channel activation and infantile epileptic encephalopathy (Estacion et al. 2014). Benign familial infantile seizures (BFIS), paroxysmal kinesigenic dyskinesia (PKD), and their combination - known as infantile convulsions and paroxysmal choreoathetosis (ICCA) - are related autosomal dominant diseases involving SCN8A (Gardella et al. 2015).  Mutations can lead to chronic movement disorder in the mouse (Jones et al. 2016), and loss of function mutations in humans can lead to intellectual disability without seizures (Wagnon et al. 2017). Nav1.6 has been quantitated in mouse brain and proved to be present in 2-fold decreased amounts in epileptic mice (Sojo et al. 2019). SCN8A developmental and epileptic encephalopathy results in intractable seizures including spasms, focal seizures, neonatal status epilepticus, and nonconvulsive status epilepticus (Kim et al. 2019). Mutations in the SCN8A gene causes early infantile epileptic encephalopathy (Pan and Cummins 2020). Amitriptyline is a tricyclic antidepressant that binds to the anesthetic binding site in the α-subunit of the channel protein (Wang et al. 2004). A heterobivalent ligand (mu-conotoxin KIIIA, which occludes the pore of the NaV channels, and an analogue of huwentoxin-IV, a spider-venom peptide that allosterically modulates channel gating (TC#8.B.3.1.3)) slows ligand dissociation and enhances potency (Peschel et al. 2020).


Nav1.6 of Homo sapiens (Q9UQD0)


The voltage-gated Na+ channel α-subunit, Nav1.9. It is present in excitable membranes and is resistant to tetrodotoxin and saxitoxin (Bosmans et al., 2011).  The mutation, S360Y, makes NaV1.9 channels sensitive to tetrodotoxin and saxitoxin, and the unusual slow open-state inactivation of NaV1.9 is mediated by the isoleucine-phenylalanine-methionine inactivation motif located in the linker connecting domains III and IV (Goral et al. 2015).  Gain-of function mutations can lead to heritable pain disorders, and painful small-fibre neuropathy (Han et al. 2016). It is a threshold channel that regulates action potential firing, and is preferentially expressed in myenteric neurons, the small-diameter dorsal root ganglion (DRG) and trigeminal ganglion neurons including nociceptors. There is a monogenic Mendelian link of Nav1.9 to human pain disorders including episodic pain due to a N816K mutation (Huang et al. 2019).




Nav1.9 of Homo sapiens (Q9UI33)


TC#NameOrganismal TypeExample

TC#NameOrganismal TypeExample
1.A.1.11.1Voltage-sensitive Ca2+ channel (transports Ca2+, Ba2+ and Sr2+) Animals Voltage-sensitive Ca2+ channel, α-1 chain of Rattus norvegicus

Plasma membrane voltage-gated, high affinity Ca2+ channel, Cch1/Mid1; activated by mating pheromones and environmental stresses; required for growth in low Ca2+ (Locke et al., 2000; Paidhungat and Garrett, 1997). Also essential for tolerance to cold stress and iron toxicity (Peiter et al., 2005). Ecm7, (448aas; 4 TMS; TC# 1.H.1.4.6), a member of the PMP-22/EMP/MP20 Claudin superfamily of transmembrane proteins that includes gamma-subunits of voltage-gated calcium channels appears to interact with Mid1 TC# 8.A.41.1.1) and regulate the activity of the Cch1/Mid1 channel (Martin et al., 2011). Ecm7p is related to members of TC families 1.H.1, 1.H.2 and 1.A.81. The two indispensable subunits, Cch1 and Mid1 are equivalent to the mammalian pore-forming α1 and auxiliary α2 /δ subunits, respectively. Cho et al. 2016 screened candidate proteins that interact with Mid1 and identified the plasma membrane H+-ATPase, Pma1 (TC#3.A.3.3.6). Mid1 co-immunoprecipitated with Pma1. At the nonpermiss, and Mid1-EGFP colocalized with Pma1-mCherry at the plasma membrane.  Using a temperature-sensitive mutant, pma1-10, the membrane potential was less negative, and Ca2+ uptake was lower than in wild-type cells. Thus, Pma1 interacts physically with Cch1/Mid1 Ca2+ channels to enhance their activity via its H+-pumping activity (Cho et al. 2016).


Cch1/Mid1 of Saccharomyces cerevisiae
Cch1 (P50077)
Mid1 (P41821)
Ecm7p (Q06200) 


The Cav1.4 Ca2+ channel (gene CACNA1F). Mutations resulting in increased activity cause x-linked incomplete congenital stationary night blindness (CSNB2) (Hemara-Wahanui et al., 2005; Peloquin et al., 2007).  Aland Island eye disease (AIED), also known as Forsius-Eriksson syndrome, is an X-linked recessive retinal disease characterized by a combination of fundus hypopigmentation, decreased visual acuity, nystagmus, astigmatism, protan color vision defect, progressive myopia, and defective dark adaptation. Since the clinical picture of AIED is quite similar to CSNB2, these disorders are allelic or form a single entity. Thus, AIED is also caused by CACNA1F gene mutations (Jalkanen et al. 2007).


Cav1.4 of Homo sapiens


T-type Ca2+ channel (CACNA1G; Cav3.1d), (σ1G T-type Ca2+ channel) in developing heart (fetal myocardium (Cribbs et al., 2001)) and elsewhere. Both Cav3.1 and Cav3.2 are permeated by divalent metal ions, such as Fe2+ and Mn2+, and possibly Cd2+ (Thévenod, 2010).  CaV3.1 channels are activated at low votage and regulate neuronal excitability in the spinal cord (Canto-Bustos et al. 2014).  It is regulated by protein kinase C (PKC) and the RanBPM protein (Q96S59) (Kim et al. 2009).  T-type calcium channels belong to the "low-voltage activated (LVA)" group and are strongly blocked by mibefradil. A particularity of this type of channel is an opening at quite negative potentials and voltage-dependent inactivation. T-type channels serve pacemaking functions in both central neurons and cardiac nodal cells, and support calcium signaling in secretory cells and vascular smooth muscle (Coutelier et al. 2015). The human ortholog is 85% identical to the mouse protein. These channels also determines the angiogenic potential of pulmonary microvascular endothelial cells (Zheng et al. 2019).



Cav3.1d of Mus musculus (Q9WUT2)


Two-pore Ca2+ channel protein 1, TPC1 (Km(Ca2+))=50 µM; voltage gated; 461 aas; 12 TMSs) (Hashimoto et al., 2004; Kurusu et al, 2004; 2005). Each TPC subunit contains 12 TMSs that can be divided into two homologous copies of an S1-S6 Shaker-like 6-TMS domain. A functional TPC channel assembles as a dimer. The plant TPC channel is localized in the vacuolar membrane and is also called the SV channel for generating the slow vacuolar (SV) current. Three subfamilies of mammalian TPC channels have been defined - TPC1, 2, and 3 - with the first two being ubiquitously expressed in animals and TPC3 being expressed in some animals, but not in humans. Mammalian TPC1 and TPC2 are localized to endolysosomal membranes (She et al. 2022).


TPC1 of Oryza sativa (Q5QM84)

1.A.1.11.14Voltage-dependent calcium channel, α-1 subunit (1911aas), CyCaα1AnimalsCyCaα1 of Cyanea capillata (O02038)

Neuronal nonselective cation channel, NALCN (forms background leak conductance and controls neuronal excitability; Lu et al., 2007).  It is also found in the pancreatic β-cell (Swayne et al. 2010). NALCN serves as a variable sensor that responds to calcium or sodium ion flux, depending on whether the total cellular current density is generated more from calcium-selective or sodium-selective channels (Senatore and Spafford 2013). It functions in a complex with Unc80 (3258 aas; Q8N2C7) and Unc79 (2635 aas; Q9P2D8) (Bramswig et al. 2018). Heterozygous de novo NALCN missense variants in the S5/S6 pore-forming segments lead to congenital contractures of the limbs and face, hypotonia, and developmental delay (Bramswig et al. 2018). Overexpression of the NALCN gene ablates allyl isothiocyanate-promoting pain reception by nociceptors (Eigenbrod et al. 2019).


NALCN of Homo sapiens (Q6P2S6)

1.A.1.11.164 domain-type voltage-gated ion channel, α-1 subunit NCA-2 (Jospin et al., 2007) (dependent on Unc-80 (3225aas; CAB042172) for proper localization).AnimalsNCA-2 of Caenorhabditis elegans (Q06AY4)

The high affinity Ca2+ channel; associates with elongation factor 3 (EF3) to target Cch1/Mid1 to the plasma membrane (Liu and Gelli, 2008).


Cch1/Mid1 of Cryptococcus neoformans
Cch1 (Q1HHN2)
Mid1 (Q5KM96) 


The nicotinic acid adenine dinucleotide phosphate (NAADP)- dependent two pore Ca2+- channel, TPC3 (Brailoiu et al., 2010). Phosphoinositides regulate dynamic movement of the S4 voltage sensor in the second repeat in two-pore channel 3 (Hirazawa et al. 2021). Each TPC subunit contains 12 TMSs that can be divided into two homologous copies of an S1-S6 Shaker-like 6-TMS domain. A functional TPC channel assembles as a dimer. The plant TPC channel is localized in the vacuolar membrane and is also called the SV channel for generating the slow vacuolar (SV) current. Three subfamilies of mammalian TPC channels have been defined - TPC1, 2, and 3 - with the first two being ubiquitously expressed in animals and TPC3 being expressed in some animals, but not in humans. Mammalian TPC1 and TPC2 are localized to endolysosomal membranes (She et al. 2022).



Two pore Ca2+ channel 3, TPC3 of Bos taurus (C4IXV8)


The phosphoinositide (PI(3,5)P2)-activated Na+ two pore channel-2, TPC2, in endosomes and lysosomes (Wang et al. 2012). Previously thought, incorectly, according to Wang et al. 2012, to be a nicotinic acid adenine dinucleotide phosphate (NAADP)-dependent two pore Ca2+ channel.  TPC2, like TPC1, has a 12 TMS topology (two channel units) (Hooper et al., 2011). The two domains of human TPCs can insert into the membrane independently (Churamani et al., 2012).  Cang et al. (2013), showed that TPC1 and TPC2 together form an ATP-sensitive two-pore Na+ channel that senses the metabolic state of the cell.  The channel complex detects nutrient status, becomes constitutively open upon nutrient removal, and controls the lysosome's membrane potential, pH stability, and amino acid homeostasis.  Essential for Ebola virus (EBOV) host entry. Several inhibitors of TPC2 that act in the nM (tetrandrine) or μM (verapamil; Ned19) range block channel activity, prevent Ebola Virus from escaping cell vesicles and may be used to treat the disease (Sakurai et al. 2015).  TPC2 may transport both Na+ and Ca2+ (Sakurai et al. 2015). Lipid-gated monovalent ion fluxes, mediated by TPC1 and TPC2 in mice, regulate endocytic traffic and support immune surveillance. This is in part achieved by catalyzing Na+ export from visicles derived from the plasma membrane by phagocytosis or pinocytosis, causing contraction and allowing the maintenance of a uniform cell volume (Freeman et al. 2020). This system is important for melanocyte function (Wiriyasermkul et al. 2020).


TPC2 of Homo sapiens (Q8NHX9)


Muscle plasmalemma, voltage-gated, L-type dihydropyridine receptor Ca2+ channel, α-1 subunit (DHPR) (Ba2+ > Ca2+), Cav1.1, CACNA1S,CACH1 CDCN1, CACNL1A3 of 1873 aas in the human orthologue.  Distinc voltage sensor domains control voltage sensitivity and kinetics of current activation (Tuluc et al. 2016). Rapid changes in the transmembrane potential are detected by the voltage-gated Ca2+ channel, dihydropyridine receptor (DHPR), embedded in the sarcolemma. DHPR transmits the contractile signal to another Ca2+ channel, the ryanodine receptor (RyR1), embedded in the membrane of the sarcoplasmic reticulum (SR), which releases a large amounts of Ca2+ from the SR that initiate muscle contraction (Shishmarev 2020).


DHPR of Oryctolagus cuniculus


The voltage-gated Ca2+ channel, L-type α-subunit, Eg1-19 regulated by Macoilin (8.A.38.1.2)


Eg1-19 of Caenorhabditis elegans (A8PYS5)


Voltage-gated Ca2+ channel, Egl-19, isoform a


Egl-19 of C. elegans (G5EG02)


The phosphoinositide (PI(3,5)P2)-activated Na+ two pore channel-1, TPC1 of endosomes and lysosomes (Wang et al. 2012). Previously thought, incorectly, according to Wang et al. (2012), to be an NAADP-activated two pore voltage-dependent calcium channel protein.  However, Cang et al. (2013), showed that TPC1 and TPC2 (TC# 1.A.1.11.19) together form an ATP-sensitive two-pore Na+ channel that senses the metabolic state of the cell.  The channel complex detects nutrient status, becomes constitutively open upon nutrient removal, and controls the lysosome's membrane potential, pH stability, and amino acid homeostasis.  May be regulated by the HCLS-associated X-1 (HAX-1) protein (Lam et al. 2013). The cryoEM 3-D structure has been ellucidated (She et al. 2018). This voltage-dependent, phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2)-activated Na+ channel was solved in both the apo closed state and ligand-bound open state. The channel has a coin-slot-shaped ion pathway in the filter that defines the selectivity of mammalian TPCs. Only the voltage-sensing domain from the second 6-TMS domain confers voltage dependence while endolysosome-specific PtdIns(3,5)P2 binds to the first 6-TMS domain and activates the channel under conditions of depolarizing membrane potential. Structural comparisons between the apo and PtdIns(3,5)P2-bound structures show the interplay between voltage and ligand activation. These MmTPC1 structures reveal lipid binding and regulation in a 6-TMS voltage-gated channel (She et al. 2018).


Tpcn1 of Mus musculus


Cch1 calcium channel, alpha subunit; acts with Mid1 (8.A.41.1.7) which is required for function.


Mid1 of Schizosaccharomyces pombe


Voltage-sensitive calcium channel of 2693 aas (Docampo et al. 2013). Found to be essential for bloodstream-form Trypanosoma brucei through a genome-wide RNAi screen (Schmidt et al. 2018).

Euglenozoa (Protozoa)

Calcium channel of Trypanosoma brucei


Endosomal/lysosomal, two pore Na+and Ca2+-release channel  (Na+> Ca2+) protein of 816 aas and 12 TMSs, TPC1 or TPCN1 (Guo et al. 2017).  Endosomes and lysosomes are electrically excitable organelles (Cang et al. 2014). In a subpopulation of endolysosomes, a brief electrical stimulus elicits a prolonged membrane potential depolarization spike. The organelles have a depolarization-activated, non-inactivating Na+ channel (lysoNaV). The channel is formed by a two-repeat six-transmembrane-spanning (2x6 TMS) protein, TPC1, which represents the evolutionary transition between 6 TMS and 4x6 TMS voltage-gated channels. Luminal alkalization also opens lysoNaV by markedly shifting the channel's voltage dependence of activation toward hyperpolarization. Thus, TPC1 is a voltage-gated Na+ channel that senses pH changes and confers electrical excitability to organelles (Cang et al. 2014). Essential for Ebola virus (EBOV) host entry.  Several inhibitors act in the nM (tetrandrine) or μM (verapamil; Ned19) range to block Na+ and Ca2+ channel activity, inhibit virus escape from membrane vesicles and may possibly be used to treat the disease (Sakurai et al. 2015). A cluster of arginine residues in the first domain required for selective voltage-gating of TPC1 map not to the voltage-sensing fourth transmembrane region (S4) but to a cytosolic downstream region (S4-S5 linker). These residues are conserved between TPC isoforms suggesting a generic role in TPC activation. Accordingly, mutation of residues in TPC1 but not the analogous region in the second domain prevents Ca2+ release by NAADP in intact cells (Patel et al. 2017). Dramatic conformational changes in the cytoplasmic domains communicate directly with the VSD during activation (Kintzer et al. 2018).


TPC1 of Homo sapiens


Two pore Ca2+ > Na+, Li+ or K+ (non-selective for these three monovalen caions) channel protein of 733 aas and 12 TMSs, TPC1 (Guo et al. 2017). The crystal structure of this vacuolar two-pore channel, a homodimer, has been solved (Guo et al. 2015) (Kintzer and Stroud 2016). Activation requires both voltage and cytosolic Ca2+. Ca2+ binding to the cytosolic EF-hand domain triggers conformational changes coupled to the pair of pore-lining inner helices from the first 6-TMS domains, whereas membrane potential only activates the second voltage-sensing domain, the conformational changes of which are coupled to the pair of inner helices from the second 6-TMS domains. Luminal Ca2+ or Ba2+ modulates voltage activation by stabilizing the second voltage-sensing domain in the resting state and shift voltage activation towards more positive potentials. The basis for understanding ion permeation, channel activation, the location of voltage-sensing domains and regulatory ion-binding sites is partially explained by the 3-d structure (Kintzer and Stroud 2016). Only the second Shaker domain senses voltage (Jaślan et al. 2016). It has a selectivity filter that is passable by hydrated divalent cations (Demidchik et al. 2018). Dickinson et al. 2022 determined structures at different stages along its activation coordinate. These structures of activation intermediates, when compared with the resting-state structure, portray a mechanism in which the voltage-sensing domain undergoes dilation and in-membrane plane rotation about the gating charge-bearing helix, followed by charge translocation across the charge transfer seal. These structures, in concert with patch-clamp electrophysiology, showed that residues in the pore mouth sense inhibitory Ca2+ and are allosterically coupled to the voltage sensor. These conformational changes provide insight into the mechanism of voltage-sensor domain activation in which activation occurs vectorially over a series of elementary steps (Dickinson et al. 2022).  Inhibition of the Akt/PKB kinase increases Nav1.6-mediated currents and neuronal excitability in CA1 hippocampal pyramidal neurons (Marosi et al. 2022).


TPC1 of Arabidopsis thaliana


Voltage-dependent P/Q-type Ca2+ channel subunit α1A, CACNA1A (CACH4; CACN3; CACNL1A4) of 2,505 aas. The CACNA1A gene is widely expressed throughout the CNS. The encoding protein is 90% identical to 1.A.1.11.8.  Associated with four neurological phenotypes: familial and sporadic hemiplegic migraine type 1 (FHM1, SHM1), episodic ataxia type 2 (EA2), spinocerebellar ataxia type 6 (SCA6) and epileptic encephalopathy with nerve atrophy (Reinson et al. 2016). A gain of function mutation gave symptoms of congenital ataxia, abnormal eye movements and developmental delay with severe attacks of hemiplegic migraine (García Segarra et al. 2014). Mutations can cause F/SHM with high penitrance (Prontera et al. 2018). CACNA1A variants lead to a wide spectrum of neurological disorders including epileptic or non-epileptic paroxysmal events, cerebellar ataxia, and developmental delay. The variants are either gain of function GOF) or loss of function (LOF) mutations (Zhang et al. 2020). CACNA1A pathogenic variants have been linked to several neurological disorders including severe early onset developmental encephalopathies and cerebellar atrophy. Y1384 variants exhibit differential splice variant-specific effects on recovery from inactivation (Gandini et al. 2021). Patients with CACNA1A mutational variants located in the transmembrane region may be at high risk of status epilepticus (Niu et al. 2022).


CACNA1A Ca2+ channel of Homo sapiens


Voltage-dependent L-type calcium channel subunit α, VDCC, CCA-1 or CaACNa1S, of 1873 aas and 24 TMSs. Ca2+ channels containing the alpha-1S subunit play an important role in excitation-contraction coupling in skeletal muscle.  They are regulated by dystrophin-1 (Zhan et al. 2014).

VDCC of Caenorhabditis elegans


Voltage-gated calcium channel (VDCC) of 3097 aas and 24 TMSs, Cav7 (Wheeler and Brownlee 2008). 

Cav7 of Chlamydomonas reinhardtii


Voltage-dependent R-type Ca2+ channel, α-1E subunit (Cav2.3) (brain Ca2+ channel type II) (Ca2+ > Ba2+). Interacts with V-type ATPases (3.A.2), specifically, the G1-subunit, to regulate its activity (Radhakrishnan et al., 2011).  Syntaxin-3 (Syn-3) interacts directly with Cav2.3 to regulate its activity (Xie et al. 2016).


R-type Ca2+ channel of Mus musculus


TPC calcium channel protein with two transmembrane domains of 6 TMSs each (720 aas and 12 TMSs) (Wheeler and Brownlee 2008).

TPC of Physcomitrella patens


Voltage-sensitive calcium channel (VSCC), CAV1.3, encoded by the CACNA1D gene, of 2161 aas and 24 TMSs (Singh et al. 2008). CaV1.3-R990H channels conduct omega-currents at hyperpolarizing potentials, but not upon membrane depolarization compared with wild-type channels (Monteleone et al. 2017). A CACNA1D de novo mutation causes a severe neurodevelopmental disorder (Hofer et al. 2020).

