Two TMS K⁺ and water channel (conducts K⁺ (K_D = 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., 2011; Pau 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). Under equilibrium conditions, in the absence of a transmembrane voltage, both water and K⁺ occupy the selectivity filter of the KcsA channel in the closed conductive state (Ryan et al. 2023).

Gram-positive bacteria

Skc1 (KcsA) of Streptomyces lividans

Voltage-sensitive Na⁺ channel, Na_V1.7 (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). Naview is a library for drawing and annotating voltage-gated sodium channel membrane diagrams (Afonso et al. 2022). Deltamethrin (DLT) is a type-II pyrethroid ester insecticide used in agricultural and domestic applications as well as in public health. Exposure to DLT produced a differential and dose-dependent stimulation of peak Na+ currents, Conversely, tefluthrin (Tef), a type-I pyrethroid insecticide, accentuates I(Na) with a slowing in inactivation time course of the current (Lin et al. 2022). MicroRNA-335-5p suppresses voltage-gated sodium channel expression and may be a target for seizure control (Heiland et al. 2023).  Voltage-gated sodium channels are enhancing factors in the metastasis of metastatic prostate cancer cells (Yildirim-Kahriman 2023). Decreasing microtubule detyrosination modulates Nav1.5 subcellular distribution and restores sodium current in Mdx cardiomyocytes (Nasilli et al. 2024).

Animals

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 and 24 TMSs, 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). Na_V1.2 has a single pore-forming alpha-subunit and two transmembrane beta-subunits. Expressed primarily in the brain, Na_V1.2 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). The beta4-subunit and PRRT2 form a push-pull system that finely tunes the membrane expression and function of Na_V channels and the intrinsic neuronal excitability (Valente et al. 2022). Icariin can be used to treat epilepsy by inhibiting neuroinflammation via promoting microglial polarization to the M2 phenotype (Wang et al. 2023).

Animals

SCN2A of Homo sapiens

Voltage-sensitive Na⁺ channel of 2821 or 2844 aas (see Uniprot Q9W0Y8) 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). It's homologue in honeybees, CaV4, has distinct permeation, inactivation, and pharmacology from homologous NaV channels (Bertaud et al. 2024). Specifically, honeybee Ca_V4 has distinct permeation, being specific for Ca²⁺,  and exhibits inactivation, and pharmacology differing from homologous Na_V channels (Bertaud et al. 2024).

Animals

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). A novel strategy for screening mutations in the voltage-gated sodium channel gene of Aedes albopictus based on multiplex PCR-mass spectrometry minisequencing technology, has appeared (Mu et al. 2023).

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)

Na⁺ channel, α-subunit, SCAP1, of 1993 aas and 24 TMSs (Dyer et al. 1997).

Metazoa

SCAP1 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.

t

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.

The Na⁺-activated Na⁺ channel (Nax; also called SCN7A; of 1737 aas and ~24 TMSs) and salt-inducible kinase (SIK, see TC# 8.A.104.1.14) are stimulated by increases in local Na⁺ concentration, affecting the Na⁺,K⁺-ATPase activity (see TC# 3.A.3.1.1). It mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a sodium-selective channel through which Na⁺ ions may pass in accordance with their electrochemical gradient (Gonsalez et al. 2023). Rare SCG genetic variants may contribute to the development of painful neuropathy (Almomani et al. 2023).

Nax of Homo sapiens

Ca²⁺-regulated heart Na⁺ channel, Na_v1.5, 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). Na_v1.5, the principal Na⁺ channel in the heart, possesses an ankyrin binding site, and direct interaction with ankyrin-G is required for the expression of Na_v1.5 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). Cardiac sodium channel complexes play a role in arrhythmia, and the structural and functional roles of the beta1 and beta3 subunits have been determined (Salvage et al. 2022). Brugada Syndrome (BrS) treatment is electrocardiography with ST-segment elevation in the direct precordial derivations. The clinical presentation of the disease is highly variable. Patients can remain completely asymptomatic, but they can also develop episodes of syncope, atrial fibrillation (AF), sinus node dysfunction (SNF), conduction disorders, asystole, and ventricular fibrillation (VF). This disease is caused by mutations in the genes responsible for the potential action of cardiac cells. The most commonly involved gene is SCN5A, which controls the structure and function of the heart's sodium channel (Brugada 2023). Postoperative supraventricular tachycardia and polymorphic ventricular tachycardia can be due to SCN5A variants (Kato et al. 2020).