CAv1.3 of Homo sapiens


Pore-forming, alpha-1S subunit of the voltage-gated calcium channel, of 1873 aas and 24 TMSs, Cav1.1; CACNA1S; CACN1; CACH1; CACNL1A3, that gives rise to L-type calcium currents in skeletal muscle. Calcium channels containing the alpha-1S subunit play an important role in excitation-contraction coupling in skeletal muscle via their interaction with RYR1, which triggers Ca2+ release from the sarcplasmic reticulum and ultimately results in muscle contraction. Long-lasting (L-type) calcium channels belong to the 'high-voltage activated' (HVA) group (Jiang et al. 2018). The 3-d structure of a bacterial homologue has been solved (Jiang et al. 2018). Mutations in arginly residues in the TMS4 voltage lead to increased leak currently that may be responsible for hypokalaemic periodic paralysis (Kubota et al. 2020). Mutations in the voltage sensor domain of CaV1.1, the alpha1S subunit of the L-type calcium channel in skeletal muscle cause hypokalemic periodic paralysis (HypoPP), and these mutations give rise to gating pore currents (Wu et al. 2021).



Cav1.1 of Homo sapiens


Calcium channel protein of 2556 aas and 24 TMSs.  Inhibited by 1,4-dihydrophyridines such as nifedipine (Tempone et al. 2009). The effects of nifedipine and calcium ions on cellular electrophysiology have been examined (Tsai et al. 2021).

Ca2+ channel of Leishmania donovani


Calcium channel of 913 aas and 12 TMSs. Ca2+ channels in trophozoites are inhibited by Amlodipine (Baig et al. 2013).

Calcium channel of Acanthamoeba castellanii


Calcium channel of 2725 aas and 24 TMSs.  T. cruzi calcium channels are inhibited by fendiline and bepridil (Reimão et al. 2011).

Ca2+ channel of Trypanosoma cruzi


Two pore segment channel 1 of 790 aas and 12 TMSs in a 3 + 3 (N-terminal half) + 2 + 2 + 2 (C-terminal half) TMS arrangement. In the trunk of developing zebrafish embryos, adjacent myotome blocks transmit contractile force via myoseptal junctions (MJs), dynamic structures that connect the actin cytoskeleton of skeletal muscle cells to extracellular matrix components via transmembrane protein complexes in the sarcolemma. Rice et al. 2022 reported that the endolysosomal ion channel, TPC1, generates highly localized, non-propagating Ca2+ transients that play a distinct and required role in the capture and attachment of superficial slow skeletal muscle cells (SMCs) at MJs. Disruption of the tpcn1 gene resulted in abnormal MJ phenotypes including SMCs detaching from or crossing the myosepta. TPC1-decorated endolysosomes are dynamically associated with MJs in a microtubule-dependent manner, and  attenuating tpcn1 expression or function disrupted endolysosomal trafficking and resulted in an abnormal distribution of beta-dystroglycan (a key transmembrane component of the dystrophin-associated protein complex). Thus, localized TPC1-generated Ca2+ signals facilitate essential endolysosomal trafficking and membrane contact events, which help form and maintain MJs following the onset of SMC contractile activity (Rice et al. 2022).

TPC1 of Danio rerio (Zebrafish) (Brachydanio rerio)


The voltage-dependent L-type Ca2+ channel α-subunit-1C (L-type Cav1.2), CACNA1C (CACH2, CACN2, CACNL1A1, CCHL1A1) of 2221 aa. Mutations cause Timothy's syndrome, a disorder associated with autism (Splawski et al., 2006). The C-terminus of Cav1.2 encodes a transcription factor (Gomez-Ospina et al., 2006). Cav1.2 associates with the α-2, δ-1, β and γ subunits (Yang et al., 2011). The CRAC channel activator STIM1 binds and inhibits L-type voltage-gated calcium channel, Cav1.2 (Park et al., 2010).  This channel appears to function as the molecular switch for synaptic transmission (Atlas 2013). Intramembrane signalling occurs with syntaxin 1A for catecholamine release in chromaffin cells (Bachnoff et al. 2013).  miR-153 intron RNA is a negative regulator of both insulin and dopamine secretion through its effect on Cacna1c expression, suggesting that IA-2beta and miR-153 have opposite functional effects on the secretory pathway (Xu et al. 2015).   Co-localizes with Syntaxin-1A in nano clusters at the plasma membrane (Sajman et al. 2017). It is a high voltage-activated Ca2+ channel in contrast to Cav3.3 which is a low voltage-activated Ca2+ channel (Sanchez-Sandoval et al. 2018). Nifedipine blocks and potentiates this and other L-type VIC Ca2+ channels (Wang et al. 2018).  Cav1.2 is upregulated when STIM1 is deficient (Pascual-Caro et al. 2018). CaV1.2 regulates chondrogenesis during limb development (Atsuta et al. 2019). CACNA1C may be a prognostic predictor of survival in ovarian cancer (Chang and Dong 2021).


CACNA1C of Homo sapiens (2221 aas; Q13936)


The voltage-dependent L-type Ca2+ channel α-subunit-1H (T-type Cav3.2), CACNA1H (mutations can cause an increased propensity for autism spectrum disorders (ASD) characterized by impaired social interactions, communication skills and restricted and repetitive behaviors) (Splawski et al., 2006). Also called Cav3.2 or VSCC. Involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, cell division and cell death. The isoform alpha-1H gives rise to T-type calcium currents, ''low-voltage activated'' currents blocked by nickel and mibefradil. Defective in Childhood Absence Epilepsy. Are permeated by divalent metal ions, such as Fe2+ and Mn2+ , and possibly Cd2+ (Thévenod, 2010).  Patented inhibitors of T-type calcium channels have been reviewed (Giordanetto et al. 2011).  Regulated by Syntaxin-1A (Xie et al. 2016). T-type calcium channel blockade induces apoptosis in C2C12 myotubes and skeletal muscle via endoplasmic reticulum stress activation (Chen et al. 2020).


CACNA1H of Homo sapiens (2353 aas; Q95180)


Voltage-dependent L-type Ca2+ channel subunit α-1C (αCav1.2) of cardiac muscle [A C-terminal fragment of Cav1.2 translocates to the nucleus and regulates transcription, explaining how a channel can directly activate transcription and differentiation of excitable cells.] (Gomez-Ospina et al., 2006). Cav1.2 associates with the α-2, δ-1, β and γ subunits (Yang et al., 2011).


α-Cav1.2 of Mus muscultus (2139 aas; Q01815)


The voltage-dependent Ca2+ channel subunit α-1I, Cav3.3, CACNA1I (isoform CRA_c (2223 aas and 24 TMSs)) (Hamid et al. 2006). It is a low voltage-activated Ca2+ channel in contrast to Cav1.2 (TC# 1.A.1.11.4) which is a high voltage-activated Ca2+ channel (Sanchez-Sandoval et al. 2018). The homolog in Cynops pyrrhogaster (85% identical) is inhibited by Ni2+ and may play a role in the sperm acrosome reaction (Kon et al. 2019).



Ca2+ channel CRA_c of Homo sapiens (Q9P0X4)


Voltage-dependent Ca2+ channel α-1A subunit (2212 aas), Cav2.1 (P/Q-type) (when mutated in humans, leads to a human channelopathy (episodic ataxia type-2 (EA2)) due to protein misfolding and retention in the E.R. (Mezghrani et al., 2008; Kleopa, 2011).  Mutations give rise to familial and sporadic hemiplegic migraine type 1 (FHM1, SHM1), episodic ataxia type 2 (EA2), and spinocerebellar ataxia type 6 (SCA6) (García Segarra et al. 2014).  Syntaxin 1A (Sx1A), SNAP-25 and synaptotagmin (Syt1), either alone or in combination, modify the kinetic properties of voltage-gated Ca2+ channels (VGCCs) including Cav2.1 (Cohen-Kutner et al. 2010).


Cav2.1 of Rattus norvegicus (P54282)


Voltage-dependent Ca2+ channel -subunit 1B (2339 aas), Cav2.2 (N-type) or NCC receptor of 2237 aas. Anchorin B interacts with Cav2.2 in the loop between TMSs 2 and 3.  TSPAN-13 specifically interacts with the α-subunit and modulates the efficiency of coupling between voltage sensor activation and pore opening of the channel while accelerating the voltage-dependent activation and inactivation of the Ba2+ current through CaV2.2 (Mallmann et al. 2013). The structure of the closed state in the pore forming domains have been modeled (Pandey et al. 2012). Amlodipine, cilnidipine and nifedipine compounds are potent channel antagonists.  CaV2.2 also interacts with reticulon 1 (RTN1) (TC# 8.A.102), member 1 of solute carrier family 38 (SLC38, TC#2.A.18), prostaglandin D2 synthase (PTGDS) and transmembrane protein 223 (TMEM223; TC#8.A.115). Of these, TMEM223 and, to a lesser extent, PTGDS, negatively modulate Ca2+ entry, required for transmitter release and/or for dendritic plasticity under physiological conditions (Mallmann et al. 2019).


Cav2.2 of Mus musculus (O55017)


TC#NameOrganismal TypeExample

Paramecium bursaria Chlorella virus 1 (PBCV-1) K+ channel, Kcv1. (The viral-encoded K+ channel inserts into the green algal host membrane to aid ejection of DNA from the viral particle into the cytoplasm (Neupartl et al., 2007)). It may mediate host cell membrane depolarization and K+ loss (Agarkova et al., 2008; Balss et al., 2008).  It is inhibited by Ba2+ and amantidine. (Reviewed by Thiel et al., 2010). The presence of charged amino acids which form dynamic inter- and intra- subunit salt bridges is crucial for channel activity (Hertel et al. 2010).


Kcv1 K+ channel of Chlorella virus PBCV-1


Acanthocystis turfacea chlorella virus cation, K+-preferring, channel, ATCV1 (82aas and 2 TMSs) (Gazzarrini et al., 2009; Siotto et al. 2014). The difference in open probability between close isoforms is caused by one long closed state in KcvS versus KcvNTS. This state is structurally created in the tetrameric channel by a transient, Ser mediated, intrahelical hydrogen bond. The resulting kink in the inner transmembrane domain swings the aromatic rings from downstream Phenylalanines in the cavity of the channel, which blocks ion flux. The most conserved region of the Kcv protein is the filter, the turret and the pore helix, and the outer and the inner transmembrane domains of the protein are the most variable (Murry et al. 2020).

Algal virus

ATCV1 (KCVS/KCVNTS) of Acanthocystis turfacea chlorella virus (A7K9J5)


The viral K+ channel, Kesv of 124 aas.  It is inhibited by Ba2+ and amantidine.  It is important for infection and replication in marine brown algae (Chen et al. 2005;  Balss et al., 2008; Siotto et al. 2014).


Kesv of Ectocarpus siliculosus virus 1 (Q8QN67)


Viral K+ channel of 96 aas and 2 TMSs, Kcv (Siotto et al. 2014).  Mechanical perturbation of the N-terminus can be transmitted to the C-terminal channel gates (Hoffgaard et al. 2015).


Kcv of Paramecium bursaria Chlorella virus


Potassium ion channel protein of 86 aas and 2 TMSs (Greiner et al. 2018).

K+ channel protein of Micromonas pusilla virus SP1


Potassium channel of 101 aas and 2 TMSs (Kukovetz et al. 2020).

K+ channel of Rhizochromulina virus RhiV-SA1


TC#NameOrganismal TypeExample

6TMS K+ channel (Munsey et al. 2002; Kuo et al., 2003).  The kch gene, the only known potassium channel gene in E. coli, has the property to express both full-length Kch and its cytosolic domain (RCK) due to a methionine at position 240. The RCK domains form an octameric ring structure and regulate the gating of the potassium channels after having bound certain ligands. Several different gating ring structures have been reported for the soluble RCK domains.  The octameric structure of Kch may be composed of two tetrameric full-length proteins through RCK interaction (Kuang et al. 2013).  The RCK domains face the solution, and an RCK octameric gating ring arrangement does not form under certain conditions (Kuang et al. 2015).

Gram-negative bacteria

Kch of E. coli


K+ channel protein with 343 aas and 2 N-terminal TMSs, MjK2.  Binding of the MjK2 RCK domain to membranes takes place via an electrostatic interaction with anionic lipid surfaces (Ptak et al. 2005).

MjK2 of Methanocaldococcus jannaschii (Methanococcus jannaschii)


2 TMS ( P-loop) Ca2+-gated K+ channel, MthK (see Jiang et al., 2002 for the crystal structure, and Parfenova et al., 2006 for mutations affecting open probability). For the studies of ion permeation and Ca2+ blockage, see Derebe et al., 2011. (structures: 3LDD_A and 2OGU_A.). Voltage-dependent K+ channels including MthK which lacks a canonical voltage sensor can undergo a gating process known as C-type inactivation, which involves entry into a nonconducting state through conformational changes near the channel's selectivity filter (Thomson and Rothberg, 2010). C-type inactivation may involve movements of transmembrane voltage sensor domains. In the absence of Ca2+, a single structure in a closed state was observed by cryoEM that was highly flexible with large rocking motions of the gating ring and bending of pore-lining helices (Fan et al. 2020). In Ca2+-bound conditions, several open-inactivated conformations were present with the different channel conformations being distinguished by rocking of the gating rings with respect to the transmembrane region. In all conformations displaying open channel pores, the N-terminus of one subunit of the channel tetramer sticks into the pore and plugs it. Deletion of this N terminus led to non-inactivating channels with structures of open states without a pore plug, indicating that this N-terminal peptide is responsible for a ball-and-chain inactivation mechanism (Fan et al. 2020). Lipid-protein interactions influence the conformational equilibrium between two states of the channel that differ according to whether a TMS has a kink. Two key residues in the kink region mediate crosstalk between two gates at the selectivity filter and the central cavity, respectively. Opening of one gate eventually leads to closure of the other (Gu and de Groot 2020). Activation of MthK is exquisitely regulated by temperature (Jiang et al. 2020).



MthK of Methanothermobacter thermoautotrophicus (Methanobacterium thermoautotrophicum)(O27564)

1.A.1.13.3Divalent cation (Ca2+, Mg2+, Mn2+, Ni2+)-activated K+ channel, TuoK (contains a RCK domain) (Parfenova et al., 2007)


TuoK of Thermoplasma volcanium (Q979Z2)



The Biofilm-inducing putative K+ channel, BikC or YugO (Prindle et al. 2015). BikC has an N-terminal 2 TMS + P-loop channel domain and a C-terminal NADB_Rossman superfamily domain (TrkA domain). YugO is in a two cistronic operon where Mistic (MstX; 9.A.66; Debnath et al., 2011; Roosild et al., 2005) is encoded by the gene that precedes yugO. Both play a role in biofilm formation, probably by functioning together (Lundberg et al. 2013; Marino et al. 2015). These K+ channels in bacterial biofilms provide an active, long-range electrical signalling for cellular communities (Prindle et al. 2015).  Metabolic co-dependency gives rise to collective electrical oscillations in biofilms (Liu et al. 2015). This oscillatory electrical signalling, due to periodic release of K+, giving rise to K+ gradients, increasing as swimming cells approach the biofilm that generates the gradiens, allows cells of the same and different speices to find and then incorporate themselves into existing biofilms (Humphries et al. 2017).


BikC of Bacillus subtilis (Q795M8)


Putative 2 TMS ion channel protein (N-terminus) with C-terminal TrkA_N (NADB Rossman) domain.


Ion channel protein of Streptomyces coelicolor


Ca2+-activated K+ channel, SynCaK. Functions in the regulation of photosynthesis (Checchetto et al. 2013; Checchetto et al. 2013).


K+ channel of Synechocystis PCC6803


Putative K+ channel, TrkA1, of 365 aas and 2 N-terminal TMSs, with a C-terminal NAD binding domain.


K+ channel of Synechocystis PCC6803


Potassium channel protein, MjK1 of 333 aas and 6 TMSs. Seems to conduct potassium at low membrane potentials (Hellmer and Zeilinger 2003). Also called TrkA3, a Trk channel with a C-terminal NAD-binding domain.


MjK1 of Methanocaldococcus jannaschii (Methanococcus jannaschii)


K+ channel of 387 aas and 2 TMSs, KchA.  KchA is essential for growth at low concentrations of K+. This K+ uptake system is essential for gastric colonization and the persistence of H. pyloriin the stomach (Stingl et al. 2007). This protein is of the two-transmembrane RCK (regulation of K+ conductance) domain family (Stingl et al. 2007).

KchA of Helicobacter pylori


TC#NameOrganismal TypeExample

Voltage-activated, Ca2+  channel blocker-inhibited, Na+ channel, NaChBac (Ren et al., 2001; Zhao et al., 2004Nurani et al, 2008; Charalambous and Wallace, 2011). Arginine residues in the S4 segment play a role in voltage-sensing (Chahine et al. 2004). Transmembrane and extramembrane regions contribute to thermal stability (Powl et al., 2012). Deprotonation of arginines in S4 is involved in NaChBac gating (Paldi, 2012). Hinge-bending motions in the pore domain of NaChBac have been reported (Barber et al., 2012).  The C-terminal coiled-coli stabilizes subunit interactions (Mio et al. 2010).  Within the 4 TMS voltage sensor, coupling between residues in S1 and S4 determines its resting conformation (Paldi and Gurevitz 2010). The conserved asparagine was changed to aspartate, N225D, and this substitution shifted the voltage-dependence of inactivation by 25 mV to more hyperpolarized potentials. The mutant also displays greater thermostability (O'Reilly et al. 2017).  Possibly, the side-chain amido group of asn225 forms one or more hydrogen bonds with different channel elements, and  these interactions are important for normal channel function. The T1-tetramerization domain of Kv1.2 (TC# 1.A.1.2.10) rescues expression and preserves the function of a truncated form of the NaChBac sodium channel (D'Avanzo et al. 2022).

Gram-positive bacteria

NaChBac of Bacillus halodurans

1.A.1.14.2Voltage-gated Na+ channel, NavPZ (Koishi et al., 2004)Gram-negative bacteriaNavPZ of Paracoccus zeaxanthinifaciens (CAD24429)
1.A.1.14.3Na+ channel, NavBP, involved in motility, chemotaxis and pH homeostasis (Ito et al., 2004). NavBP colocalizes with a methyl-accepting chemotaxis protein (MCP) at the cell poles (Fujinami et al., 2007). BacteriaNavBP of Bacillus pseudofirmus (AAT21291)

Voltage-gated Na+ channel, VGSC (Koishi et al., 2004; McCusker et al., 2011) Changing the selectivity filter from LESSM to LDDWSD yielded a Calcium-selective channel (Shaya et al., 2011).


VGSC of Silicibacter pomeroyi (56676695)


Voltage-gated Na+ channel, NavCh or NavAb. The 3d-structure is known (3ROW; Payandeh et al., 2011; 4MW3A-D; 4+ selectivity through partial dehydration of Na+ via its direct interaction with conserved glutamate side chains). The pore is preferentially occupied by two ions, which can switch between different configurations by crossing low free-energy barriers (Furini and Domene, 2012). Jiang et al. 2018 presented high-resolution structures of NavAb with the analogous gating-charge mutations that have similar functional effects as in the human channels that cause hypokalaemic and normokalaemic periodic paralysis.  Wisedchaisri et al. 2019 presented a cryo-EM structure of the resting state and a complete voltage-dependent gating mechanism via the voltage sensor (VS). The S4 segment of the VS is drawn intracellularly, with three gating charges passing through the transmembrane electric field. This movement forms an elbow connecting S4 to the S4-S5 linker, tightens the collar around the S6 activation gate, and prevents its opening. This structure supports the classical "sliding helix" mechanism of voltage sensing and provides a complete gating mechanism for voltage sensor function, pore opening, and activation-gate closure based on high-resolution structures of a single sodium channel protein (Wisedchaisri et al. 2019).

(see also TC#s 1.A.1.10.4 and 1.A.1.11.32).

The transport reaction catalyzed by NavCh is:

Na+ (in) ⇌ Na+ (out)


NavCh of Arcobacter butzleri (A8EVM5)


Bacterial voltage-gated sodium channel, Nav.  3-d crystal structures of vaious conformations are known (4P_3A A-D; 4PA7_A-D; 4P9P_A-D. etc.)  (McCusker et al. 2012).  It has its internal cavity accessible to the cytoplasmic surface as a result of a bend/rotation about a central residue in the carboxy-terminal TMS that opens the gate to allow entry of hydrated sodium ions. The molecular dynamics of ion transport through the open conformation has been analyzed (Ulmschneider et al. 2013).  The C-terminal four helix coiled coil bundle domain couples inactivation with channel opening, depedent on the negatively charged linker region (Bagnéris et al. 2013). A NaVSp1-specific S4-S5 linker peptide induced both an increase in NaVSp1 current density and a negative shift in the activation curve, consistent with the S4-S5 linker stabilizing the open state (Malak et al. 2020).


Nav of Magnetococcus marinus (also called sp. strain MC-1)


Tetrameric 6 TMS subunit Na+ channel protein, NaV.  Two low resolution cyroEM structures revealed two conformations reconstituted in lipid bilayers (Tsai et al. 2013). Despite a voltage sensor arrangement identical with that in the activated form, Tsai et al. 2013 observed two distinct pore domain structures: a prominent form with a relatively open inner gate, and a closed inner-gate conformation similar to the first prokaryotic Nav structure. Structural differences, together with mutational and electrophysiological analyses, indicated that widening of the inner gate was dependent on interactions among the S4-S5 linker, the N-terminal part of S5 and its adjoining part in S6, and on interhelical repulsion by a negatively charged C-terminal region subsequent to S6 (Tsai et al. 2013).


Nav of Caldalkalibacillus thermarum


Voltage-gated Na+ channel, Nsv, of 277 aas and 6 TMSs with a structually defined C-terminal regulatory domain (Miller et al. 2016). Voltage-gated sodium channels (NaVs) are activated by transiting the voltage sensor from the deactivated to the activated state. Tang et al. 2017 identified peptide toxins stabilizing the deactivated VSM of bacterial NaVs. A cystine knot toxin, called JZTx-27, from the venom of the tarantula Chilobrachys jingzhao proved to be a high-affinity antagonist. JZTx-27 stabilizes the inactive form of the voltage sensor, thereby inhibiting channel activity (Tang et al. 2017).

Nsv of Bacillus alcalophilus


Bacterial type voltage-activated sodium channel of 718 aas, NaV.

NaV of Phaeodactylum tricornutum


TC#NameOrganismal TypeExample

6 TMS basolateral tracheal epithelial cell/voltage-gated, small conductance, K+ α-chain, KCNQ1, [acts with the KCNE3 β-chain]. Mutations in human Kv7 genes lead to severe cardiovascular and neurological disorders such as the cardiac long QT syndrome and neonatal epilepsy (Haitin and Attali, 2008). KCNE3 can co-assemble with KCNQ1 (1.A.1.15.6) (Kang et al., 2010). KCNQ1 regulates insulin secretion in  the MIN6 beta-cell line (Yamagata et al., 2011).  The S4-S5 linker of KCNQ1 forms a scaffold with S6 controlling gate closure (Labro et al. 2011).  The KCNQ1 channel is differentially regulated by KCNE1 and KCNE2 (Li et al. 2014Slow-activating channel complexes formed by KCNQ1 and KCNE1 are essential for human ventricular myocyte repolarization, while constitutively active KCNQ1-KCNE3 channels are important in the intestine. Inherited sequence variants in human KCNE1 and KCNE3 cause cardiac arrhythmias but by different mechanisms, and each is important for hearing in unique ways (Abbott 2015). The topology and dynamics of the voltage sensor domain of KCNQ1 reconstituted in a lipid bilayer environment has been studied (Dixit et al. 2019).  KCNQ1 (Kv 7.1) alpha-subunits and KCNE1 beta-subunits co-assemble to form channels that conduct the slow delayed rectifier K+ current (IKs) in the heart. Mutations in either subunit cause long QT syndrome (LQTS), an inherited disorder of cardiac repolarization (Seebohm et al. 2005). KCNE1 modulates KCNQ1 potassium channel activation by an allosteric mechanism (Kuenze et al. 2020).


KCNQ1 K+ channel of Mus musculus


    6 TMS voltage-gated K+ channel, KCNQ2 or Kv7.2.  Mutations cause benign familial neonatal convulsions (BNFC; epilepsy; Maljevic et al. 2016; Soldovieri et al. 2019).  It forms homotetramers or heterotetramers with KCNQ3/Kv7.3) (Soldovieri et al., 2006; Uehara et al., 2008)). Like all other Kv7.2 channels, it is activated by phosphatidyl inositol-4,5-bisphosphate and hence can be regulated by various neurotransmitters and hormones (Telezhkin et al. 2013).  Gating pore currents that go through the gating pores in TMSs1-4 (the voltage sensor) may give rise to peripheral nerve hyperexcitability (Moreau et al. 2014). Retigabine and ICA73, two anti-epileptic drugs, act via distinct mechanisms due to interactions with specific residues that underlie subtype specificity of KCNQ channel openers (Wang et al. 2016). A  tight spatial and functional relationship between the DAT/GLT-1 transporters and the Kv7.2/7.3 potassium channel immediately readjusts the membrane potential of the neuron, probably to limit the neurotransmitter-mediated neuronal depolarization (Bartolomé-Martín et al. 2019). E-2-dodecenal from cilantro (Coriandrum sativum) is a potent activator and anticonvulsant that binds with an affinity of 60 nM to TMS5 in several KCNQ channels including KCNQ2 and 3 (Manville and Abbott 2019). The activities of Kv7 channels are modulated by polyunsaturated fatty acids (Larsson et al. 2020).


KCNQ2 K+ channel of Homo sapiens (O43526)


6 TMS voltage-gated K+ channel, KCNQ3 or Kv7.3.  Mutations cause benign familial neonatal convulsions (BNFC; epilepsy; Maljevic et al. 2016). Forms homotetramers or heterotetramers with KCNQ2 (Soldovieri et al., 2006; Uehara et al., 2008).  Retigabine and ICA73, two anti-epileptic drugs, act via distinct mechanisms due to interactions with specific residues that underlie subtype specificity of KCNQ channel openers (Wang et al. 2016). Gabapentin at low concentrations is a activator of KCNQ3, KCNQ2/3 and KCNQ5 but not KCNQ2 or KCNQ4 (Manville and Abbott 2018). At high concentrations it can be inhibitory.  A  tight spatial and functional relationship between the DAT/GLT-1 transporters and the Kv7.2/7.3 potassium channel immediately readjusts the membrane potential of the neuron, probably to limit the neurotransmitter-mediated neuronal depolarization (Bartolomé-Martín et al. 2019). E-2-dodecenal from cilantro (Coriandrum sativum) is a potent activator and anticonvulsant that binds with an affinity of 60 nM to TMS5 in several KCNQ channels including KCNQ2 and 3 (Manville and Abbott 2019). Pathogenic variants in KCNQ2 and KCNQ3, paralogous genes encoding Kv7.2 and Kv7.3 voltage-gated K+ channel subunits, are responsible for early-onset developmental/epileptic disorders characterized by heterogeneous clinical phenotypes ranging from benign familial neonatal epilepsy (BFNE) to early-onset developmental and epileptic encephalopathy (DEE). KCNQ2 variants account for the majority of pedigrees with BFNE, and KCNQ3 variants are responsible for a much smaller subgroup (Miceli et al. 2020). The M240R variant mainly affects the voltage sensitivity, in contrast to previously analyzed BFNE Kv7.3 variants that reduce current density (Miceli et al. 2020).


KCNQ3 K+ channel of Homo sapiens (O43525)


6 TMS cell volume sensitive, voltage-gated K+ channel, KCNQ4 or Kv7.4 (mutations cause DFNA2, an autosomal dominant form of progressive hearing loss) (forms homomers or heteromers with KCNQ3) (localized to the basal membrane of cochlear outer hair cells and in several nuclei of the central auditory pathway in the brainstem). Four splice variants form heterotetramers; each subunit has different voltage and calmodulin-sensitivities (Xu et al., 2007).  Autosomal dominant mutant forms leading to progressive hearing loss (DFNA2) have been characterized (Kim et al. 2011). Phosphatidylinositol 4,5-bisphosphate (PIP2) and polyunsaturated fatty acids (PUFAs) impact ion channel function (Taylor and Sanders 2016). This channel may be present in mitochondria (Parrasia et al. 2019). Polyunsaturated fatty acids are modulators of KV7 channels (Larsson et al. 2020). The pathogenicity classification of KCNQ4 missense variants in clinical genetic testing has been described (Zheng et al. 2022).


KCNQ4 K+ channel of Homo sapiens


The KCNQ5 K+ channel (modulated by Zn2+ , pH and volume change) (Jensen et al., 2005).  A triple cysteine module within M-type K+ channels mediates reciptrocal channel modulation by nitric oxide and reactive oxygen species (Ooi et al. 2013). Gabapentin at low concentrations is a activator of KCNQ3, KCNQ2/3 and KCNQ5 but not of KCNQ2 or KCNQ4 (Manville and Abbott 2018). At high concentrations, it can be inhibitory.


KCNQ5 of Mus musculus


K+ voltage-gated channel, LQT-like subfamily; Kv7.1; KvLQT1. KCNQ1 (regulated by KCNE peptides (TC# 8.A.58) affect voltage sensor equilibrium (Rocheleau and Kobertz, 2007). Almost 300 mutations of KCNQ1 have been identified in patients, and most are linked to the long QT syndrome (LQT1), some in the voltage sensor (Peroz et al., 2008; Eldstrom et al. 2010; Qureshi et al. 2013; Ikrar et al. 2008). KCNQ1-KCNE1 complexes may interact intermittently with the actin cytoskeleton via the C-terminal region (Mashanov et al., 2010). The stoichiometry of the KCNQ1 - KCNE1 complex is flexible, with up to four KCNE1 subunits associating with the four KCNQ1 subunits of the channel (Nakajo et al., 2010). A familial mutation in the voltage-sensor of the KCNQ1 channel results in a cardiac phenotype (Henrion et al., 2012). KCNQ1 regulates insulin secretion in the MIN6 beta-cell line (Yamagata et al., 2011; Gofman et al., 2012).  Electrostatic interactions of S4 arginines with E1 and S2 contribute to gating movements of S4, but coupling requires the lipid phosphatidylinositol 4,5-bisphosphate (PIP2) as voltage-sensing domain activation failed to open the pore in the absence of PIP2 (Zaydman et al. 2013). The D242N mutation causes impaired action potential adaptation to exercise and an increase in heart rate. Moreover, the D242 amino acyl position is involved in the KCNE1-mediated regulation of the voltage-dependence of activation of the KV7.1 channel (Moreno et al. 2017). The KCNQ1 channel interacts with MinK (KCNE1) to cause pore constriction, generating the slow delayed rectifier (IKs) current in the heart (Jalily Hasani et al. 2018). KCNQ1 rescues TMC1 plasma membrane expression but not mechanosensitive channel activity (Harkcom et al. 2019). Activation of the neuronal Kv7/KCNQ/M-current represents an attractive therapeutic strategy for treatment of hyperexcitability-related neuropsychiatric disorders such as epilepsy, pain, and depression, and channel openers for treatment of antiepilepsy have been developed (Zhang et al. 2019). The relationship between mutation locations in KCNQ1, which is a major gene in long QT syndrome (LQTS), and phenotype has been analyzed and used for risk stratification (Yagi et al. 2018). The proximal C-terminal regions of KCNQ1 and KCNE1 participate in a physical and functional interaction during channel opening that is sensitive to perturbation (Chen et al. 2019). Retigabine analogs are activators of Kv7 channels (Ostacolo et al. 2020). People with borderline QTc prolongations were carriers of KCNQ1 mutations in TMSs 2 and 5, leading to haploinsufficiency, and they are potentially at risk of developing drug-induced arrhythmia (Gouas et al. 2004). Collision induced unfolding differentiates functional variants of the KCNQ1 voltage sensor domain (Fantin et al. 2020). The activated KCNQ1 channel promotes a fibrogenic response in hereditary gingival fibromatosis via clustering and activation of Ras (Gao et al. 2020). QT syndrome (LQTS) increases the risk of life-threatening arrhythmia in young individuals with structurally normal hearts. It may involve sixteen genes such as the KCNQ1, KCNH2, and SCN5A (Lin et al. 2020). The human KCNQ1 voltage sensing domain (VSD) has been studied in lipodisq nanoparticles by electron paramagnetic resonance (EPR) spectroscopy (Sahu et al. 2020).


KCNQ1 of Homo sapiens (P51787)


Ion  channel transporter of 296 aas and 5 putative TMSs.

Ion channel of Mycoplasma sp. Pen4



KCNQ1 of 647 aas and 6 TMSs. Xiong et al. 2022 characterized KCNQ1 which functions in shell biomineralisation of pearl oyster, Pinctada fucata martensii.

KCNQ1 of Pinctada fucata martensii


TC#NameOrganismal TypeExample

TC#NameOrganismal TypeExample

TC#NameOrganismal TypeExample

The small conductance Ca2+-activated K+ channel, SkCa2, Sk2 or Kcnn2 (not inhibited by arachidonate) (activated by three small organic molecules, the 1-EBIO and N5309 channel enhancers and the DCEBIO channel modulation (Pedarzani et al., 2005)).  It is inhibited by protonation of outer pore histidine residues (Goodchild et al., 2009). The same is true for SK3 (K(Ca) 2.3 (Q9UGI6)). Regulates endothelial vascular function (Sonkusare et al., 2012).  Distinct subcellular mechanisms enhance the surface membrane expression by its interacting proteins, α-actinin 2 (TC# 8.A.66.1.3) and filamin A (TC# 8.A.66.1.4) (Zhang et al. 2016). SK channel activators can compensate for age-related changes of the autorhythmic functions of the cerebellum (Karelina et al. 2017). SK2 proteins are more abundant in Purkinje cells than in the ventricular myocytes of normal rabbit ventricles (Reher et al. 2017). Apamin inhibits and isoproterenol activates this and other SK (KCNN) channels, and activation by isoproterenol is sex-dependent (Chen et al. 2018).  Diverse interactions between KCa and TRP channels integrate cytoplasmic Ca2+, oxidative, and electrical signaling affecting cardiovascular physiology and pathology (Behringer and Hakim 2019). This channel may be present in mitochondria (Parrasia et al. 2019). A non-neuronal hSK3 isoform has a dominant-negative effect on hSK3 currents (Wittekindt et al. 2004). Medicinal plant products can interact with SKCa (Rajabian et al. 2022).


SkCa2 of Homo sapiens


The intermediate conductance, Ca2+-activated K+ channel, Kcnn4, SK4, Sk4, Smik, Ik1 hIK1, IKCa or KCa3.1, also called the Gardos channel, of 543 aas and 6 TMSs. It is inhibited by 1 μM arachidonate which binds in the pore (Hamilton et al., 2003)). Nucleoside diphosphate kinase B (NDPK-B) activates KCa3.1 via histidine phosphorylation, resulting in receptor-stimulated Ca2+ flux and T cell activation (Di et al., 2010). It regulates endothelial vascular function (Sonkusare et al., 2012).  Tissue-specific expression of splice variants of the orthologous rat KCNN4 protein have been reported (Barmeyer et al. 2010).  Residues involved in gating have been identified (Garneau et al. 2014). It is also present in the inner mitochondrial membrane where increases of mitochondrial matrix [Ca2+] cause mtKCa3.1 opening, thus linking inner membrane K+ permeability and transmembrane potential to Ca2+ signalling (De Marchi et al. 2009). KCa3.1 (IKCa) channels are expressed in CA1 hippocampal pyramidal cells and contribute to the slow afterhyperpolarization that regulates spike accommodation (Turner et al. 2016). SK channel activators can compensate for age-related changes of the autorhythmic functions of the cerebellum (Karelina et al. 2017). The activation mechanism has been revealed by the cryoEM structure of the SK4-calmodulin complex (Lee and MacKinnon 2018).  It is responsible for hyperpolarization in some tumor cells (Lazzari-Dean et al. 2019). Mutations are linked to dehydrated hereditary stomatocytosis (xerocytosis) (Andolfo et al. 2015). This channel is present in mitochondria (Parrasia et al. 2019). KCNN4 promotes the progression of lung adenocarcinoma by activating the AKT and ERK signaling pathways (Xu et al. 2021). KCa3.1 channels in human microglia link extracellular ATP-evoked Ca2+ transients to changes in membrane conductance with an inflammation-dependent mechanism, and suggests that during brain inflammation, the KCa3.1-mediated microglial response to purinergic signaling may be reduced (Palomba et al. 2021).



hIK1 of Homo sapiens (AAC23541)


Small conductance calcium-gated potassium (SK) channel. Three charged residues in TMS S6 of SK channels near the inner mouth of the pore collectively control the conductance and rectification through an electrostatic mechanism (Li and Aldrich, 2011). The SK channel inhibitors NS8593 and UCL1684 prevent the development of atrial fibrillation via atrial-selective inhibition of sodium channel activity (Burashnikov et al. 2020).


SK of Drosophila melanogaster (Q7KVW5)

Small conductance Ca2+-activated K+ channel, KCNL-2 of 672 aas.  Plays a role in the rate of egg laying (Chotoo et al. 2013).


KCNL-2 of Caenorhabditis elegans


Plasma membrane small conductance calcium-activated K+ channel of 396 aas, TSKCa; probably involved in immunoregulation (Cong et al. 2009).

Animals (fish)

TSKCa of Psetta maxima (Turbot) (Pleuronectes maximus)


Small conductance calcium-activated K+ channel, KCNN1 or SK, of 543 aas and 6 TMSs.

SK of Homo sapiens


Small conductance calcium-activated potassium channel protein 3 of 736 aas and 6 TMSs, SK3 or KCNN3. It forms a voltage-independent potassium channel, activated by intracellular calcium (Bauer et al. 2019). Activation is followed by membrane hyperpolarization and is thought to regulate neuronal excitability by contributing to the slow component of synaptic after-hyperpolarization. The channel is blocked by apamin. Contrary to its bradycardic effect in the sinus node, blockage of its current by apamin accelerates ventricular automaticity and causes repeated, nonsustained, ventricular tachycardia in normal ventricles. Ryanodine receptor 2 blockage reversed the apamin effects on ventricular automaticity (Wan et al. 2019).

KCNN3 of Homo sapiens


Small conductance plasma membrane calcium-activated potassium channel of 553 aas and 6 TMSs (Paul et al. 2021).

BK channel of Leishmania donovani


TC#NameOrganismal TypeExample

The archaeal voltage-regulated K channel, KvAP (Ruta et al., 2003). X-ray and solution structures are available. The latter shows phospholipid interactions with the isolated voltage sensor domain (Butterwick and MacKinnon 2010; Li et al. 2014). The gating-charge arginine in TMS4 of the voltage sensor forms part of the helical hairpin "paddle", and it moves 15-20 Å through the membrane to open the pore (Ruta et al., 2005). The orientation and depth of insertion of the voltage-sensing S4 helix has been determined (Doherty et al., 2010). A synthetic S6 segment derived from the KvAP channel self-assembles, permeabilizes lipid vesicles, and exhibits ion channel activity in bilayer lipid membrane (Verma et al., 2011).  Thus the gating mechanism combines structural rearrangements and electric-field remodeling ( Li et al. 2014).  KvAP has been reconstituted in Giant Unilamellar Vesicles (GUVs) (Garten et al. 2015).  TMS4 (S4) which senses voltage also promotes membrane insertion of the voltage-sensor domain (Mishima et al. 2016). KvAP has a configuration consistent with a water channel, possibly underlying the conductance of protons, and other cations, through voltage-sensor domains (Freites et al. 2006). The structural dynamics of the paddle motif loop in the activated conformation of the KvAP voltage sensor have been studied from biophysical standpoints (Das et al. 2019). The S4 alpha-helix, which is straight in the experimental crystal structure solved under depolarized conditions (Vm approximately 0), breaks into two segments when the cell membrane is hyperpolarized (Vm << 0) and reversibly forms a single straight helix following depolarization (Vm = 0) ((Bignucolo and Bernèche 2020). The outermost segment of S4 translates along the normal to the membrane, bringing new perspective to previously paradoxical accessibility experiments that were initially thought to imply the displacement of the whole VSD across the membrane. The breakage of S4 under (hyper)polarization could be a general feature of Kv channels with a non-swapped topology. The surface charge of the membrane does not significantly affect the topology and structural dynamics of the sensor loop in membranes (Das and Raghuraman 2021). The dynamic variability of the sensor loop is preserved in both zwitterionic (POPC) and anionic (POPC/POPG) lipid membranes. The lifetime distribution analysis for the NBD-labelled residues by the maximum entropy method (MEM) demonstrates that, in contrast to micelles, the membrane environment not only reduces the relative discrete population of sensor loop conformations, but also broadens the lifetime distribution peaks. The local curvature of cellular membranes acts as a driving force for the targeting of membrane-associated proteins to specific membrane domains, as well as a sorting mechanism for transmembrane proteins, as demonstrated for KvAP (Kluge et al. 2022). 


KvAP of Aeropyrum pernix (Q9YDF8) 

1.A.1.17.2Voltage-gated K+ channel, Kv (Santos et al., 2008).


Kv of Listeria monocytogenes (Q8Y5K1)


TC#NameOrganismal TypeExample

The two-pore domain potassium channel, TRESK-1 (Czirjak et al., 2004) (provides the background K+ current in mouse DRG neurons (Dobler et al., 2007)) TRESK (TWIK-related spinal cord K+ channel) is reversibly activated by the calcium/calmodulin-dependent protein phosphatase, calcineurin. Czirjak et al. 2008 reported that 14-3-3 proteins directly bind to the intracellular loop to TRESK and control the kinetics of the calcium-dependent regulation. Cloxyquin (5-chloroquinolin-8-ol) is an activator (Wright et al. 2013).  A cytoplasmic loop binds tubulin (Enyedi et al. 2014). Channel activity is modified by phosphorylation (inactive) and dephosphorylation (active) of the unusually long intracellular loop between the 2nd and 3rd TMS (Lengyel et al. 2018).


TRESK-1 of Mus musculus (AAQ91836)


TRESK-2 or potassium channel subfamily K member 18 of 348 aas and 6 TMSs. TRESK-2 is a functional member of the K(2P) channel family and contributes to the background K+ conductance in many types of cells (Kang et al. 2004).