Animals

Na_v1.5 of Homo sapiens (Q14524)

The skeletal muscle Na⁺ channel, Na_V1.4 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 Na_v1.4 (Biswas et al., 2008). Na_V1.4 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 (Na_V1.4) channels (Leipold et al. 2017). the cryo-electron microscopy structure of the human Na_v1.4-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 Na_v 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). Hypokalemic periodic paralysis (HypoPP) is a rare autosomal dominant disease caused by mutations in either calcium or sodium transmembrane voltage-gated ion channels in the ER of skeletal muscle (Calise et al. 2023). Diverse biophysical mechanisms for the voltage-gated sodium channel Na_v1.4 variants are associated with myotonia (Tikhonova et al. 2024).

Animals

Na_V1.4 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). Na_v1.7 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). Sodium channel Na_V1.7 and potassium channel K_V7.2 promote and oppose excitability in nociceptors, respectively. Inflammation differentially controls transport of depolarizing Nav versus hyperpolarizing Kv channels to drive rat nociceptor activity (Higerd-Rusli et al. 2023). The structural basis for severe pain, caused by mutations in the S4-S5 linkers of voltage-gated sodium channel Na_V1.7, have been revealed (Wisedchaisri et al. 2023).

Animals

Nav1.7 of Homo sapiens (Q15858)

Tetrodotoxin-resistant voltage-gated Na⁺ channel of dorsal ganglion sensory neurons, Na_v1.8, plays a crucial role in the occurrence and development of chronic pain (Akopian et al., 1996) and is essential for pain at low temperatures (Zimmermann et al., 2007). Na_v1.8 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). Selective inhibition of Na_V1.8 with VX-548 aleviates acute pain in humans (Jones et al. 2023). N-(((1S,3R,5S)-adamantan-1-yl)methyl)-3-((4-chlorophenyl)sulfonyl)benzenesulfonamide is a novel Nav1.8 inhibitor with an analgesic profile (Song et al. 2024).

Animals

Nav1.8 of Rattus norvegicus
(Q62968)

Voltage-sensitive Na⁺ channel, Na_v1.1 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). The Melkersson-Rosenthal Syndrome and Migraine may be associated with SCN1A variants (Azzarà et al. 2023). A variant in the SCN1A gene confirms Dravet syndrome in a Moroccan child (El Mouhi et al. 2024).

Animals

Na_v1.1 of Homo sapiens (P35498)

The Voltage-gated Na⁺ channel α-subunit, Na_v1.6, 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). Several FDA‑approved drugs that are highly correlated with Nav1.6 could be candidate drugs for patients with glioma (Ai et al. 2023). Clinical and electrophysiological features of SCN8A variants cause episodic or chronic ataxia (Lyu et al. 2023). Epilepsy can be due to variants of the SCN8A gene (Zhang et al. 2024).

Animals

Na_v1.6 of Homo sapiens (Q9UQD0)

The voltage-gated Na⁺ channel α-subunit, Na_v1.9. 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 Na_V1.9 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). The human neuronal sodium channel Nav1.9 is inhibitied by ACEA (arachidonyl-2-chloroethylamide), an analogue of anandamide (Marchese-Rojas et al. 2022).

.

Animals

Na_v1.9 of Homo sapiens (Q9UI33)

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).

Yeast

Cch1/Mid1 of Saccharomyces cerevisiae
Cch1 (P50077)
Mid1 (P41821)
Ecm7p (Q06200) 

The Ca_v1.4 L-type 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). Ca_v1.4 calcium channels play roles in the pathophysiology of psoriasis (Pelletier and Savignac 2022). Cav1.4 L-type calcium channels are predominantly expressed at the photoreceptor terminals and in bipolar cells, mediating neurotransmitter release. Mutations in its gene, CACNA1F, can cause congenital stationary night-blindness type 2 (CSNB2). Water wires in both, resting and active channel states have been proposed (Heigl et al. 2023). 