TRASK-2 of Homo sapiens


TC#NameOrganismal TypeExample

Alkalinizatioin-activated Ca2+-selective channel, sperm-associated cation channel, CatSper, required for male fertility and the hyperactivated motility of spermatozoa (Kirichok et al. 2006). These channels require auxiliary subunits, CatSperβ, γ and δ for activity (Chung et al., 2011).  The primary channel protein is CatSper1 (Liu et al., 2007), and it may be a target for immunocontraception (Li et al. 2009). CatSper channels have been reported to regulate sperm motility (Vicente-Carrillo et al. 2017). Sperm competition is selective for a disulfide-crosslinked macromolecular architecture. CatSper channel opening occurs in response to pH, 2-arachidonoylglycerol, and mechanical force. A flippase function is hypothesized, and a source of the concomitant disulfide isomerase activity is found in CatSper-associated proteins beta, delta and epsilon (Bystroff 2018). More recently, it has been reported that rotational motion and rheotaxis of human sperm do not require functional CatSper channels or transmembrane Ca2+ signaling (Schiffer et al. 2020). Instead, passive biomechanical and hydrodynamic processes may enable sperm rolling and rheotaxis, rather than calcium signaling mediated by CatSper or other mechanisms controlling transmembrane Ca2+ flux. The Ca2+ channel CatSper is not activated by cAMP/PKA signaling but directly affected by chemicals used to probe the action of cAMP and PKA (Wang et al. 2020). The cation channel of sperm (CatSper) is essential for sperm motility and fertility. CatSper comprises the pore-forming proteins CATSPER1-4 and multiple auxiliary subunits, including CATSPERbeta, gamma, delta, epsilon, zeta, and EFCAB9. Lin et al. 2021 reported the cryo-EM structure of the CatSper complex isolated from mouse sperm. CATSPER1-4 conform to the conventional domain-swapped voltage-gated ion channel fold, following a counterclockwise arrangement. The auxiliary subunits CATSPERbeta, gamma, delta and epsilon - each of which contains a single transmembrane segment and a large extracellular domain - constitute a pavilion-like structure that stabilizes the entire complex through interactions with CATSPER4, 1, 3 and 2, respectively. The EM map revealed several previously uncharacterized components, exemplified by the organic anion transporter SLCO6C1. Lin et al. 2021 named this channel-transporter ultracomplex the CatSpermasome. The assembly and organizational details of the CatSpermasome lay the foundation for the development of CatSpermasome-related treatments for male infertility and non-hormonal contraceptives.


CatSper of Homo sapiens
CatSper1 (Q96P76)
CatSper3 (Q86XQ3)
CatSper4 (Q7RTX7)
CatSperβ (Q9H7T0)
CatSperγ (Q6ZRH7)
CatSperδ (Tmem146) (Q86XM0)
CatSperε (B1AQM6)
CatSperzeta (Q9NTU4)
Slco6C1 (mouse; Q3V161)

1.A.1.19.2Sperm-associated cation channel, CatSper2 (6 TMS Ca2+ channel)MammalsCatSper2 of Homo sapiens (26051223)

Alkalinization-activated, Ca2+-selective cation channel of sperm 1, CatSper1, required for male fertility and the hyperactivated motility of spermatozoa. These channels require auxiliary subunits, CatSper β, γ and δ for activity (Chung et al., 2011; Liu et al., 2007).


CatSper of Mus musculus
CatSper1 (Q91ZR5)
CatSper3 (Q86XQ3)
CatSper4 (Q8BVN3)
CatSperβ (Q8C0R2)
CatSperγ (C6KI89)
CatSperδ (Tmem146) (E9Q9F6) 


TC#NameOrganismal TypeExample

Voltage-sensitive K+ channel (PNa+/PK+ ≈ 0.1) Shaker and Shab K+ channels are blocked by quinidine (Gomez-Lagunas, 2010).


Shab11 of Drosophila melanogaster


Voltage-gated K+ channel, chain A, Shaker-related, Kv1.2 or KCNA2 (Crystal structure known, Long et al., 2007; Chen et al. 2010). It functions with the auxiliary subunit, Ivβ1.2; 8.A.5.1.1) (Peters et al. 2009).  Delemotte et al. (2010) described the effects of sensor domain mutations on molecular dynamics of Kv1.2.  The Sigma 1 receptor (Q99720; Sigma non-opioid intracellular receptor 1) interacts with Kv1.2 to shape neuronal and behavioral responses to cocaine (Kourrich et al. 2013).  Amino acid substitutions cause Shaker to become heat-sensing (opens with increasing temperature as for TrpV1) or cold-sensing (opens with decreasing temperature as for TrpM8) (Chowdhury et al. 2014).  The Shaker Kv channel was truncated after the 4th transmembrane helix S4 (Shaker-iVSD) which showed altered gating kinetics and formed a cation-selective ion channel with a strong preference for protons (Zhao and Blunck 2016).  Direct axon-to-myelin linkage by abundant KV1/Cx29 (TC# 1.A.24.1.12) channel interactions in rodent axons supports the idea of an electrically active role for myelin in increasing both the saltatory conduction velocity and the maximal propagation frequency in mammalian myelinated axons (Rash et al. 2016). A cryoEM structure (3 - 4 Å resolution; paddle chimeric channel; closed form) in nanodiscs has been determined (Matthies et al. 2018). Possible gating mechanisms have been discussed (Kariev and Green 2018; Infield et al. 2018). Pathogenic variants in KCNA2, encoding the voltage-gated potassium channel Kv1.2, have been identified as the cause for an evolving spectrum of neurological disorders. Affected individuals show early-onset developmental and epileptic encephalopathy, intellectual disability, and movement disorders resulting from cerebellar dysfunction (Döring et al. 2021). In addition, individuals with a milder course of epilepsy, complicated hereditary spastic paraplegia, and episodic ataxia have been reported. Biophysical properties of a delayed rectifier K+ current can contribute to its role ingenerating spontaneous myogenic activity (Hu et al. 2021). The local curvature of cellular membranes acts as a driving force for the targeting of membrane-associated proteins to specific membrane domains, as well as a sorting mechanism for transmembrane proteins, as demonstrated for the chimeric channel, Kv1.2/2.1; KvChim induces a strong positive membrane curvature (Kluge et al. 2022).


Kv1.2 of Homo sapiens (P16389)


Voltage-gated K+ channel, Shab-related, Kv2.1 or KCNB1 (858aas) The crystal structure is known (Long et al., 2007). Rat Kv2.1 and Kv2.2 (long) are colocalized in the somata and proximal dendrites of cortical pyramidal neurons and are capable of forming functional heteromeric delayed rectifier channels. The delayed rectifer currents, which regulate action potential firing, are encoded by heteromeric Kv2 channels in cortical neurons (Kihira et al., 2010). Phosphorylation by AMP-activated protein kinase regulates membrane excitability (Ikematsu et al., 2011). Functional interactions between residues in the S1, S4, and S5 domains of Kv2.1 have been identified (Bocksteins et al., 2011).  Missense variants in the ion channel domain and loss-of-function variants in this domain and the C-terminus cause neurodevelopmental disorders, sometimes with seizures (de Kovel et al. 2017).  Kv2.1 channels consist of two types of alpha-subunits: (1) electrically-active Kcnb1 alpha-subunits and (2) silent or modulatory alpha-subunits plus beta-subunits that, similar to silent alpha-subunits, regulate electrically-active subunits (Jędrychowska and Korzh 2019). It plays a role  in neurodevelopmental disorders, such as epileptic encephalopathy. The N- and C-terminal domains of the alpha-subunits interact to form the cytoplasmic subunit of hetero-tetrameric potassium channels. Kcnb1-containing channels are involved in brain development and reproduction. Modification of Kv2.1 K+ currents is mediated by the silent Kv10 subunits (Vega-Saenz de Miera 2004). The clinical expression of KCNB1 encephalopathy is variable (Púa-Torrejón et al. 2021).


Kv2.1/Kv2.2 of Homo sapiens


Voltage-gated K+ channel, Kv1.1 or KCNA1. It is palmitoylated, modulating voltage sensing (Gubitosi-Klug et al. 2005). It is regulated by syntaxin (TC family 8.A.91) through dual action on channel surface expression and conductance (Feinshreiber et al., 2009).  Defects cause episodic ataxia type 1 (EA1), an autosomal dominant K+ channelopathy accompanied by short attacks of cerebellar ataxia and dysarthria (D'Adamo et al. 2014; Yuan et al. 2020). Direct axon-to-myelin linkage by abundant KV1/Cx29 channel interactions in rodent axons supports the idea of an electrically active role for myelin in increasing both the saltatory conduction velocity and the maximal propagation frequency in mammalian myelinated axons (Rash et al. 2016). Kv1.1 is present in bull sperm where it is necessary for normal sperm progressive motility, per cent capacitated spermatozoa (B-pattern) and the acrosome reaction (Gupta et al. 2018). Gating induces large aqueous volumetric remodeling (Díaz-Franulic et al. 2018). Paulhus et al. 2020 have reviewed the pathology of mutants in this protein and showed that epilepsy or seizure-related variants tend to cluster in the S1/S2 transmembrane domains and in the pore region of Kv1.1, whereas EA1-associated variants occur along the whole length of the protein, but variants at the C-terminus are more likely to suffer from seizures and neurodevelopmental disorders (Yuan et al. 2020). Mutation in KCNA1 has been identified that impairs voltage sensitivity (Imbrici et al. 2021). Altering expression of the genes encoding Kv1.1, Piezo2, and TRPA1 regulate the response of mechanosensitive muscle nociceptors (Nagaraja et al. 2021).



Kv1.1 of Homo sapiens (Q09470)


Voltage-gated K+ channel subfamily C member 3,KCNC3 or Kv3.3. It is negatively modulated by protein kinase C (Desai et al., 2008). Phosphorylation of Kv3.3 by PKC may allow neurons to maintain action potential height during stimulation at high frequencies, and therefore contributes to stimulus-induced changes in the intrinsic excitability of neurons such as those of the auditory brainstem (Desai et al., 2008).  N-glycosylation impacts the sub-plasma membrane localization and activity of Kv3.1b-containing channels, and N-glycosylation processing of Kv3.1b-containing channels contributes to neuronal excitability (Hall et al. 2017). Spinocerebellar ataxia (SCA), a genetically heterogeneous disease characterized by cerebellar ataxia, involves the abnormal expansion of repeat sequences as well as the mutation of K+ and Ca2+ channel genes (Tada et al. 2020). A missense mutation in Kcnc3 causes hippocampal learning deficits in mice (Xu et al. 2022).


Kv3.3 of Homo sapiens (Q14003)


Voltage-gated delayed rectifier K+ channel, Kv1 of the octopus. RNA editing underlies adaption (Garrett and Rosenthal, 2012).  94% identical to the squid giant axon delayed rectifier voltage-dependent potassium channel, SqKv1A (Q25376).


Kv1 of Octopus vulgaris (H2EZS9)

1.A.1.2.15Potassium voltage-gated channel subfamily S member 3 (Delayed-rectifier K(+) channel alpha subunit 3) (Voltage-gated potassium channel subunit Kv9.3)AnimalsKCNS3 of Homo sapiens
1.A.1.2.16Potassium voltage-gated channel subfamily S member 2 (Delayed-rectifier K(+) channel alpha subunit 2) (Voltage-gated potassium channel subunit Kv9.2)AnimalsKCNS2 of Homo sapiens

Potassium voltage-gated channel (KCNH) subfamily G member 3 (Voltage-gated potassium channel subunit Kv10.1) (Voltage-gated potassium channel subunit Kv6.3).  Splice variants have different properties and can activate cyclin-dependent protein kinases (Ramos Gomes et al. 2015). Control of transport (pore) function  by the voltage sensor may involve more than one mechanism (Tomczak et al. 2017).  The silent (non transporting) behaviour of Kv6.3 in the ER is caused by the C-terminal part of its sixth transmembrane domain that causes ER retention (Ottschytsch et al. 2005).  De novo missense variants in KCNH1 encoding Kv10.1 are responsible for two clinically recognisable phenotypes: Temple-Baraitser syndrome (TBS) and Zimmermann-Laband syndrome (ZLS) (Aubert Mucca et al. 2022). The clinical overlap between these two syndromes suggests that they belong to a spectrum of KCNH1-related encephalopathies. Affected patients have severe intellectual disability (ID) with or without epilepsy, hypertrichosis and distinctive features such as gingival hyperplasia and nail hypoplasia/aplasia (Aubert Mucca et al. 2022).


Kcng3 or Kv10.1of Rattus norvegicus

1.A.1.2.18Potassium voltage-gated channel subfamily F member 1 (Voltage-gated potassium channel subunit Kv5.1) (kH1)AnimalsKCNF1 of Homo sapiens

The voltage-gated K+ channel subfamily D member 3, KCND3 or Kv4.3.  Mutations cause spinocerebellar ataxia type 19 (Duarri et al. 2012). Positively charged residues in S4 contribute to channel inactivation and recovery (Skerritt and Campbell 2007). The crystal structure of Kv4.3 with its regulatory subunit, Kchip1, has been solved (2NZ0) (Wang et al. 2007).


KCND3 of Homo sapiens


Voltage-sensitive K+ channel of 498 aas and 6 TMSs, SHAW2. Modulation of the Drosophila Shaw2 Kv channel by 1-alkanols and inhaled anesthetics correlates with the involvement of the S4-S5 linker and C-terminus of S6, consistent with stabilization of the channel's closed state (Zhang et al. 2013).


Shaw2 of Drosophila melanogaster


Shaker K+ channel, Shk-1, Shk1, Kv1 of 536 aas and 6 TMSs.  Mediates the voltage-dependent potassium ion permeability of excitable membranes. Has an important role in repolarization and in regulating the pattern of action potential firing. Isoform a expresses currents in a more depolarized voltage range than isoform d (Liu et al. 2011).

Shk-1 of Caenorhabditis elegans


Shal (SHL-1, Kv4) K+ channels of 578 aas and 6 TMSs are the predominant transient outward current in C. elegans muscle. SHL-1 expression occurs in a subset of neurons, body wall muscle and in male-specific diagonal muscles (Fawcett et al. 2006) and control the excitability of neurons and cardiac myocytes by conducting rapidly activating-inactivating currents. Activity is modulated by three K+ channel interacting (KChIP) soluble auxiliary subunits, NCS-4, NCS-5, and NCS-7. All three ceKChIPs alter electrical characteristics of SHL-1 currents by slowing down inactivation kinetics and shifting voltage dependence of activation to more hyperpolarizing potentials. Native SHL-1 current is completely abolished in cultured myocytes of Triple KO worms in which all three KChIP genes are deleted (Chen et al. 2015).

Shal of Caenorhabditis elegans


K+ channel, jShak1 of 487 aas and 6 TMSs. Intramolecular interactions control voltage sensitivity (Sharmin and Gallin 2016).

jShak1 of Polyorchis penicillatus (Hydromedusa; jellyfish)


Voltage-gated potassium channel subunit Kv8.2, KCNC2, of 545 aas and 6 TMSs. Mutation causes central ellipsoid loss which involves cone dystrophy with supernormal rod electroretinogram. It is a monogenic disease due to KCNV2 gene mutations that affect KCNC2 channel function in rod and cone photoreceptors (Xu et al. 2017).

KCNC2 of Homo sapiens


Voltage-gated K+ channel, KCNC1 (Kv3.1) of 511 aas and 6 TMSs.  It plays an important role in the rapid repolarization of fast-firing brain neurons. The channel opens in response to the voltage difference across the membrane, forming a potassium-selective channel through which potassium ions pass in accordance with their electrochemical gradient (Muona et al. 2015). Can form functional homotetrameric channels and heterotetrameric channels that contain variable proportions of KCNC2 (TC# 1.A.1.2.23), and possibly other family members as well. Contributes to fire sustained trains of very brief action potentials at high frequency in pallidal neurons. Causes various genetic neurological disorders when functioning abnormally such as attention deficit/hyperactivity (Yuan et al. 2017), myoclonus epilepsy and ataxia (Oliver et al. 2017) and intellectual disability (Poirier et al. 2017). The lipid environment, including 7-ketocholesterol (7KC), 24S-hydroxycholesterol (24S-OHC) and tetracosanoic acid (C24:0) affects Kv3.1b channel expression/functionality (Bezine et al. 2018).


KCNC1 of Homo sapiens


Potassium voltage-gated channel subfamily B member 2, Kv2.2 or KCNB2 of 911 aas and 6 TMSs. Selective expression of HERG (TC# 1.A.1.20.1) and Kv2 channels influences proliferation of uterine cancer cells (Suzuki and Takimoto 2004).

Kv2.2 of Homo sapiens


Potassium voltage-gated channel subfamily G member 4, KCNG4, of 519 aas and 6 TMSs.  Potassium channel subunit that does not form functional channels by itself, but can form functional heterotetrameric channels with KCNB1; modulates the delayed rectifier voltage-gated potassium channel activation and deactivation rates of KCNB1 (Mederos Y Schnitzler et al. 2009).

KCNG4 of Homo sapiens


Potassium voltage-gated channel subfamily G member 1, KCNG1, of 513 aas and 6 TMSs. Expressed in brain and placenta, and at much lower levels in kidney and pancreas (Su et al. 1997). This potassium channel subunit does not form functional channels by itself, but can form functional heterotetrameric channels with KCNB1. It modulates the delayed rectifier voltage-gated potassium channel activation and deactivation rates of KCNB1 (Mederos Y Schnitzler et al. 2009). KCNG1 mutations cause a syndromic form of congenital neuromuscular channelopathy (Jacinto et al. 2021).


KCNG1 of Homo sapiens


Potassium voltage-gated channel subfamily D member 1, Kv4.1 of 647 aas and 6 TMSs.  Pore-forming α-subunit of a voltage-gated rapidly inactivating A-type potassium channel. It may contribute to I(To) current in the heart and I(Sa) current in neurons. Channel properties are modulated by interactions with other α-subunits and with regulatory subunits, KChIP-1 and DPPX-S. The complex voltage-dependent gating rearrangements are not limited to the membrane-spanning core but must include the intracellular T1-T1 tetramerization domains interface (Wang and Covarrubias 2006).


Kv4.1 of Homo sapiens


K+ channel of 529 aas and 6 TMSs, Kv1.6 or KCNA6. It can form functional homotetrameric channels and heterotetrameric channels that contain variable proportions of KCNA1, KCNA2, KCNA4, KCNA6, and possibly other family members (). channel properties depend on the type of alpha subunits that are part of the channel. Channel properties are modulated by cytoplasmic beta subunits that regulate the subcellular location of the alpha subunits and promote rapid inactivation (By similarity). Homotetrameric channels display rapid activation and slow inactivation (Grupe et al. 1990). It is inhibited by 0.6 μM β-defensin 3 (BD3) (Zhang et al. 2018) as well as by neurotoxic cone snail peptide μ-GIIIA and other conotoxins (Leipold et al. 2017).

Kv1.6 of Homo sapiens


Voltage-sensitive fast transient outward current K+ channel in neurons and muscle of flies and worms (Fawcett et al., 2006)


Shal2 of Drosophila melanogaster


Potassium channel protein of 542 aas and 10 TMSs in a 2 + 2 + 6 TMS toplogy, where the last 6 TMSs comprise the voltage-gated K+ channel.

K+ channel of Haloplasma contractile


The KCNA4 OR Kv1.4 K+ channel of 653 aas and 6 TMSs (potassium voltage-gated channel subfamily A member 4).  The channel alternates between opened and closed conformations in response to the voltage difference across the membrane (Ramaswami et al. 1990); Po et al. 1993).It can form functional homotetrameric channels and heterotetrameric channels that contain variable proportions of KCNA1, KCNA2, KCNA4, KCNA5, and possibly other family members; channel properties depend on the type of alpha subunits that are part of the channel (Po et al. 1993). Channel properties are modulated by cytoplasmic beta subunits that regulate the subcellular location of the alpha subunits and promote rapid inactivation. In vivo, membranes probably contain a mixture of heteromeric potassium channel complexes. The Molecular basis involved in the blocking effect of the antidepressant, metergoline, on C-type inactivation has been reported (Bai et al. 2018). The molecular basis for the inactivation of the channel by the antidepressant, metergoline, has been presented (Bai et al. 2018).


KCNA4 of Homo sapiens


Margatoxin-sensitive voltage-gated K+ channel, Kv1.3 (in plasma and mitochondrial membranes of T lymphocytes) (Szabò et al., 2005). Kv1.3 associates with the sequence similar (>80%) Kv1.5 protein in macrophage forming heteromers that like Kv1.3 homomers are r-margatoxin sensitive (Vicente et al., 2006). However, the heteromers have different biophysical and pharmacological properties. The Kv1.3 mitochondrial potassium channel is involved in apoptotic signalling in lymphocytes (Gulbins et al., 2010). Interactions between the C-terminus  of Kv1.5 and Kvβ regulate pyridine nucleotide-dependent changes in channel gating (Tipparaju et al., 2012).  Intracellular trafficking of the KV1.3 K+ channel is regulated by the pro-domain of a matrix metalloprotease (Nguyen et al. 2013).  Direct binding of caveolin regulates Kv1 channels and allows association with lipid rafts (Pérez-Verdaguer et al. 2016). Addtionally, NavBeta1 interacts with the voltage sensing domain (VSD) of Kv1.3 through W172 in the transmembrane segment to modify the gating process (Kubota et al. 2017). During insertion of Kv1.3, the extended N-terminus of the second α-helix, S2, inside the ribosomal tunnel is converted into a helix in a transition that depends on the nascent peptide sequence at specific tunnel locations (Tu and Deutsch 2017). The microRNA, mmumiR449a, reduced the mRNA expression levels of transient receptor potential cation channel subfamily A member 1 (TRPA1), and calcium activated potassium channel subunit alpha1 (KCNMA1) and increased the level of transmembrane phosphatase with tension homology (TPTE) in the DRG cells (Lu et al. 2017). This channel is regulation by sterols (Balajthy et al. 2017). Loss of function causes atrial fibrillation, a rhythm disorder characterized by chaotic electrical activity of cardiac atria (Olson et al. 2006). The N-terminus and S1 of Kv1.5 can attract and coassemble with the rest of the channel (i.e. Frag(304-613)) to form a functional channel independently of the S1-S2 linkage (Lamothe et al. 2018). This channel may be present in mitochondria (Parrasia et al. 2019). Kv1.3 plays an essential role in the immune response mediated by leukocytes and is functional at both the plasma membrane and the inner mitochondrial membrane. Plasma membrane Kv1.3 mediates cellular activation and proliferation, whereas mitochondrial Kv1.3 participates in cell survival and apoptosis (Capera et al. 2022). Kv1.3 uses the TIM23 complex to translocate to the inner mitochondrial membrane. This mechanism is unconventional because the channel is a multimembrane spanning protein without a defined N-terminal presequence. Transmembrane domains cooperatively mediate Kv1.3 mitochondrial targeting involving the cytosolic HSP70/HSP90 chaperone complex as a key regulator of the process (Capera et al. 2022).


Kv1.3 homomers and Kv1.3/Kv1.5 heteromers of Homo sapiens (P22001)
Kv1.3 (P22001)
Kv1.5 (P19024)


Voltage-gated K+ channel subfamily D, member 2, Kv4.2 or KCND2, in neurons and muscle; forms complexes with auxiliary subunits and scaffolding proteins via its N-terminus, influencing trafficking, temperature-sensitivity and gating (Radicke et al. 2013).These subunits are (1) dipeptidyl-peptidase-like type II transmembrane proteins typified by DPPX-S (e.g., protein 6, P42658; 865 aas, TC#8.A.51), and (2) cytoplasmic Ca2+ binding proteins known as K+ channel interacting proteins (KChIPs; TC#8.A.82.2.2; Q6PIL6) (Seikel and Trimmer 2009).  The C-terminus interacts with KChIP2 to influence gating, surface trafficking and gene expression (Han et al., 2006; Schwenk et al., 2008). KChIPs (250 aas for mouse KChIP4a; Q6PHZ8) are homologous to domains in NADPH oxidases (5.B.1). Heteropoda toxin 2 (P58426; PDB 1EMX; TC#8.B.5.2.2) interactions with Kv4.3 and Kv4.1 give rise to differences in gating modifications (DeSimone et al., 2011).  Mutations cause autism and seizures due to a slowing of channel inactivation (Lee et al. 2014).  The stoichiometry of Kv4.2 and DPP6 is 4:4 (Soh and Goldstein 2008). Neferine, an isoquinoline alkaloid from plants, inhibits Kv4.3 channels, probably by blocking the open state (Wang et al. 2015). SUMOylating (derivatizing with a small ubiquitin-like modifier) at two distinct sites on Kv4.2 increases surface expression and decreases current amplitude (Welch et al. 2019). Modulation of voltage-gated potassium (Kv) channels by auxiliary subunits is central to the physiological function of channels in the brain and heart. Native Kv4 tetrameric channels form macromolecular ternary complexes with two auxiliary beta-subunits-intracellular Kv channel-interacting proteins (KChIPs) and transmembrane dipeptidyl peptidase-related proteins (DPPs)-to evoke rapidly activating and inactivating A-type currents, which prevent the backpropagation of action potentials (see above). Kise et al. 2021 investigated the modulatory mechanisms of Kv4 channel complexes, reporting cryo-EM structures of the Kv4.2-DPP6S-KChIP1 dodecameric complex, the Kv4.2-KChIP1 and Kv4.2-DPP6S octameric complexes, and Kv4.2 alone. The structure of the Kv4.2-KChIP1 complex revealed that the intracellular N terminus of Kv4.2 interacts with its C-terminus that extends from the S6 gating helix of the neighbouring Kv4.2 subunit. KChIP1 captures both the N and the C terminus of Kv4.2. Thus, KChIP1 prevents N-type inactivation and stabilizes the S6 conformation to modulate gating of the S6 helices within the tetramer. Unlike the reported auxiliary subunits of voltage-gated channel complexes, DPP6S interacts with the S1 and S2 helices of the Kv4.2 voltage-sensing domain, which suggests that DPP6S stabilizes the conformation of the S1-S2 helices. DPP6S may therefore accelerate the voltage-dependent movement of the S4 helices. KChIP1 and DPP6S do not directly interact with each other in the Kv4.2-KChIP1-DPP6S ternary complex. Thus, two distinct modes of modulation contribute in an additive manner to evoke A-type currents from the native Kv4 macromolecular complex (Kise et al. 2021).


Kv4.2 of Homo sapiens (Q9NZV8)


Voltage-gated K+ channel, Shaker. Shaker and Shab K+ channels are blocked by quinidine (Gomez-Lagunas, 2010). Also regulated by unsaturated fatty acids (Börjesson and Elinder, 2011).  TMSs 3 and 4 comprise the voltage sensor paddle (Xu et al. 2013).  Partially responsible for action potential repolarization during synaptic transmission (Ford and Davis 2014). Shaker K+ channels can be mutated in S4 to create an analogous "omega" pore (Held et al. 2018). The NMR structure of the isolated Shaker voltage-sensing domain in LPPG micelles has been reported (Chen et al. 2019). Substituting the first S4 arginine with a smaller amino acid opens a high-conductance pathway for solution cations in the Shaker K+ channel at rest. The cationic current does not flow through the central K+ pore and is influenced by mutation of a conserved residue in S2, suggesting that it flows through a protein pathway within the voltage-sensing domain (Tombola et al. 2005). The current can be carried by guanidinium ions, suggesting that this is the pathway for transmembrane arginine permeation. Tombola et al. 2005 proposed that when S4 moves, it ratchets between conformations in which one arginine after another occupies and occludes to ions in the narrowest part of this pathway. Specific resin acids activate and open voltage-gated channels  dependent on its exact binding dynamics (Silverå Ejneby et al. 2021).



Shaker of Drosophila melanogaster (CAA29917)


Electrically silent lens epithelium K+ channel (Delayed rectifier K+ channel α-subunit, Kv9.1 (Shepard & Rae, 1999))


Kv9.1 of Homo sapiens


Voltage gated K+ channel/MiNK related peptide (MiRP) complex, KVS1(α)/MPS-1/MiRPβ (expressed in chemo- and mechano-sensory neurons. Involved in chemotaxis, mechanotransduction and locomotion (Bianchi et al., 2003)). KVS-1 and KVS-2 are homologous; MPS-1 is member of the MiNK family (8.A.10). KVS-1/MPS-1 association involves hydrophobic forces (Wang and Sesti, 2007).


KVS-1 (α)/ MPS-1 (MiRPβ) of Caenorhabditis elegans
KVS-1 (α) (Q86GI9)
MPS-1 (MiRPβ) (Q86GJ0)


Brain-specific regulatory α-chain homologue that coassembles with other α-subunits to form active heteromultimeric K+ channels of unique kinetic properties, Kv2.3r. The functional expression of this regulatory α-subunit represents a novel mechanism without precedents in voltage-gated channels, which contributes to the functional diversity of K+ channels (Castellano et al., 1997). Beta subunits regulate the response of human Kv4.3 to protein kinae C phosphorylation and provide a potential mechanism for modifying the response of ion conductance to alpha-adrenergic regulation in vivo (Abbott 2017).


Kv2.3r of Rattus norvegicus (P97557)


TC#NameOrganismal TypeExample

K+ voltage-gated ether-a-go-go-related channel, H-ERG (KCNH2; Erg; HErg; Erg1, Kv11.1) subunit Kv11.1 (long QT syndrome type 2) (Gong et al., 2006; Chartrand et al. 2010; McBride et al. 2013). Selective expression of HERG and Kv2 channels influences proliferation of uterine cancer cells (Suzuki and Takimoto 2004). H-ERG forms a heteromeric K+ channel regulating cardiac repolarization, neuronal firing frequency and neoplastic cell growth (Szabó et al., 2011). Oligomerization is due to N-terminal interactions between two splice variants, hERG1a and hERG1b (Phartiyal et al., 2007). Structure function relationships of ERG channel activation and inhibition have been reviewed (Durdagi et al., 2010). Interactions between the N-terminal domain and the transmembrane core modulate hERG K channel gating (Fernández-Trillo et al., 2011). The marine algal toxin azaspiracid is an open state blocker (Twiner et al., 2012). Verapamil blocks channel activity by binding to Y652 and F656 in TMS S6 (Duan et al. 2007).  Hydrophobic interactions between the voltage sensor and the channel domain mediate inactivation (Perry et al. 2013), but voltage sensing by the S4 segment can be transduced to the channel gate in the absence of physical continuity between the two modules (Lörinczi et al. 2015).  Mutations give rise to long QT syndrome (Osterbur et al. 2015).  Polyphenols such as caffeic acid, phenylethyl ester (CAPE) and curcumin inhibit by modification of gating, not by blocking the pore (Choi et al. 2013). Potassium ions can inhibit tumorigenesis through inducing apoptosis of hepatoma cells by upregulating potassium ion transport channel proteins HERG and VDAC1 (Xia et al. 2016).  Incorrectly folded hERG can be degraded by Bag1-stimulated Trc-8-dependent proteolysis (Hantouche et al. 2016). The S1 helix regulates channel activity. Thus, S1 region mutations reduce both the action potential repolarizing current passed by Kv11.1 channels in cardiac myocytes, as well as the current passed in response to premature depolarizations that normally helps protect against the formation of ectopic beats (Phan et al. 2017). Interactions of beta1 integrins with hERG1 channels in cancer cells stimulate distinct signaling pathways that depended on the conformational state of hERG1 (Becchetti et al. 2017). ERG1 is sensitive to the alkaloid, ginsenoside 20(S) Rg3 which alters the gating of hERG1 channels by interacting with and stabilizing the voltage sensor domain in an activated state (Gardner et al. 2017). Channels split at the S4-S5 linker, at the intracellular S2-S3 loop, and at the extracellular S3-S4 loop are fully functional channel proteins (de la Peña et al. 2018). IKr is the rapidly activating component of the delayed rectifier potassium current, the ion current largely responsible for the repolarization of the cardiac action potential. Inherited forms of long QT syndrome (LQTS) in humans are linked to functional modifications in the Kv11.1 (hERG) ion channel and potentially life threatening arrhythmias. hERG1b affects the generation of the cardiac Ikr and plays an important role in cardiac electrophysiology (Perissinotti et al. 2018). X-ray crystallography and cryoEM have revealed features of the "nonswapped" transmembrane architecture, an "intrinsic ligand," and small hydrophobic pockets off a pore cavity. Drug block and inactivation mechanisms are discussed (Robertson and Morais-Cabral 2019). It forms a complex with β-integrin (TC#9.B.87.1.25) and NHE1 (TC# 2.A.36.1.13) (Iorio et al. 2020). Cardiotoxicity is caused mainly by the inhibition of human ether-a-go-go related gene (hERG) channel protein which leads to a life-threatening condition known as cardiac arrhythmia and is due to probable collapse of the pore. (Koulgi et al. 2021). Transmembrane hERG channel currents have been measured based on solvent-free lipid bilayer microarrays (Miyata et al. 2021). A computational method for identifying an optimal combination of existing drugs to repair the action potentials of SQT1 ventricular myocytes has been published (Jæger et al. 2021). Ginsenoside Rg3 may be a promising cardioprotective agent against vandetanib-induced QT interval prolongation through targeting hERG channels (Zhang et al. 2021).

Animals (Mammals)

H-ERG of Homo sapiens (Q12809)


Erg2 (Kv11.2; KCNH6) K+ channel with slowly activating delayed rectifier (expressed only in the nervous system) (Shi et al., 1997). The human ortholog of 994 aas and 6 TMSs (Q9H252) is 86% identical to the rat protein. KCNH6 in humans and mice plays a key role in insulin secretion and glucose hemostasis (Yang et al. 2018).


Erg2 of Rattus norvegicus


Erg3, Kv11.3, Eag3, KCNH7, K+ channel with a large transient current at positive potentials (expressed only in the nervous system) (Shi et al., 1997). Erg3-mediated suppression of neuronal intrinsic excitability prevents seizure generation (Xiao et al. 2018). The human ortholog (Q9NS40) is 1196 aas long with 6 TMSs and is 94% identical to the rat protein.


Erg3 of Rattus norvegicus


K+ voltage-gated channel, rEAG1; Kv10.1; rat ether a go-go channel 1 (962 aas). Blocked by Cs+, Ba2+ and quinidine (Schwarzer et al., 2008). Cysteines control the N- and C-linker-dependent gating of KCNH1 potassium channels  (Sahoo et al., 2012).  The 3-d structure has been determined at 3.8 Å resolution using single-particle cryo-EM with calmodulin bound. The structure suggests a novel mechanism of voltage-dependent gating. Calmodulin binding closes the potassium pore (Whicher and MacKinnon 2016). Eag1 has three intracellular domains: PAS, C-linker, and CNBHD. Whicher and MacKinnon 2019 demonstrated that the Eag1 intracellular domains are not required for voltage-dependent gating but likely interact with the VS to modulate gating. Specific interactions between the PAS, CNBHD, and VS domains modulate voltage-dependent gating, and VS movement destabilizes these interactions to promote channel opening. Mutations affecting these interactions render Eag1 insensitive to calmodulin inhibition (Whicher and MacKinnon 2019). The structure of the calmodulin insensitive mutant in a pre-open conformation suggests that channel opening may occur through a rotation of the intracellular domains, and calmodulin may prevent this rotation by stabilizing interactions between the VS and the other intracellular domains. Intracellular domains likely play a similar modulatory role in voltage-dependent gating of the related Kv11-12 channels. The human ortholog, EAG or EAG-1, is 989 aas long and is 95% identical to the rat protein.  In ether-a-go-go K+ channels, voltage-dependent activation is modulated by ion binding to a site located in an extracellular-facing crevice between transmembrane segments S2 and S3 in the voltage sensor. Silverman et al. 2004 found that acidic residues, D278 in S2 and D327 in S3, are able to coordinate a variety of divalent cations, including Mg2+, Mn2+, and Ni2+, which have qualitatively similar functional effects, but different half-maximal effective concentrations. EAG (ether-a-go-go) voltage-dependent K+ channels with similarities and Differences in the structural organization and gating (Barros et al. 2020).


EAG1 of Rattus norvegicus (Q63472)


Potassium voltage-gated channel subfamily H member 3 (Brain-specific eag-like channel 1, BEC1) (Ether-a-go-go-like potassium channel 2) (ELK channel 2, ELK2) (Voltage-gated potassium channel subunit, Kv12.2). Deletion causes hippocampal hyperexcitability and epilepsy (Zhang et al. 2010). A selective inhibitor is ASP2905 (Takahashi et al. 2017).


KCNH3 of Homo sapiens


Cyclic nucleotide-binding, voltage-gated, Mg2+-dependent, CaMKII-regulated K+ channel, Eag.  Eag recruits CASK (TC# 9.B.106.3.2) to the plasma membrane; forms a heterotetramer (Liu et al. 2010). Phosphorylation is catalyzed by CaMKII (TC# 8.A.104.1.11)


Eag of Drosophila melanogaster


Cyclic nucleotide-gated K+ channel, CNGC or CNG1 of 894 aas and 6 TMSs (Wheeler and Brownlee 2008).

CNG1 of Chlamydomonas reinhardtii


Aureochrome 1-like protein of 370 aas and a probable C-terminal 2 TMS ion channel domain.

Aureochrome 1 of Chattonella antiqua


Potassium voltage-gated channel subfamily H member 5 of 988 aas and 6 TMSs, EAG2 or KCNH5.  This pore-forming α-subunit of voltage-gated potassium channel elicits a non-inactivating outward rectifying current. The channel properties may be modulated by cAMP and subunit assembly (Bauer and Schwarz 2018).

Eag2 of Homo sapiens


TC#NameOrganismal TypeExample

K+- and Na+-conducting NaK channel, NaK2K of 97 aas and 2 TMSs. The 3-D structure has been solved with Na+ and K+bound (Shi et al., 2006).  It exhibits tight structural and dynamic coupling between the selectivity filter and the channel scaffold (Brettmann et al. 2015). A hydrophobic residue at the bottom of the selectivity filter, Phe92, appears in dual conformations. One of the two conformations of Phe92 restricts the diameter of the exit pore around the selectivity filter, limiting ion flow through the channel, while the other conformation of Phe92 provides a larger-diameter exit pore from the selectivity filter. Thus, Phe92 acts as a hydrophobic gate (Langan et al. 2020).


NaK channel of Bacillus cereus (2AHYB) (Q81HW2)


Two pore domain potassium channel family protein of 122 aas and 2 TMSs.

K+ channel of Anaerolineales bacterium


Two pore domain potassium channel family protein of 140 aas and 2 TMSs.

K+ channel of Methanosarcina mazei


TC#NameOrganismal TypeExample
1.A.1.22.1The cyclic nucleotide-gated K+ channel, MmaK. (Activated by cyclic AMP and cyclic GMP; inactivated at slightly acidic pH (Kuo et al., 2007))Gram-negative bacteria MmaK of Magnetospirillum magnetotacticum (Q2W0I8)

TC#NameOrganismal TypeExample

The pea symbiosis protein, essential for nodulation, mycorrhization, and Nod-factor-induced calcium spiking, SYM8 or DMI1 (Does not make infections 1). (Most similar to 1.A.1.13.2; 894aas; 4 TMSs between residues 136 and 339) (Edwards et al., 2007).


SYM8 of Pisum sativum

1.A.1.23.2Root nuclear envelope CASTOR: homomeric ion channel (preference of cations such as K+ over anions) (Charpentier et al., 2008) (62% identical to 1.A.1.23.1).


CASTOR of Lotus japonicus (Q5H8A6)

1.A.1.23.3POLLUX homomeric ion channel (preference for cations over anions) (Charpentier et al., 2008) (81% identical to 1.A.1.23.1).


POLLUX of Lotus japonicus (Q5H8A5)


putative ion channel (N-terminal domain) protein with C-terminal TrkA-N domain (DUF1012); NAD-binding lipoprotein.


Ion channel protein of Streptomyces coelicolor


TC#NameOrganismal TypeExample
1.A.1.24.1The cyclic nucleotide regulated K+ channel, CNR-K+ channel (412 aas)BacteriaCNR-K+ channel of Rhodopseudomonas palustris (Q02006)

K+ channel protein homologue 


K+ channels protein homologue of Stigmatella aurantiaca (Q08U57)


Putative 6 TMS potassium channel


Potassium ion channel of Myxococcus xanthus


Putative K+ channel


K channel of Cyanotheca (Synechococcus) sp PCC8801


Cyclic nucleotide-gated K+ channel of 459 aas.


Channel of Labenzia aggregata


Uncharacterized ion channel protein of 276 aas and 6 TMSs

UP of Flavobacterium psychrolimnae


TC#NameOrganismal TypeExample

The 6TMS bacterial cyclic nucleotide-regulated, voltage independent channel, MlotiK1 or MloK1 (Clayton et al., 2008). Gating involves large rearrangements of the cyclic nucleotide-binding domains (Mari et al., 2011).  The electron crystalographic structure is available (PDB 4CHW) revealing ligand-induced structural changes (Schünke et al. 2011; Scherer et al. 2014; Kowal et al. 2014). Such changes may be lipid dependent (McCoy et al. 2014). High-speed atomic force microscopy has been used to measure millisecond to microsecond dynamics (Heath and Scheuring 2019).


MlotiK1 of Mesorhizobium loti (Q98GN8)


TC#NameOrganismal TypeExample
1.A.1.26.1The rodent malaria parasite K+ channel, PfKch1 (929aas) (Ellekvist et al., 2008).EukaryotesKch1 of Plasmodium berghei (Q4YNK7)

Voltage-gated potassium channel, KCh1, of 1966 aas with 12 TMSs in a 2 (residues 50 - 100) + 10 (residues 550 - 900) TMS arrangement (Wunderlich 2022).

KCh1 of Plasmodium falciparum


Uncharacterized protein of 1949 aas and 11 - 13 TMSs in a 2 + 8 - 10 +1 TMS arrangement (Wunderlich 2022).

UP of Plasmodium falciparum


TC#NameOrganismal TypeExample

Putative 4 TMS ion channel protein.  TMSs 1-2 may not be homologous to TMSs 3-4 which probably form the channel.