Animals

Ca_v1.4 of Homo sapiens
(O60840)

T-type Ca²⁺ channel (CACNA1G; Ca_v3.1d), (σ1G T-type Ca²⁺ channel) in developing heart (fetal myocardium (Cribbs et al., 2001)) and elsewhere. Both Ca_v3.1 and Ca_v3.2 are permeated by divalent metal ions, such as Fe²⁺ and Mn²⁺, and possibly Cd²⁺ (Thévenod, 2010).  Ca_V3.1 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). Selective inhibition of T-type calcium channels preserves ischemic pre-conditioning mediated neuroprotection during cerebral ischemia reperfusion injury in diabetic mice (Sharma et al. 2024).

Animals

Ca_v3.1d of Mus musculus (Q9WUT2)

Two-pore Ca²⁺ channel protein 1, TPC1 (K_m(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).

Plants

TPC1 of Oryza sativa (Q5QM84)

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).

Animals

NALCN of Homo sapiens (Q6P2S6)

The high affinity Ca²⁺ channel; associates with elongation factor 3 (EF3) to target Cch1/Mid1 to the plasma membrane (Liu and Gelli, 2008).

Fungi

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).

Animals

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).  Convergent activation of two-pore channels mediated by the NAADP-binding proteins JPT2 and LSM12 has been reported (Gunaratne et al. 2023).  The lysosomal two-pore channels 2 (TPC2) and IP3 receptors (IP3Rs) located in the endoplasmic reticulum may be coupled (Yuan et al. 2024).

Animals

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).

Animals

DHPR of Oryctolagus cuniculus

The voltage-gated Ca²⁺ channel, L-type α-subunit, Eg1-19 regulated by Macoilin (8.A.38.1.2)

Animals

Eg1-19 of Caenorhabditis elegans (A8PYS5)

Voltage-gated L-type Ca²⁺ channel, Egl-19, isoform a. There are three isoforms encoded by the same gene, isoforms a, b and c, and all are expressed in all types of muscle (McDonald et al. 2023).

Animals

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).

Animals

Tpcn1 of Mus musculus

Cch1 calcium channel, alpha subunit; acts with Mid1 (8.A.41.1.7) which is required for function.

Fungi

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).  PGRMC1 (the progesterone receptor membrane component1), an ER transmembrane protein that undergoes a unique heme-dependent dimerization, is an interactor of the endosomal two pore channel, TPC1. It regulates ER-endosomal coupling with functional implications for cellular Ca²⁺ dynamics (Gunaratne et al. 2023).  Convergent activation of two-pore channels mediated by the NAADP-binding proteins JPT2 and LSM12 has been reported (Gunaratne et al. 2023).

Animals

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).

Plants

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). Patients with ataxia in the absence of epilepsy can be caused by a CACNA1A mutationand respond to pyridoxine (Du et al. 2017). lamotrigine can be used to treat patients with refractory epilepsy due to calcium channel mutations (Hu et al. 2022; De Romanis and Sopranzi 2018). Eupatilin depresses glutamate exocytosis from cerebrocortical synaptosomes by decreasing P/Q-type Ca²⁺ channels and synapsin I phosphorylation and alleviates glutamate excitotoxicity caused by kainic acid by preventing glutamatergic alterations in the mamalian cortex. Thus, eupatilin is a potential therapeutic agent in the treatment of brain impairment associated with glutamate excitotoxicity (Lu et al. 2022). Episodic ataxia (EA2) is caused by mutations in CACNA1A, encoding a neuronal voltage-gated calcium channel (Graves et al. 2024). Albiflorin decreases glutamate release from rat cerebral cortex nerve terminals (synaptosomes) through depressing P/Q-type calcium channels and protein kinase A activity (Lu et al. 2024).

Animals

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). The photoreceptor potential in Chlamydomonas triggers the generation of all or no flagellar Ca²⁺ currents that cause membrane depolarization across the eyespot and flagella (Sanyal et al. 2023). Modulation in membrane potential causes changes in the flagellar waveform, and hence, alters the beating patterns of Chlamydomonas flagella. The eyespot membrane potential is rhodopsin-mediated and is generated by the photoreceptor Ca²⁺ current or P-current. However, flagellar Ca²⁺ currents are mediated by unidentified voltage-gated calcium (VGCC or CaV) and potassium channels (VGKC). The voltage-dependent ion channel that associates with ChRs to generate Ca²⁺ influx across the flagella and its cellular distribution has been identified. Sanyal et al. 2023 presented evidence on Chlamydomonas reinhardtii predicting that CrVGCC4 localizes to the eyespot and flagella and associates with channelrhodopsins. Further in silico interactome analysis of CrVGCCs suggested that they interact with photoreceptor proteins, calcium signaling, and intraflagellar transport components. Expression analysis indicated that these VGCCs and their putative interactors can be perturbed by light stimuli. Thus, VGCCs in general, and VGCC4 in particular, might be involved in the regulation of the phototactic response of Chlamydomonas.

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).  A Ca_v3.2 calcium channel missense variant is associated with epilepsy and hearing loss (Stringer et al. 2023). Structural insights into the allosteric effects of the antiepileptic drug topiramate on the Ca_V2.3 channel have been published (Gao et al. 2024).

Animals

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), CA_V1.3, encoded by the CACNA1D gene, of 2161 aas and 24 TMSs (Singh et al. 2008). Ca_V1.3-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). Snapin (a synaptic junction complex (see TC# 1.F.1.1.1) directly interacts with the C-terminal extension (long) of Ca_v1.3_L, leading to up-regulation of Ca_v1.3_L channel activity via facilitating channel opening probability (Jeong et al. 2021).  Germline gain-of-function missense variants in the Cav1.3 alpha1-subunit (CACNA1D gene) confer high risk for a severe neurodevelopmental disorder (Török et al. 2023).

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). The voltage-gated T-type calcium channel is modulated by kinases and phosphatases (Sharma et al. 2023). Advances in Ca_V1.1 gating, dealing with permeation and voltage-sensing mechanisms, have been reviewed (Bibollet et al. 2023). It is possible to prevent calcium leak associated with short-coupled polymorphic ventricular tachycardia in patient-derived cardiomyocytes (Sleiman et al. 2023). Far-infrared ameliorates Pb-induced renal toxicity via voltage-gated calcium channel-mediated calcium influx (Ko et al. 2023). Verapamil mitigates chloride and calcium bi-channelopathy in a myotonic dystrophy mouse model (Cisco et al. 2024).

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 Ca_v1.2), 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 Ca_v1.2 encodes a transcription factor (Gomez-Ospina et al., 2006). Ca_v1.2 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, Ca_v1.2 (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 Ca_v3.3 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). Kinase and phosphatase modulation of T-type Ca²⁺ channel (TTCC) isoforms Cav3.1, Cav3.2, and Cav3.3, are mostly described for roles unrelated to cellular excitability (Sharma et al. 2023), and potential modulations that are yet to be explored are also discussed. Palmitoylation of the pore-forming subunit of Ca(v)1.2 controls channel voltage sensitivity and calcium transients in cardiac myocytes (Kuo et al. 2023).  A novel binding site between the voltage-dependent calcium channel Ca_V1.2 subunit and the Ca_Vβ2 subunit has been discovered using a new analysis method for protein-protein interactions (Murakami et al. 2023). CACNA1C is one of the top risk genes for schizophrenia; A novel 17-variant block across introns 36-45 of CACNA1C was significantly associated with schizophrenia; a novel 17-variant block across introns 36-45 of CACNA1C was responsible (Guo et al. 2023). A novel binding site has been found between the voltage-dependent calcium channel Ca_V1.2 subunit and Ca_Vβ2 subunit (Murakami et al. 2023). The Ca_V1.2 distal carboxy terminus functions in the regulation of L-type current (Arancibia et al. 2024).