Hypothetic VIC family member of Streptomyces coelicolor


Putative 4 TMS potassium ion channel protein.  TMSs 1-2 may not be homologous to TMSs 3-4 which probably form the channel.


Putative ion channel of Streptomyces coelicolor


Uncharacterized protein of 114 aas


UP of Rhizobium meliloti


Uncharacterized protein of 148 aas and 3 or 4 TMSs

UP of Marinobacter hydrocarbonoclasticus


TC#NameOrganismal TypeExample

Putative K+ channel


Putative K+ channel of Klebsiella varicola (D3RJS6)


Putative K+ channel


Putative K+ channel of Pseudomonas fluorescens (C3K1P0) 


Thylakoid membrane 6 TMS voltage-sensitive K+ channel, SnyK; important for photosynthesis (Checchetto et al. 2012).


SynK of Synechocystis sp.


Putative voltage-dependent K+ channel


K+ channel of Vibrio alginolyticus


Putative voltage-dependent K+ channel


K+ channel of E. coli


Putative voltage-dependent K+ channel


K+ channel of Acinetobacter baumannii


Uncharacterized protein of 228 aas and 6 TMSs

UP of Methanoculleus bourgensis (Methanogenium bourgense)


Two pore domain potassium channel family protein of 246 aas and 6 TMSs.

Putative K+ channel of Planctomycetes bacterium


TC#NameOrganismal TypeExample

The 2 - 4 TMS K+ channel, LctB (Wolters et al. 1999).

Gram-positive bacteria

LctB of Bacillus stearothermophilus


Uncharacterized protein of 481 aas and 2 TMSs.  (Pfam CL0030)


UP of Pyrococcus furiosus


Uncharacterized protein of 326 aas and 2 TMSs

UP of Pseudoalteromonas luteoviolacea


C-terminal 2 TMS channel protein of 723 aas with 5 N-terminal pentapeptide repeats in a YjbI domain of unknown function

Channel protein of Natrinema altunense


Ion transport 2 domain-containing protein of 345 aas and 2 TMSs

Ion transport 2 domain-containing protein of Halococcus salifodinae


Putative cation transporting channel-2 of 288 aas with 2 N-terminal TMSs (Hug et al. 2016).

Channel-2 of Candidatus Peribacter riflensis


Putative K+ channel of 317 aas and 2 TMSs with a central P-loop.

K+ channel of Candidatus Woesearchaeota archaeon (marine sediment metagenome)


TC#NameOrganismal TypeExample

Large conductance, voltage- and Ca2+-activated K+ (BK or Slo) channel. Four pairs of RCK1 and RICK2 domains form the Ca2+-sensing apparatus known as the "gating ring" in Big Potassium (BK) channel proteins (Savalli et al., 2012). Gating of BK channels does not seem to require a physical gate. Instead, changes in the pore shape and surface hydrophobicity in the Ca2+-free state allow the channel to readily undergo hydrophobic dewetting transitions, giving rise to a large free energy barrier for K+ permeation (Jia et al. 2018).  Voltage-dependent dynamics of the BK channel cytosolic gating ring are coupled to the membrane-embedded voltage sensor (Miranda et al. 2018). Slo channels are targets for insecticides and antiparasitic drugs. Raisch et al. 2021 reported structures of Drosophila Slo in the Ca2+-bound and Ca2+-free forms and in complex with the fungal neurotoxin verruculogen and the anthelmintic drug emodepside. The architecture and gating mechanism of Slo channels are conserved, but potential insect-specific binding pockets are present. Verruculogen inhibits K+ transport by blocking the Ca2+-induced activation signal and precludes K+ from entering the selectivity filter while emodepside decreases the conductance by suboptimal K+ coordination and uncouples ion gating from Ca2+ and voltage sensing (Raisch et al. 2021). In neurosecretion, allosteric communication between voltage sensors and Ca2+ binding in BK channels is crucially involved in damping excitatory stimuli. Carrasquel-Ursulaez et al. 2022 demonstrated that two arginines in the transmembrane segment S4 (R210 and R213) function as the BK gating charges. The energy landscape of the gating particles is electrostatically tuned by a network of salt bridges contained in the voltage sensor domain (VSD). 


Ca2+-activated K+ channel of Drosophila melanogaster


Calcium-, magnesium- and voltage-activated K+ channel, Slo1 (Kcma1; KCNMA, KCNMA1), a BK channel, of 1236 aas and 6 N-terminal TMSs. Its activation dampens the excitatory events that elevate the cytosolic Ca2+ concentration and/or depolarize the cell membrane. It therefore contributes to repolarization of the membrane potential, and it plays a key role in controlling excitability in a number of systems. Ethanol and carbon monoxide-bound heme increase channel activation while heme inhibits channel activation (Tang et al. 2003). The molecular structures of the human Slo1 channel in complex with beta4 has been solved revealing four beta4 subunits, each containing two transmembrane helices, encircling Slo1, contacting it through helical interactions inside the membrane. On the extracellular side, beta4 forms a tetrameric crown over the pore. Structures with high and low Ca2+ concentrations show that identical gating conformations occur in the absence and presence of beta4, implying that beta4 serves to modulate the relative stabilities of 'pre-existing' conformations rather than creating new ones (Tao and MacKinnon 2019). BK channels show increased activities in Angelman syndrome due to genetic defects in the ubiquitin protein ligase E3A (UBE3A) gene (Sun et al. 2019). It is a large-conductance potassium (BK) channel that can be synergistically and independently activated by membrane voltage and intracellular Ca2+. The only covalent connection between the cytosolic Ca2+-sensing domain and the TM pore and voltage sensing domains is a 15-residue 'C-linker' which plays a direct role in mediating allosteric coupling between BK domains (Yazdani et al. 2020).  Site specific deacylation by the alpha/beta acyl-hydrolase domain-containing protein 17A, ABHD17a (Q96GS6, 310 aas), controls BK channel splice variant activity (McClafferty et al. 2020). Compared with the structure of isolated hSlo1 Ca2+ sensing gating rings, two opposing subunits in hBK unfurled, resulting in a wider opening towards the transmembrane region of hBK. In the pore gate domain, two opposing subunits moved downwards relative to the two other subunits (Tonggu and Wang 2022).


Kcma1 of Homo sapiens


Large conductance or L-type Ca2+ and voltage-activated K+ channel (LTCC), α-subunit (subunit α1), BK, BKCa, Kca1.1, Slowpoke, Slo1, KCNMA1 or MaxiK (functions with four β-subunits (TC# 8.A.14) encoded by genes KCNMB1-4 and the γ subunit (TC# 8.A.43) in humans (Toro et al. 2013; Li et al. 2016); the positions of beta2 and beta3 have been determined (Wu et al. 2013).  The KB channel is inhibited by 3 scorpion toxins, charybda toxin, iberiotoxin and slotoxin.  It forms a ''Ca2+  nanodomain'' complex with Cav1.2 (L-type; 1.A.1.11.4), Cav2.1 (P/Q-type; 1.A.1.11.5) and Cav2.2 (N-type; 1.A.1.11.6) where Ca2+ influx through the Cav channel activates BKCa (Berkefeld et al., 2006; Romanenko et al., 2006). The RCK2 domain is a Ca2+ sensor (Yusifov et al., 2008). Binding of Ca2+ to D367 and E535 changes the conformation around the binding site and turns the side chain of M513 into a hydrophobic core, explaining how Ca2+ binding opens the activation gate of the channel (Zhang et al., 2010). A structural motif in the C-terminal tail of Slo1 confers carbon monoxide sensitivity to human BKCa channels (Williams et al., 2008; Hou et al., 2008). These channels are present in the inner mitochondrial membrane of rat brain (Douglas et al., 2006).The Stress-Axis Regulated Exon (STREX) is responsible for stretch sensitivity. Ca2+ binds to two sites. Ca2+ binding to the RCK1 site is voltage dependent, but Ca2+ binding to the Ca2+ bowl is not (Sweet and Cox et al., 2008). Type 1 IP3 receptors activate BKCa channels via local molecular coupling in arterial smooth muscle cells (Zhao et al., 2010). The open structure is known (Yuan et al., 2012). BKCa is essential for ER calcium uptake in neurons and cardiomyocytes (Kuum et al., 2012) and link Ca2+ signaling to action potential firing and neurotransmitter release via serotonin receptors in many types of neurons (Rothberg 2012). The molecular mechanism of pharmacological activation of BK channels has been discussed by Gessner et al. (2012). The first TMS of the β2-subunit binds to TMS S1 of the α-subunit (Morera et al., 2012).  Mutations in Cav1.2 give rise to Timothy syndrome (Dixon et al. 2012).  Exhibits low voltage activation by interaction with Cav3 (Rehak et al. 2013) as well as Ca2+-gating (Berkefeld and Fakler 2013). Single-channel kinetics have been reported (Geng and Magleby 2014). The γ-subunit has TC# 8.A.43.1.8.  RBK channels regulate myogenesis in vascular smooth muscle cells (Krishnamoorthy-Natarajan and Koide 2016). Latorre et al. 2017 reviewed molecular, physiological and pathological aspects of Slo1. The microRNA, mmumiR449a, reduced the mRNA expression levels of transient receptor potential cation channel subfamily A member 1 (TRPA1), and calcium activated potassium channel subunit alpha1 (KCNMA1) and increased the level of transmembrane phosphatase with tension homology (TPTE) in the DRG cells (Lu et al. 2017), thereby reducing pain. The N-terminal sequence determines its modification by β-subunits (Lorca et al. 2017). Inhibition of BKCa negatively alters cardiovascular function (Patel et al. 2018). BKCa may be the target of verteporfin, a benzoporphyrin photosensitizer that alters membrane ionic currents (Huang et al. 2019). Globotriaosylceramide (Gb3) accumulates due to mutations in the gene encoding alpha-galactosidase A. Gb3 deposition in skin fibroblasts impairs KCa1.1 activity and activate the Notch1 signaling pathway, resulting in an increase in pro-inflammatory mediator expression, and thus, contributing to cutaneous nociceptor sensitization as a potential mechanism of FD-associated pain (Rickert et al. 2019). This channel may be present in mitochondria (Parrasia et al. 2019). The Slo3 (TC# 1.A.1.3.5) cytosolic module confers pH-dependent regulation whereas the Slo1 cytosolic module confers Ca2+-dependent regulation (Xia et al. 2004). Elevated extracellular Ca2+ aggravates iron-induced neurotoxicity because LTCCs mediate iron transport in dopaminergic neurons and this, in turn, results in elevated intracellular Ca2+ and further aggravates iron-induced neurotoxicity (Xu et al. 2020). Agonists include BMS-191011, NS1619, NS11021, epoxyeicosatrienoic acid isoforms, while inhibitors include iberiotoxin and penitrem A which have been used to study the system in megakaryocytes and platelets (Balduini et al. 2021). Medicinal plant products can interact with BKCa (Rajabian et al. 2022).


BKCa or MaxiK channel of Rattus norvegicus (Q62976)


Ca2+-activated K+ channel Slo-1 (Maxi K; BK channel) (ethanol-activated; responsible for intoxication) (Davies et al., 2003); tyrosyl phosphorylation regulates BK channels via cortactin (Tian et al. 2008a), but palmitoylation gates phosphorylation-dependent regulation of BK potassium channels (Tian et al., 2008b). Also regulated by Mg2+ which mediates interaction between the voltage sensor and cytosolic domain to activate BK channels (Yang et al., 2007). Modulated by the ss2 subunit (Lee et al., 2010). The structure of the gating ring from the human large-conductance Ca2+-gated K+ channel has been reported (Wu et al., 2010). Four pairs of RCK1 and RICK2 domains form the Ca2+-sensing apparatus known as the "gating ring" in BK channel proteins (Savalli et al., 2012).  The dystrophin (Q9TW65) dystrobrevin (Q9Y048) complex controls BK channel localization and muscle activity as well as neurotroansmitter release (Kim et al. 2009, Chen et al. 2011).  Syntrophin (Q93646) links various receptors and transporters to the actin cytoskeleton and the dystrophin glycoprotein complex (DGC), and α-catulin (CTN-1; 759 aas, 0 TMSs) facilitates targeting. The BK channel is a tetramer where the pore-forming α-subunit contains seven transmembrane segments (González-Sanabria et al. 2021). It has a modular architecture containing a pore domain with a highly potassium-selective filter, a voltage-sensor domain and two intracellular Ca2+ binding sites at the C-terminus. BK is found in the plasma membrane of different cell types, the inner mitochondrial membrane (mitoBK) and the nuclear envelope's outer membrane (nBK). Like BK channels in the plasma membrane (pmBK), the open probability of mitoBK and nBK channels are regulated by Ca2+ and voltage and modulated by auxiliary subunits. BK channels share common pharmacology to toxins such as iberiotoxin, charybdotoxin, paxilline, and agonists of the benzimidazole family (González-Sanabria et al. 2021).



BK K+ channel of Caenorhabditis elegans (Q95V25)


The one or two component intracellularly Na+ and Cl--activated delayed rectifier K+ channel, rSlo2.2 (Slack; KCNT1)/r Slo2.1 (Slick; KCNT2; TC# 1.A.1.3.6) provides protection against ischemia (Yuan et al., 2003). The N-terminal domain of Slack determines the formation and trafficking of Slick/Slack heteromeric sodium-activated potassium channels (Chen et al., 2009). Slick and Slack can also form separate homooligomeric channels. These channels are widely distributed in the mammalian CNS and they play roles in slow afterhyperpolarization, generation of depolarizing afterpotentials and in setting and stabilizing the resting potential (Rizzi et al. 2015). The small cytoplasmic protein beta-synuclein TC# 1.C.77.1.2) and the transmembrane protein 263 (TMEM 263; TC# 8.A.101.1.1) are interaction partners of both Slick and Slack channels. The inactive dipeptidyl-peptidase (DPP 10) and the synapse associated protein 102 (SAP 102) are constituents of the Slick and Slack channel complexes (Rizzi et al. 2015).


Slo2 of Rattus norvegicus (Q9Z258)


Sperm Slo3 high conductance K+ channel, activated by voltage and intracellular alkalinization. In sperm, it gives rise to pH-dependent outwardly rectifying K+ currents. (required for the ensuing acrosome reaction; activated by phosphatidylinositol 4,5-bisphosphate (PIP(2)) (Tang et al., 2010). The Slo3 cytosolic module confers pH-dependent regulation whereas the Slo1 (TC# 1.A.1.3.2)  cytosolic module confers Ca2+-dependent regulation (Xia et al. 2004). When mammalian sperm are released in the female reproductive tract, they are incapable of fertilizing the oocyte. They need a prolonged exposure to the alkaline medium of the female genital tract before their flagellum gets hyperactivated and the acrosome reaction can take place, allowing the sperm to interact with the oocyte (de Prelle et al. 2022). Ionic fluxes across the sperm membrane are involved in two essential aspects of capacitation: the increase in intracellular pH and membrane hyperpolarization. The SLO3 potassium channel and the sNHE sodium-proton exchanger are necessary for the capacitation process to occur. As the SLO3 channel is activated by an increase in intracellular pH and sNHE is activated by hyperpolarization, they act together as a positive feedback system (de Prelle et al. 2022).


Slo3 of Mus musculus (O54982)


Human outward rectifying potassium channel, Slo2.1 (also called KCNT2 and Slick) of 1135 aas. Produces rapidly activating outward rectifier K+ currents. Activated by high intracellular sodium and chloride levels. Channel activity is inhibited by ATP and by inhalation of anesthetics such as isofluraneInhibited upon stimulation of G-protein coupled receptors such as CHRM1 and GRIA1.  Orthologous to 1.A.1.3.4 (Garg et al. 2013) and can form a heteromeric complex with it and several other proteins (see TC# 1.A.1.3.4).  Hydrophobic interactions between residues in S5 and the C-terminal end of the pore helix stabilize Slo2.1 channels in a closed state (Suzuki et al. 2016). Despite their apparent high levels of expression, the activities of somatic KNa (Slo2.1 and Slo2.2) channels are tightly regulated by the activity of the Na+/K+ pump (Gray and Johnston 2021).


Slo2.1 of Homo sapiens


Slo2.2 sodium-activated potassium channel subfamily T member 1 of 1217 aas and 6 putative N-terminal TMSs plus a P-loop.  Cryo electron microscopic structures of the chicken orthologue at 4.5 Å resolution has been solved, revealing a large cytoplasmic gating ring in which resides the Na+-binding site and a transmembrane domain that closely resembles voltage-gated K+ channels (Hite et al. 2015).

Slo2.2 of Homo sapiens


SLOwpoke K+ channel, SLO-2 or Slo2, of 1107 aas and 6 TMSs, present in motor neurons.  It has six putative TMSs with a K+-selective pore and a large C-terminal cytosolic domain (Lim et al. 1999). Its requirements for both Cl- and Ca2+ are synergistic and associated with the same functional domain (Yuan et al. 2000) which serves to counteract hypoxia stress when cytoplasmic Cl- and Ca2+ concentrations increase (Yuan et al. 2003; Santi et al. 2003).  SLO2 protects from hypoxic injury by increasing the permeability of the mitochondrial inner membrane to K+ (Wojtovich et al. 2011). SLO-2 is functionally coupled with CaV1 and regulates neurotransmitter release (Liu et al. 2014).  Partially responsible for action potential repolarization during synaptic transmission (Ford and Davis 2014).

Slo-2 of Caenorhabditis elegans


Voltage-gated calcium-activated potassium channel of 862 aas and 6 or 7 TMSs.

VIC protein of Entamoeba histolytica


TC#NameOrganismal TypeExample

Uncharacterized putative chloride channel protein of 219 aas and 2 TMSs.

UP of Vibrio phage 1.081.O._10N.286.52.C2


TC#NameOrganismal TypeExample

Uncharacterized VIC superfamily member of 230 aas and 6 or 7 TMSs (Anwar and Samudrala 2018).

UP of Entamoeba histolytica


TC#NameOrganismal TypeExample

K+ channel, AKT1; may form heteromeric channels with KC1 (TC # 1.A.1.4.9) (Geiger et al., 2009).  Required for seed development and postgermination growth in low potassium (Pyo et al. 2010).  Functions optimally with intermediate potassium concentrations (~1 mM) (Nieves-Cordones et al. 2014). In barley, it may play a role in drought resistance (Cai et al. 2019).  HAK/KUP/KT8, GrAKT2.1 and GrAKT1.1 potassium channels may function in response to abiotic stress in Gossypium raimondii (Azeem et al. 2021). Plants obtain nutrients from the soil via transmembrane transporters and channels in their root hairs, from which ions radially transport in toward the xylem for distribution across the plant body. Dickinson et al. 2021 determined structures of the hyperpolarization-activated channel, AKT1, from Arabidopsis thaliana, which mediates K+ uptake from the soil into plant roots. The structures of AtAKT1, embedded in lipid nanodiscs, show that the channel undergoes a reduction of C4 to C2 symmetry, possibly to regulate its electrical activation.



AKT1 of Arabidopsis thaliana

1.A.1.4.10Inward rectifier K+ channel AKT1 (45% identical to 1.A.1.4.1; 944aas) (Garciadeblas et al., 2007).


Akt1 of Physcomitrella patens (A5PH36)


Potassium channel, KCN11.  The UniProt entry included here is not complete. The correct gene ID is Cre06.g278111 in the Chlamydomonas genome database Phytozome. The complete sequence and description of its function are published by Xu et al. (2016).  KCN11 is a 6 TMS organelle K+ channel found exclusively in the contractile vacuole. It is required for osmoregulation under hypotonic conditions (Xu et al. 2016).

KCN11 of Chlamydomonas reinhardtii (Chlamydomonas smithii)


Synthetic light-sensitive K+ channel, BLINK2, of 406 aas and 2 TMSs with a P-loop between the two TMSs (residues 158 - 233). Residues 8 - 142 are derived from residues 403 - 537 of NPH1-1, a light-sensitive ser/thr protein kinase of the oat plant, Avena sativa ( acc # AAC05083); residues 143 - 234 are derived from residues 3 - 94 of the Paramecium bursaria Chlorella virus 1 (PBCV-1) K+ channel, Kcv1 (TC# 1.A.1.12.1); residues 235 - 404 derive from residues 506 - 675 of another K+ channel protein, KAT1 (TC# 1.A.1.12.1). BLINK1 has been used to manipulate stomatal kinetics to improve carbon assimilation, water use, and growth of A. thaliana (Papanatsiou et al. 2019).

Synthetic light-sensitive K+ channel, BLINK2.

1.A.1.4.2K+channel, KDC1 (voltage and pH-dependent; inward rectifying). Does not form homomeric channels. The C-terminus functions in the formation of heteromeric complexes with other potassium alpha-subunits such as KAT1 (1.A.1.4.7) (Naso et al., 2009).


KDC1 of Daucus carota

1.A.1.4.3Inward rectifying, pH-independent K+ channel, KZM1 (Philippar et al., 2003)PlantsKZM1 of Zea mays (CAD18901)

Guard cell outward rectifying K+ out channel, GORK, controls leaf stomatal pore opening (by increasing solute content) and closing (by decreasing solute content), which in turn controls gas and water loss (Schroeder, 2003).


GORK of Arabidopsis thaliana (CAC17380)


Root stelar K+ outward rectifying channel, SKOR (involved in K+ release into the xylem sap; part of the plant water stress response) (Gaymard et al., 1998). SKOR is an outwardly rectifying K+ channel that mediates the delivery of K+ from stelar cells to the xylem in the roots, a critical step in the long-distance distribution of K+ from roots to the upper parts of the plant. Liu et al. 2006 and Johansson et al. 2006 reported that SKOR channel activity is strictly dependent on intracellular and extracellular K+ concentrations. Activation by K+ did not affect the kinetics of voltage dependence, indicating that a voltage-independent gating mechanism underlies K+ sensing. The C-terminal non-transmembrane region is required for sensing. The intracellular K+ sensing mechanism couples SKOR activity to the K+ status of the 'source cells', thereby establishing a supply-based unloading system for the regulation of K+ distribution (Liu et al. 2006; Johansson et al. 2006). SKOR may be involved in droght resistance in barley (Cai et al. 2019).


SKOR of Arabidopsis thaliana (AAF26975)


Heterotetrameric K+ channel, KAT2/AKT2/KCT2 (Nieves-Cordones et al. 2014). Forms heteromeric channels (2:2 stoichiometry) with KAT1 (1.A.1.4.7) (Lebaudy et al., 2010) (Properties differ from those of homomeric channels; Xicluna et al., 2007).  KAT2 also forms homomeric channels in the plasma membrane (Nieves-Cordones et al. 2014). AKT2 functions in phloem loading and unloading and operates as an inward-rectifying channel that allows H+-ATPase-energized K+ uptake. Through reversible post-translational modifications, it can also function as an open, K+-selective channel, providing energy for transmembrane transport processes. It is present in a complex of several proteins in which it interacts with the receptor-like kinase, MRH1/MDIS2 (Sklodowski et al. 2017). The ortholog in Brassica rapa (Chinese cabbage), KCT2, is induced by stress. It has a TxxTxGYGD motif in the P-domain and a putative cyclic nucleotide-binding-like domain within a long C-terminal region (Zhang et al. 2006). HAK/KUP/KT8, GrAKT2.1 and GrAKT1.1 potassium channels may function in response to abiotic stress in Gossypium raimondii (Azeem et al. 2021).




AKT2/KAT2 of Arabidopsis thaliana
AKT2 (Q38898)
KAT2 (Q38849)


The voltage-sensitive inward rectifying K+ channel, KAT1 (similar to 1.A.1.4.3; activated by protein 14-3-3 (AAF87262)) (Sottocornola et al., 2006). May also transport Na+ and Cs+ (Nakamura and Gaber, 2009). Forms heterotetrameric channels with KAT2 with a stoichiometry of 2:2 (Lebaudy et al., 2010). The pH-sensor is built of a sensory cloud rather than of single key amino acids (Gonzalez et al., 2011). The transmembrane core region of KAT1 is important for its activity in S. cerevisiae, and this involves not only the pore region but also parts of its voltage-sensor domain (Saito et al. 2017). Electromechanical coupling and gating polarity in KAT1 displays a depolarized voltage sensor, which interacts with a closed pore domain directly via two interfaces and indirectly via an intercalated phospholipid. Direct interaction between the sensor and the C-linker hairpin in the adjacent pore subunit is the primary determinant of gating polarity (Clark et al. 2020). Possibly an inward motion of the S4 sensor helix of 5-7 Å underlies a direct-coupling mechanism, driving a conformational reorientation of the C-linker and ultimately opening the activation gate formed by the S6 intracellular bundle. KAT1, and presumably other hyperpolarization-gated plant CNBD channels, can open from an S4-down VSD conformation homologous to the divalent/proton-inhibited conformation of EAG family K+ channels (Zhou et al. 2021).


KAT1 of Arabidopsis thaliana (Q39128)

1.A.1.4.8Inward rectifying Shaker K+ channel SPIK (AKT6) (expressed in pollen, and involved in pollen tube development) (Mouline et al., 2002). PlantsSPIK of Arabidopsis thaliana

The KC1 (KAT3) potassium channel-like subunit; regulates other channels such as AKT1 (1.A.1.4.1) and KAT1 (1.A.1.4.7) (Duby et al., 2008); may form heteromeric channels with AKT1 (Geiger et al., 2009). It forms a tripartite SNARE-K+ channel complex which regulates KAT3 channel opening (Honsbein et al., 2009).  Tripartite interactions with SNARE (SYP121; SYR1; PEN1) and AKT1 control gating (Grefen et al. 2010).  ZKC1 also forms homoleric channels in the endoplasmic reticulum (Nieves-Cordones et al. 2014).


KC1 of Arabidopsis thaliana (P92960)


TC#NameOrganismal TypeExample

Cyclic nucleotide-gated (CNG) hyperpolarization-activated nonselective cation HCN channel (PNa+ /PK+ ≈ 1.0) of 682 aas and 6 TMSs. 


CNG channel of Ictalurus punctatus


Orthologue K+/Na+ pacemaker channel, Hcn4 (Scicchitano et al., 2012).  Hyperpolarization-activated cyclic nucleotide-regulated HCN channels underlie the Na+-K+ permeable IH pacemaker current. As with other voltage-gated members of the 6-transmembrane KV channel superfamily, opening of HCN channels involves dilation of a helical bundle formed by the intracellular ends of S6, but this is promoted by inward, not outward, displacement of S4. Direct agonist binding to a ring of cyclic nucleotide-binding sites, one of which lies immediately distal to each S6 helix, imparts cAMP sensitivity to HCN channel opening. At depolarized potentials, HCN channels are further modulated by intracellular Mg2+ which blocks the open channel pore and blunts the inhibitory effect of outward K+ flux. Lyashchenko et al. 2014 showed that cAMP binding to the gating ring enhances not only channel opening but also the kinetics of Mg2+ block.  Mutations in HCN4 cause sick sinus and the Brugada syndrome, cardiac abnormalities. HCN4 is associated with famiial sinus bradycardia (Boulton et al. 2017). Activation of Hcn4 by cAMP has been reviewed (Porro et al. 2020). The HCN1-4 channel family is responsible for the hyperpolarization-activated cation current If/Ih that controls automaticity in cardiac and neuronal pacemaker cells. Saponaro et al. 2021 presented cryo-EM structures of HCN4 in the presence or absence of bound cAMP, displaying the pore domain in closed and open conformations. Analysis of cAMP-bound and -unbound structures shed light on how ligand-induced transitions in the channel cytosolic portion mediate the effect of cAMP on channel gating and highlighted the regulatory role of a Mg2+ coordination site formed between the C-linker and the S4-S5 linker. Comparison of open/closed pore states shows that the cytosolic gate opens through concerted movements of the S5 and S6 transmembrane helices. Furthermore, in combination with molecular dynamics analyses, the open pore structures provide insights into the mechanisms of K+/Na+ permeation (Saponaro et al. 2021). 


Hcn4 of Homo sapiens (Q9Y3Q4)


Hyperpolarization-activated cyclic nucleotide-gated (HCN) inward current carrying cationic channel, I(f), (HCN2/HCN4) (Ye and Nerbonne, 2009).  Functional interactions between the HCN2 TM region and C-terminal region govern multiple CNB fold-mediated mechanisms, implying that the molecular mechanisms of autoinhibition, open-state trapping, and Quick-Activation include participation of TM region structures (Page et al. 2020). Rhythmic activity in pacemaker cells, as in the sino-atrial node in the heart, depends on the activation of HCN channels. As in depolarization-activated K+ channels, the fourth transmembrane segment S4 functions as the voltage sensor in hyperpolarization-activated HCN channels (Wu et al. 2021). S4 in HCN channels moves in two steps in response to hyperpolarizations, and the second S4 step correlates with gate opening (Wu et al. 2021).


HCN2/HCN4 channels of Homo sapiens 
HCN2 (Q9UL51)
HCN4 (Q9Y3Q4) 


Cyclic nucleotide-gated cation channel α3 (CNGA3 or CNG3); photoreceptor cGMP-gated channel α-subunit. Also possibly expressed in inner ear cell cells where it binds to an intracellular C-terminal domain of EMILIN1 (Selvakumar et al., 2012).  Elastic network model analysis of the CNGA3 channel supports a modular model of allosteric gating, according to which protein domains are quasi-independent: they can move independently but are coupled to each other allosterically (Gofman et al. 2014). An intact S4 is required for proper protein folding and/or assembly involving two glycosylation sites in the endoplasmic reticulum membrane (Faillace et al. 2004). It may function with CNGB3 (TC# 1.A.1.5.37; Q9NQW8; 809 aas and 6 TMSs).


CNGA3 of Homo sapiens (Q16281) 


Trout cyclic nucleotide-gated cation channel α3 (CNGA3 or CNG3). Expressed in inner ear cell cells where it binds to an intracellular C-terminus domain of EMILIN1 (Selvakumar et al., 2012). 


CNGA3 of Oncorhynchus mykiss (G9BHJ0)

1.A.1.5.14Probable cyclic nucleotide-gated ion channel 6 (AtCNGC6) (Cyclic nucleotide- and calmodulin-regulated ion channel 6)PlantsCNGC6 of Arabidopsis thaliana

Cyclic nucleotide gated K+ channel of 650 aas


Channel of Naegleria gruberi


Cyanobacterial cyclic nuceotide K+ channel of 454 aas (Brams et al. 2014).


Channel of Trichodesmium erythraeum


Cyclic nucleotide-gated K+channel of 430 aas, probably with 6 TMSs in a 2 + 2 + 1 + P-loop + 1 TMS arrangement.  The channel is activated by cAMP, not by cGMP, and is highly specific for K+ over Na+.  It has a C-terminal hydrophilic cAMP-binding domain linked to the 6 TMS channel domain (Brams et al. 2014). An SthK C-linker domain is essential for coupling cyclic nucleotide binding to channel opening (Evans et al. 2020). An agonist-dependent conformational change in which residues of the B'-helix displayed outward movement with respect to the symmetry axis of the channel in the presence of cAMP was observed, but not with the partial agonist, cGMP. This conformational rearrangement was observed both in detergent-solubilized SthK and in channels reconstituted into lipid nanodiscs. In addition to outward movement of the B'-helix, channel activation involves upward translation of the cytoplasmic domain with formation of state-dependent interactions between the C-linker and the transmembrane domain (Evans et al. 2020).


Channel of Spirochaeta thermophila


Cyclic nucleotide-gated cation (CNG) channel of 665 aas.

Animals (Insects)

CNG of Drosophila melanogaster


TAX-2 cyclic nucleotide-gated cation channel-B (CNGB) of 800 aas (Wojtyniak et al. 2013).


TAX-2 CNGB of Caenorhabditis elegans


Hyperpolarization-activated and cyclic nucleotide-gated K+ channel, HCN (bCNG-1) (PNa+/PK+ ≈ 0.3). The human orthologue (O88703) is 863 aas in length and also catalyzes mixed monovalent cation currents K+:Na+= 4:1 (Lyashchenko and Tibbs et al., 2008). Biel et al. (2009) presented a detailed review of hyperpolarization-activated cation-channels. They are inhibited by nicotine and epibatidine which bind to the inner pore (Griguoli et al., 2010). They control cardiac and neuronal rhythmicity. HCN channels contain cyclic nucleotide-binding domains (CNBDs) in their C-terminal regions, linked to the pore-forming transmembrane segment with a C-linker. The C-linker couples the conformational changes caused by the direct binding of cyclic nucleotides to the HCN pore opening. Cyclic dinucleotides antagonize the effect of cyclic nucleotides in HCN4 but not in HCN2 channels. Interaction of the C-linker/CNBD with other parts of the channel appears to be necessary for cyclic-dinucleotide binding in HCN4 channels (Hayoz et al. 2017).


HCN of Mus musculus


TAX-4 cyclic nucleotide-gated cation channel A (CNGA) of 733 aas (Wojtyniak et al. 2013).  Li et al. 2017 determined the 3.5 Å resolution single-particle electron cryo-microscopy structure  in the cyclic guanosine monophosphate (cGMP)-bound open state. The channel has an unusual voltage-sensor-like domain, accounting for its deficient voltage dependence. A carboxy-terminal linker connecting S6 and the cyclic-nucleotide-binding domain interacts directly with both the voltage sensor-like domain and the pore domain, forming a gating ring that couples conformational changes triggered by cyclic nucleotide binding to the gate. The selectivity filter is lined by the carboxylate side chain of a functionally important glutamate and three rings of backbone carbonyls (Li et al. 2017).


TAX-4 CNGA of Caenorhabditis elegans


K+ channel protein, PAK2.1 of 543 aas.  Contains a cyclic nucleotide-binding domain (Ling et al. 1998; Jegla and Salkoff 1995).

Alveolata (ciliates)

PAK2.1 of Paramecium tetraurelia


K+ channel protein, PAK11-MAC of 772 aas.  Contains a cyclic nucleotide-binding domain (Ling et al. 1998; Jegla and Salkoff 1995).

Alveolata (ciliates)

PAK11-MAC of Paramecium tetraurleia


Cyclic nuceotide-gated Na+ channel of 729 aas and 6 putative TMSs, CNGC19.  It is constitutively expressed in roots but induced in leaves and shoots under conditions of salt (NaCl) stress (Kugler et al. 2009). CNG19 and CNGC20 self-associate, form heteromeric complexes, and these complexes arei phosphorylated and stabilized by BOTRYTIS INDUCED KINASE1 (BIK1). Tight control of the CNG19/CNGC20 Ca2+ ion channel is important for regulating immunity (Zhao et al. 2021).

CNGC19 of Arabidopsis thaliana


Cyclic nucleotide-gated Na+ channel of 764 aas and 6 putative TMSs, CNGC20.  Induced in shoots in response to salt (NaCl) stress (Kugler et al. 2009). CNGC20 self-associates, forms heteromeric complexes with CNGC19, and is phosphorylated and stabilized by BOTRYTIS INDUCED KINASE1 (BIK1). Tight control of the CNGC20 Ca2+ ion channel is important for regulating immunity (Zhao et al. 2021). Spermidine may play a role in salt stress in rice (Saha et al. 2020).

CNGC20 of Arabidopsis thaliana


Cyclic nuceotide gated channel of 706 aas, CNGC18.  It is the essential Ca2+ channel for pollen tube guidance (Gao et al. 2016). MLO5 and MLO9 selectively recruit the Ca2+ channel CNGC18-containing vesicles to the plasma membrane through the R-SNARE proteins, VAMP721 and VAMP722 in trans mode. Meng et al. 2020 identified members of the conserved 7 TMS MLO family (expressed in the pollen tube) as tethering factors for Ca2+ channels, revealing a mechanism of molecular integration of extracellular ovular cues and selective exocytosis. This work sheds light on the general regulation of MLO proteins in cell responses to environmental stimuli (Meng et al. 2020).

CNGC18 of Arabidopsis thaliana (Mouse-ear cress)


CNGC15 of 678 aas and 6 TMSs.  In Medicago truncatula, three such channels, CNGC15a, b and c, are required for nuclear calcium oscillations, spiking and subsequent symbiotic responses. These three channels form a complex with the potassium permeable channel, DMI1 (TC# 1.A.1.23.1), in the nuclear envelope.  They are expressed in flowers and pods, and mutants in these channels have decreased fertilization rates (Charpentier et al. 2016). 

CNG15 of Arabidopsis thaliana


The cyclic nucleotide-gated cation channel, CNG-1 of 661 aas and 6 TMSs. CNG-1 functions in multiple capacities to link nutritional information with behavioral output (He et al. 2016).

CNG-1 of Caenorhabditis elegans


spHCN1 is a pacemaker hyperpolarization-activated cyclic nucleotide-gated (HCN) non-selective cation channel of 767 aas and 6 TMSs that opens due to inward movement of the positive charges in the fourth TMS (S4). This channel is similar to a COOH-terminal-deleted HCN1 channel, suggesting that the main functional differences between spHCN and HCN1 channels are due to differences in their COOH termini (Vemana et al. 2004). These channels open after only two S4s have moved, and S4 motion is rate limiting during voltage activation of spHCN channels (Bruening-Wright et al. 2007). HCN channels regulate electrical activity in the heart and brain. Distinct from mammalian isoforms, the sea urchin (spHCN) channel exhibits strong voltage-dependent inactivation in the absence of cAMP (Idikuda et al. 2018). The voltage sensor undergoes a large downward motion during hyperpolarization (Dai et al. 2019). Sea urchin HCN1 and 2 (TC# 1.A.1.5.33) (spHCN) channels undergo inactivation with hyperpolarization which occurs only in the absence of cyclic nucleotide (Dai et al. 2021). Removing cAMP produces a largely rigid-body rotation of the C-linker relative to the transmembrane domain, bringing the A' helix of the C-linker in close proximity to the voltage-sensing S4 helix. In addition, rotation of the C-linker is elicited by hyperpolarization minus cAMP. Thus, in contrast to electromechanical coupling for channel activation - the A' helix serves to couple the S4-helix movement for channel inactivation, which is likely a conserved mechanism for CNBD-family channels (Dai et al. 2021).


HPN1 of Strongylocentrotus purpuratus (Purple sea urchin)


Heterotetrameric (3A:1B) rod photoreceptor cyclic GMP-gated cation channel, CNGA1 or CNCG or CNCG1 (Zhong et al., 2002) of 686 aas and 5 or 6 TMSs. Cyclic nucleotides are required to open the channel. Gating is proposed to be initiated by an anticlockwise rotation of the N-terminal region of the C-linker, which is then, transmitted through the S6 transmembrane helices to the P-helix, and in turn from this to the pore lumen, which opens from 2 to 5 Å, thus allowing for ion permeation (Giorgetti et al. 2005). Defects produce channelopathies (Biel & Michalakis, 2007). A ring of four glutamate residues (Glu363) in the outer vestibule, and a ring of four threonines (Thr360) in the inner vestibule of the pore of CNGA1 channels constitute binding sites for permeating ions (Marchesi et al., 2012).  The tetraspanning peripherin-2 (TC# 8.A.40.1.2) links rhodopsin to this cyclic nucleotide-dependent channel in the outer segments of rod photoreceptors.  The G266D retinitis pigmentosa mutation in TMS 4 of rhodopsin abolishes binding of peripherin-2 and prevents association with the CNGA1/CNGB1a subunits present in the complex (Becirovic et al. 2014).  External protons cause inactivation (Marchesi et al. 2015). CNG transmembrane domains have dynamic structures, undergoing conformational rearrangements (Maity et al. 2015).  Moreover, structural heterogeneity of CNGA1 channels has been demonstrated (Maity et al. 2016).


CNG of Homo sapiens
Subunit A1 (CNGA1)
Subunit B1 (CNGB1)


Hyperpolarization-activated cyclic nucleotide-modulated cation channel splice variant ABs-II of 682 aas and probably 6 TMSs, Ih channel encoded by the PIIH gene (Ouyang et al. 2007). 

Ih channel of Panulirus interruptus (California spiny lobster) (Palinurus interruptus)


Multi-domain cation channel with a C-terminal cyclic nucleotide-binding domain; of 465 aas and 6 TMS, LliK.  Cyclic nucleotide-gated (CNG) and hyperpolarization-activated cyclic nucleotide-regulated (HCN) channels play roles in phototransduction, olfaction, and cardiac pace making.  James et al. 2017 used cryoEM to determine the structure of the intact LliK CNG channel. A short S4-S5 linker connects voltage-sensing and pore domains to produce a non-domain-swapped transmembrane architecture. The conformation of the LliK structure may represent a functional state of this channel family not seen before (James et al. 2017).

LliK of Leptospira licerasiae


HCN1 is a hyperpolarization-activated cyclic nucleotide-gated (HCN) channel of 890 aas and 6 TMSs that opens due to inward movement of the positive charges in the fourth transmembrane domain (S4).  These channels open after only two S4s have moved, and S4 motion is rate limiting during voltage activation of spHCN channels (Bruening-Wright et al. 2007). HCN1 exhibits weak selectivity for potassium over sodium ions.  It's structure (3.5 Å resolution) is known (Lee and MacKinnon 2017).  It contributes to the native pacemaker currents in heart and neurons. It may also mediate responses to sour stimuli. It is inhibited by Cs+, zatebradine, capsazepine and ZD7288 (Gill et al. 2004). HCN1 mutational variants include epileptic encephalopathy and common generalized epilepsy. HCN1 has a pivotal function in brain development and control of neuronal excitability (Marini et al. 2018). The interaction with filamin A seems to contribute to localizing HCN1 channels to specific neuronal areas and to modulating channel activity (Gravante et al. 2004). The HCN domain is required for HCN channel cell-surface expression, and it couples voltage- and cAMP-dependent gating mechanisms (Wang et al. 2020). Changes in the local S4 environment provide a voltage-sensing mechanism for mammalian hyperpolarization-activated HCN channels (Bell et al. 2004).

HCN1 of Homo sapiens


Hyperpolarization-gated and cyclic nucleotide regulated K+ channel of 638 aas and 6 TMSs, HCN2, present in the flagellum of sea urchin sperm (Galindo et al. 2005).  See also TC# 1.A.1.5.29.