Animals

CACNA1C of Homo sapiens (2221 aas; Q13936)

The voltage-dependent L-type Ca²⁺ channel α-subunit-1H (T-type Ca_v3.2), 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). Gabapentin disrupts binding of perlecan to the α₂δ₁ voltage-sensitive calcium channel subunit and impairs skeletal mechanosensation (Reyes Fernandez et al. 2022). Kinase and phosphatase modulation of T-type Ca²⁺ channel (TTCC) isoforms Cav3.1, Cav3.2, and Cav3.3,  are mostly described for roles unrelated to cellular excitability (Sharma et al. 2023), and potential modulations that are yet to be explored are also discussed. A subtle role for T-type calcium channels in regulating lymphatic contraction has been established (Davis et al. 2023). A Ca_v3.2 calcium channel missense variant is associated with epilepsy and hearing loss (Stringer et al. 2023).

Animals

CACNA1H of Homo sapiens (2353 aas; Q95180)

Voltage-dependent L-type Ca²⁺ channel subunit α-1C (αCa_v1.2) of cardiac muscle [A C-terminal fragment of Ca_v1.2 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). Ca_v1.2 associates with the α-2, δ-1, β and γ subunits (Yang et al., 2011). Voltage-gated Ca²⁺ influx and mitochondrial Ca²⁺ initiate secretion from Aplysia neuroendocrine cells (Hickey et al. 2013).

Animals

α-Ca_v1.2 of Mus musculus (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 Ca_v1.2 (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). Kinase and phosphatase modulation of T-type Ca²⁺ channel (TTCC) isoforms Cav3.1, Cav3.2, and Cav3.3,  are mostly described for roles unrelated to cellular excitability (Sharma et al. 2023), and potential modulations that are yet to be explored are also discussed. A possible involvement of CaV3 in carcinogenic processes and is a potential pharmacological target in new therapies for breast cancer treatment (Aguiar et al. 2023).  G protein β subunits regulate Ca_v3.3 T-type channel activity and current kinetics via interaction with the Ca_v3.3 C-terminus (Jeong et al. 2024).

Animals

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).

Animals

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.  Ca_V2.2 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). Phillygenin suppresses glutamate exocytosis in rat cerebrocortical nerve terminals (synaptosomes) through the inhibition of Ca_v2.2 calcium channels (Lee et al. 2024).

Animals

Cav2.2 of Mus musculus (O55017)

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).

Virus

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 Kcv_S versus Kcv_NTS. 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).  A combination of hydrophobicity and codon usage bias determines sorting of the Kesv K⁺ channel protein to either mitochondria or the endoplasmic reticulum (Engel et al. 2023).

Phaeovirus

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).

Viruses

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

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).

Euryarchaea

MthK of Methanothermobacter thermoautotrophicus (Methanobacterium thermoautotrophicum)(O27564)

Archaea

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).

Bacteria

BikC of Bacillus subtilis (Q795M8)

Putative 2 TMS ion channel protein (N-terminus) with C-terminal TrkA_N (NADB Rossman) domain.

Actinobacteria

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).

Cyanobacteria

K⁺ channel of Synechocystis PCC6803

Putative K⁺ channel, TrkA1, of 365 aas and 2 N-terminal TMSs, with a C-terminal NAD binding domain.

Cyanobacteria

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

Voltage-activated, Ca²⁺  channel blocker-inhibited, Na⁺ channel, NaChBac (Ren et al., 2001; Zhao et al., 2004; Nurani 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). The structure of NaChBac embedded in liposomes has been solved by cryo electron tomography (Chang et al. 2023). The small channel has most of its residues embedded in the membrane, and these are flexible, determining the channel dimensions.

Gram-positive bacteria

NaChBac of Bacillus halodurans

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).

Proteobacteria

VGSC of Silicibacter pomeroyi (56676695)

Voltage-gated Na⁺ channel, Na_vCh or Na_vAb. 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).