HCN2 of Strongylocentrotus purpuratus (Purple sea urchin)


Cyclic nucleotide-binding domain-containing protein, Cng-3, of 626 aas and 5 - 7 TMSs. It is essential for thermotolerance (Cho et al. 2004). CNG-3 is required in the AWC for adaptation to short (thirty minute) exposures of odor, and contains a candidate PKG phosphorylation site required to tune odor sensitivity (O'Halloran et al. 2017). Cyclic nucleotide-gated channel, CNG-3, determines the timing of transition of temperature preference after a shift in cultivation temperature (Aoki et al. 2018).

Cng-3 of Caenorhabditis elegans


The cyclic ABP-gated K+ channel, SthK of 430 aas and 6 TMSs in a 2 + 2 + 1 + P-loop +1 TMS arrangement. This channel and others have been studied by high-speed atomic force microscopy (HS-AFM) which has made it possible to characterized the conformational dynamics of single unlabeled transmembrane channels and transporters (Heath and Scheuring 2019).

SthK of Spirochaeta thermophila


Cyclic nucleotide-gated ion channel 17, CNGC17, of 720 aas and 6 TMSs. It forms a functional cation-translocating unit with AHAs that is activated by PSKR1/BAK1 and possibly other BAK1/RLK complexes (Ladwig et al. 2015) and is required for PSK-induced protoplast expansion.

CNGC17 of Arabidopsis thaliana (Mouse-ear cress)


Cyclic GMP-gated ion channel β-subunit of 809 aas and 6 TMSs. It may function with CNGA3 (TC# 1.A.1.5.12), but it does not correct mutational defects in the S4 TMS of the α-subunit, CNGA3 (Faillace et al. 2004).

CNGB3 of Homo sapiens

1.A.1.5.4Olfactory heteromeric cyclic nucleotide-gated cation (mainly Na+, Ca2+) channel CNGA2/CNGA4/CNGB1b (present in sensory cilia of olfactory receptor neurons; activated by odorant-induced increases in cAMP concentration) (Michalakis et al., 2006).AnimalsCNGA2 complex of Mus musculus
CNGA2 (Q62398)
CNGA4 (AAI07349)
CNGB1b (NP_001288)

The cyclic nucleotide- and voltage-gated ion (K+, Rb+, Cs+) channel, CNGC1 (inward rectifying) (functions in heavy metal and cation transport, as does CNGC10) (Dreyer and Uozumi, 2011; Zelman et al., 2012).


CNGC1 of Arabidopsis thaliana (O65717)


The cyclic nucleotide-gated ion (K+, Rb+, Cs+) channel, CNGC2 (functions in plant defense responses, as does CNGC4) (Zelman et al., 2012).


CNGC2 of Arabidopsis thaliana (O65718)


The cyclic nucleotide-gated ion (K+, Rb+, Cs+) channel, HLM1 (CNGC4) It mediates the hypersensitive response (HR) of plants in programmed cell death. Mutants show abnormal cell death and resistance to infection by Pseudomonas syringae (Balagué et al., 2003; Zelman et al., 2012).


HLM1 of Arabidopsis thaliana


The non-selective cation transporter involved in germination, CNGC3 (Gobert et al., 2006; Zelman et al., 2012).


CNG3 of Arabidopsis thaliana (Q9SKD7)

1.A.1.5.9The cyclic nucleotide-gated K+ channel, Sp-tetraKCNG (2238 aas) (Galindo et al., 2007)AnimalsSp-tetraKCNG of Strongylocentrotus purpuratus (ABN14774)

TC#NameOrganismal TypeExample

K+ channel, MthK or MVP of 209 aas and 6 TMSs.  Voltage-gated potassium-selective channel opened by hyperpolarization (Hellmer and Zeilinger 2003).  Mediates K+ uptake and sensitivity.  The structure and local dynamics of the closed activation gate (lower S6 region) of MVP have been reported (Randich et al. 2014).


MthK channel protein of Methanocaldococcus jannaschii (Methanococcus jannaschii)


TC#NameOrganismal TypeExample

Tok1 twin (dual) barrel outward rectifying K+ channel with exterme assymmetry which includes an extra 4 N-terminal TMSs for a total of 16 TMSs.  (Transports K+ and Cs+) (Bertl et al., 2003; Roller et al. 2008).  TOKs are outwardly rectifying K+ channels in fungi with two pore-loops and eight transmembrane spans. Lewis et al. 2020 described the TOKs from four fungal pathogens. These TOKs pass large currents only in the outward direction like this ScTOK. ScTOK, AfTOK1 (Aspergillus fumigatus), and H99TOK (Cryptococcus neoformans grubii) are K+-selective and pass current above the K+ reversal potential. CaTOK (Candida albicans) and CnTOK (Cryptococcus neoformans neoformans) pass both K+ and Na+ and conduct above a reversal potential, reflecting the mixed permeability of their selectivity filter. Mutations in CaTOK and ScTOK at sites homologous to those that open the internal gates in classical K+ channels are shown to produce inward TOK currents. Possibly the reversal potential determines ion occupancy, and thus, conductivity, of the selectivity filter gate that is coupled to an imperfectly restrictive internal gate, permitting the filter to sample ion concentrations on both sides of the membrane (Lewis et al. 2020).


Tok1 outward rectifier K+ channel of Saccharomyces cerevisiae


TOK1 of 741 aas and 8 TMSs in a 6 + 2 TMS arrangement with P-loops between TMSs 5 and 6 as well as 7 and 8.  It transports both Na+ and K+, and has been characterized by Lewis et al. 2020. See 1.A.7.1.1 for a more detailed description.

TOK1 of Candida albicans (Yeast)


AtTPK4 two-pore K+ channel 4 (Becker et al., 2004). Asp86 and Asp200 are essential for K+ permeation as well as inward rectification (Marcel et al., 2010).  Reviewed by González et al. 2014.


AtTPK4 of Arabidopsis thaliana (AAP82009)


The 2-pore (4TMS) outward rectifying K+ channel, KCO1 or TPK1. Possesses two tandem Ca2+-binding EF-hand motifs, and cytosolic free Ca2+ (~300 nM) activates (Czempinski et al., 1997).  Reviewed by González et al. 2014 and Basu and Haswell 2017.


KCO1 of Arabidopsis thaliana

1.A.1.7.4The two pore tonoplast TPK-type K+ channel; maintains K+ homeostasis in plant cells (Hamamoto et al., 2008); activated by 14-3-3 proteins (Latz et al., 2007).PlantsTPK1 of Nicotiniana tobacum (A9QMN9)

Two-pore potassium channel 5 (AtTPK5) (Calcium-activated outward-rectifying potassium channel 5, chloroplastic) (AtKCO5).  Reviewed by González et al. 2014.


TPK5 of Arabidopsis thaliana

1.A.1.7.6Potassium inward rectifier (Kir)-like channel 3 (AtKCO3)PlantsKCO3 of Arabidopsis thaliana

Chloroplast thylakoid two-pore calcium and proton-activated K+ channel, TPK3 of 436 aas and 4 TMSs.  Mediates ion counterbalancing, influencing photosynthetic llight utilization (Carraretto et al. 2013).  Reviewed by González et al. 2014.


TPK3 of Arabidopsis thaliana


Putative K+ channel of 96 aas nd 2 TMSs.

K+ channel of Yellowstone lake phycodnavirus 2


Outward-rectifier potassium channel TOK1 of 699 aas and 8 TMSs in a 6 + 2 TMS arrangement, where a P-loop may exist between TMSs 5 and 6 as well as TMSs 7 and 8.  The system has been characterized and compared with other fungal TOK channels by Lewis et al. 2020

TOK1 of Neosartorya fumigata (Aspergillus fumigatus)


TC#NameOrganismal TypeExample

TWIK-1 (KCNK1, HOHO1, KCNO1) inward rectifier K+ channel (Enyedi and Czirják, 2010) expressed in the distal nephron segments (Orias et al. 1997).  Lipid tails from both the upper and lower leaflets can partially penetrate into the pore (Aryal et al. 2015). The lipid tails do not sterically occlude the pore, but there is an inverse correlation between the presence of water within the hydrophobic barrier and the number of lipids tails within the lining of the pore (Aryal et al. 2015).


TWIK-1 of Mus musculus


TASK-2 (KCNK5) two-pore domain, pH-sensitive, voltage-insensitive, outward rectifying K+ channel (K+ > Rb+ >> Cs+ > NH4+ > Na+ ≈ Li+), present in renal epithelia.  Regulated [inhibited] via group 1 metabolotropic glutamate receptors and by inositol phosphates (Chemin et al., 2003).  TASK-2 gating is controlled by changes in both extra- and intracellular pH through separate sensors: arginine 224 and lysine 245, located at the extra- and intracellular ends of transmembrane domain 4, respectively. TASK-2 is inhibited by a direct effect of CO2 and is regulated by and interacts with G protein subunits. TASK-2 takes part in regulatory adjustments and is a mediator in the chemoreception process in neurons of the retrotrapezoid nucleus where its pHi sensitivity could be important in regulating excitability and therefore signalling of the O2/CO2 status. Extracellular pH increases, brought about by HCO3- efflux from proximal tubule epithelial cells may couple to TASK-2 activation to maintain electrochemical gradients favourable to HCO3- reabsorption. TASK-2 is expressed at the basolateral membrane of proximal tubule cells (López-Cayuqueo et al. 2014). Mutations are associated with the Balkan Endemic Nephropathy (BEN) chronic tubulointerstitial renal disease (Reed et al. 2016). pH sensing in TASK2 channels is conferred by the combined action of several charged residues in the large extracellular M1-P1 loop (Morton et al. 2005). TASK-2, a member of the TALK subfamily of K2P channels, is opened by intracellular alkalization, leading the deprotonation of the K245 residue at the end of the TM4 helix. This charge neutralization of K245 may be sensitive or coupled to the fenestration state. The most important barrier for ion transport under K245+ and open fenestration conditions is the entrance of the ions into the channel (Bustos et al. 2020).



TASK-2 of Homo sapiens

1.A.1.8.3The 2P-domain K+ channel, TWIK 2 (functions in cell electrogenesis (Patel et al., 2000).AnimalsTWIK2 of Homo sapiens

TC#NameOrganismal TypeExample

TC#NameOrganismal TypeExample

TREK-1 (KCNK2) K+ channel subunit (Regulated by group 1 metabotropic glutamate receptors and by diacylglycerols and phosphatidic acids) (Chemin et al., 2003). TREK-1, TREK-2 and TRAAK are all regulated by lysophosphatidic acid, converting these mechano-gated, pH voltage-sensitive channels into leak conductances (Chemin et al., 2005). The mammalian K2P2.1 potassium channel (TREK-1, KCNK2) is highly expressed in excitable tissues, where it plays a key role in the cellular mechanisms of neuroprotection, anaesthesia, pain perception and depression (Cohen et at., 2008). Alternative translation initiation in rat brain yields K2P2.1 potassium channels permeable to sodium (Thomas et al. 2008). The crystal structure of the human 2-pore domain K+ channel, K2P1 has been solved (Miller and Long, 2012). Multiple modalities converge on a common gate to control K2P channel function (Bagriantsev et al., 2011).  TREK-1 mediates fast and slow glutamate release in astrocytes upon GPCR activation (Woo et al. 2012). It is a mechanosensitive K+ channel, present in rat bladder myocytes, which is activated by swelling and arachidonic acid (Fukasaku et al. 2016). The M2-hinges of TREK-1 and TREK-2 channels control their macroscopic current, subcellular localization and gating (Zhuo et al. 2017). The human ortholog has acc # O95069 and has an additional N-terminal 15 aas. BL-1249, a compound from the fenamate class of nonsteroidal anti-inflammatory drugs, is known to activate K2P2.1(TREK-1), the founding member of the thermo- and mechanosensitive TREK subfamily (Pope et al. 2018). Spadin and arachidonic acid, are known to suppress and activate TREK-1 channels, respectively (Pappa et al. 2020).


TREK-1 of Mus musculus (P97438)



Potassium channel subfamily K member 16 (2P domain potassium channel Talk-1) (TWIK-related alkaline pH-activated K+ channel 1) (TALK-1 or KCNK16) of 309 aas and 6 TMSs. It is an outward rectifying potassium channel that produces rapidly activating and non-inactivating outward rectifier K+ currents. Allosteric coupling between transmembrane segment 4 and the selectivity filter regulates gating by extracellular pH (Tsai et al. 2022).



KCNK16 of Homo sapiens


pH-dependent, voltage-insensitive, background potassium channel protein involved in maintaining the membrane potential, KCNK9, K2P9.1 or TASK3 (TASK-3) of 374 aas  (Huang et al. 2011). Terbinafine is a selective activator of TASK3 (Wright et al. 2017). The response of the tandem pore potassium channel TASK-3 to voltage involves gating at the cytoplasmic mouth (Ashmole et al., 2009).  TASK-3 is involved in several physiological and pathological processes including sleep/wake control, cognition and epilepsy (Tian et al. 2019). N-(2-((4-nitro-2-(trifluoromethyl)phenyl)amino)ethyl)benzamide (NPBA) is an activator (Tian et al. 2019). KCC2 regulates neuronal excitability and hippocampal activity via interaction with Task-3 channels (Goutierre et al. 2019). A  biguanide compound, CHET3, is a highly selective allosteric activator, and TASK-3 is a druggable target for treating pain (Liao et al. 2019). This channel may be present in mitochondria (Parrasia et al. 2019).


KCNK9 or TASK3 of Homo sapiens

Potassium channel subunit of 330 aas. No channel activity was observed in heterologous systems. It probably needs to associate with other proteins (i.e., KCNK3 and KCNK9) to form a functional channel (Huang et al. 2011).

KCNK15 of Homo sapiens


The Kcnk10a (TREK-2A) K+ channel of 569 aas and 6 TMSs. It localizes in the brain and seems to regulate reproduction (Loganathan et al. 2017).

TREK-2A of Danio rerio (Zebrafish) (Brachydanio rerio)


Open rectifier K+ channel 1, isoform D of 1001 aas and 6 TMSs, Ork1.

ORK1 of Drosophila melanogaster (Fruit fly)


KCNK3 K+ channel (TASK1, OAT1, TBAK1) (the K+ leak conductance). TASK1 and 3 may play roles in nontumorigenic primary hyperaldosteronism (Davies et al., 2008).  KCNK3/9/15 expression limits membrane depolarization and depolarization-induced secretion at least in part by maintaining intracellular K+ (Huang et al. 2011). TWIK-related acid-sensitive potassium (TASK) channels, members of the two pore domain potassium (K2P) channel family, are found in neurons, cardiomyocytes and vascular smooth muscle cells, where they are involved in the regulation of heart rate, pulmonary artery tone, sleep/wake cycles and responses to volatile anaesthetics (Rödström et al. 2020). K2P channels regulate the resting membrane potential, providing background K+ currents controlled by numerous physiological stimuli. Unlike other K2P channels, TASK channels are able to bind inhibitors with high affinity, exceptional selectivity and very slow compound washout rates. In general, potassium channels have an intramembrane vestibule with a selectivity filter situated above and a gate with four parallel helices located below, but the K2P channels studied so far all lack a lower gate. Rödström et al. 2020 presented the X-ray crystal structure of TASK-1, and showed that it contains a lower gate designated 'X-gate', created by interaction of the two crossed C-terminal M4 transmembrane helices at the vestibule entrance. This structure is formed by six residues ((243)VLRFMT(248)) that are essential for responses to volatile anaesthetics, neurotransmitters and G-protein-coupled receptors. Mutations within the X-gate and the surrounding regions affect both the channel-open probability and the activation of the channel by anaesthetics. Structures of TASK-1 bound to two high-affinity inhibitors showed that both compounds bind below the selectivity filter and are trapped in the vestibule by the X-gate, which explains their exceptionally low washout rates (Rödström et al. 2020).


TASK1 or KCNK3 of Homo sapiens (AAG29340)


Neuronal 2-P (4 TMS) domain K+ membrane tension-gated channel, TRAAK (stimulated by arachidonic acid and polyunsaturated fatty acids (Fink et al., 1998). The crystal structures of conductive and nonconductive human K2P TRAAK K+ channel has been solved (Brohawn et al., 2012; Brohawn et al. 2014). Regulated by mechanical deformation of the membrane and temperature as well as polyunsaturated fatty acids (Brohawn et al., 2012). Multiple modalities converge on a common gate to control K2P channel function (Bagriantsev et al., 2011).  In the non-conductive state, a lipid acyl chain accesses the channel cavity through a 5 Å-wide lateral opening in the membrane inner leaflet and physically blocks ion passage. In the conductive state, rotation of transmembrane helix 4 about a central hinge seals the intramembrane opening, preventing lipid block of the cavity and permitting ion entry. Additional rotation of a membrane interacting TM2-TM3 segment, unique to mechanosensitive K2Ps, against TM4 may further stabilize the conductive conformation. Comparison of the structures provodes a biophysical explanation for TRAAK mechanosensitivity--an expansion in cross-sectional area up to 2.7 nm2 in the conductive state is expected to create a membrane-tension-dependent energy difference between conformations that promotes force activation (Brohawn et al. 2014).  TM helix straightening and buckling may underlie channel activation (Lolicato et al. 2014). A lipid chain blocks the conducting path in the closed state (Rasmussen 2016).


TRAAK of Mus musculus (O88454)


Outward rectifying mechanosensitive 2-P (4 TMS) domain K+ channel, TREK-2 (KCNKA; KCNK10; K2P10). Activated by membrane stretch, acidic pH, arachidonic acid and unsaturated fatty acids.  Dong et al. 2015 described crystal structures of the human TREK-2 channel (up to 3.4 angstrom resolution) in two conformations and in complex with norfluoxetine, the active metabolite of fluoxetine (Prozac) and a state-dependent blocker of TREK channels. Norfluoxetine binds within intramembrane fenestrations found in only one of these two conformations. Channel activation by arachidonic acid and mechanical stretch involves conversion between these states through movement of the pore-lining helices. This provides an explanation for TREK channel mechanosensitivity, regulation by diverse stimuli, and possible off-target effects of the serotonin reuptake inhibitor Prozac (Dong et al. 2015).  The unique gating properties of TREK-2 and the mechanisms by which extracellular and intracellular stimuli harness pore gating allosterically have been studied (Zhuo et al. 2016). TREK-2 moves from the """"down"""" to """"up"""" conformation in direct response to membrane stretch. Aryal et al. 2017 showed how state-dependent interactions with lipids affect the movement of TREK-2, and how stretch influences both the inner pore and selectivity filter. They also demonstrated why direct pore block by lipid tails does not represent theprincipal mechanism of mechanogating (Aryal et al. 2017). The M2-hinges of TREK-1 and TREK-2 channels control their macroscopic current, subcellular localization and gating (Zhuo et al. 2017). TREK-2 responds to a diverse range of stimuli. Two states, termed """"up"""" and """"down,"""" are known from x-ray structural crystallographic studies and have been suggested to differ in conductance. Brennecke and de Groot 2018 found that the down state is less conductive than the up state. The introduction of membrane stretch in the simulations shifts the state of the channel toward an up configuration. Membrane pressure changes the conformation of the transmembrane helices directly and consequently also influences the channel conductance (Brennecke and de Groot 2018). 3-d structures are known (PDB 4XDJ_!-D. Phosphatidyl-(3,5)-bisphosphate (PI(3,5)P2) activates (Kirsch et al. 2018).


TREK-2 of Rattus norvegicus

1.A.1.9.5The TWiK family muscle K+ channel protein 18 (TWiK or Two-P domain K+ channel family) (controls muscle contraction and organismal movement; Kunkel et al., 2000)AnimalsTWK-18 of Caenorhabditis elegans

The pH-sensitive 2 pore (4 TMS) K+ channel, TASK-4 (Expressed in liver, lung, pancreas and other tissues; Decher et al., 2001). The response of the tandem pore potassium channel TASK-3 (TC# 1.A.1.9.11) (K(2P)9.1) to voltage involves gating at the cytoplasmic mouth (Ashmole et al., 2009). Models have revealed the convergence of amino acid regions that are known to modulate anesthetic activity onto a common three-dimensional cavity that forms a putative anesthetic binding site in tandem pore potassium channels (Bertaccini et al. 2014).


TASK-4 of Homo sapiens


Sup-9 K+ channel of 329 aas and 6 TMSs. It is involved in coordination of muscle contraction (de la Cruz et al. 2003). Activity is regulated by Sup-18 (de la Cruz et al. 2014) and by Unc-93 (TC# 2.A.1.5.8).  It may also be regulated by Sup-10 (Q17374); it may be a suppressor of Unc-93 (de la Cruz et al., 2003). Mutation of a single residue promotes gating of  this channel and of several vertebrate and invertebrate two-pore domain potassium channels (Ben Soussia et al. 2019).


Sup-9 of Caenorhabditis elegans (O17185)

1.A.1.9.8TWiK family of potassium channels protein 9Wormtwk-9 of Caenorhabditis elegans
1.A.1.9.9TWiK family of potassium channels protein 12Worm

Twk-12 of Caenorhabditis elegans