2 TMS K⁺ 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).

Skc1 (KcsA) of Streptomyces lividans

Voltage-sensitive Na⁺ channel, Na_V1.7 (Cox et al., 2006). The human orthologue, SCN3A when mutated causes cryptogenic pediatric partial epilepsy (Holland et al., 2008). 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).

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).

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).

VmNa of Varroa destructor

Type 2 Na⁺ channel, SCN2A or NaV1.2, of 2,005 aas.  Mutations give rise to epileptic encephalophathy, Ohtahara syndrome (Nakamura et al. 2013).  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).

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).

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.

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

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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).

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 results in a channelopathy 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 ).

Nav1.7 of Homo sapiens (Q15858)

Tetrodotoxin-resistant voltage-gated Na⁺ channel of dorsal ganglion sensory neurons, Na_v1.8 (Akopian et al., 1996). 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).

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).

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).

Na_v1.6 of Homo sapiens (Q9UQD0)

The voltage-gated Na⁺ channel α-subunit, Na_v1.9. Present in excitable membranes. 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).

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).

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

The Ca_v1.4 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).

Ca_v1.4 of Homo sapiens
(O60840)

T-type Ca²⁺ channel (Ca_v3.1d) in developing heart (fetal myocardium (Cribbs et al., 2001). Both Ca_v3.1 and Ca_v3.2 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 (acc# Q96S59) (Kim et al. 2009).

Ca_v3.1d of Mus musculus (Q9WUT2)

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).

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).

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).

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).

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).

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).

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).

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).

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).

TPC1 of Arabidopsis thaliana

Voltage-dependent P/Q-type Ca²⁺ channel subunit α1A, CACNA1A (CACH4; CACN3; CACNL1A4) of 2,505 aas.  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 encephalopathu 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).

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

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).

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).

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).

α-Ca_v1.2 of Mus muscultus (2139 aas; Q01815)

The voltage-dependent Ca²⁺ channel subunit α-1I, Cav3.3, CACNA1I (isoform CRA_c (2223 aas)) (Hamid et al. 2006).

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 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).

Kcv1 K⁺ channel of Chlorella virus PBCV-1

Acanthocystis turfacea chlorella virus cation, K⁺-preferring, channel, ATCV1 (82aas) (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.

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

6TMS K⁺ channel (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).

Kch of E. coli

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.

MthK of Methanothermobacter thermoautotrophicus (O27564)

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

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).

MjK1 of Methanocaldococcus jannaschii (Methanococcus jannaschii)

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). Transmembrane and extramembrane contributions to thermal stability have been studied (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).

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).

VGSC of Silicibacter pomeroyi (56676695)

Voltage-gated Na⁺ channel, Na_vCh. 3d-structure known (3ROW; Payandeh et al., 2011). An anionic coordination site was proposed to confer Na⁺ 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).

Na_vCh of Arcobacter butzleri (A8EVM5)

Bacterial voltage-gated sodium channel, Nav.  The 3-d crystal structure of the open-channel conformation is known (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 opining, depedent on the negatively charged linker region (Bagnéris et al. 2013).

Nav of Magnetococcus marinus (also called sp. strain MC-1)

Tetrameric 6 TMS subunit Na⁺ channel protein, Na_V.  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 Na_v 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).

Nsv of Bacillus alcalophilus

6 TMS basolateral tracheal epithelial cell/voltage-gated, small conductance, K⁺ α-chain) [acts with the KCNE3 β-chain]. Mutations in human K_v7 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. 2014.  Slow-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).

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).  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).

KCNQ2 K⁺ channel of Homo sapiens (O43526)

6 TMS voltage-gated K⁺ channel, KCNQ3 or K_v7.3.  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).

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).

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-typ K⁺ channels mediates reciptrocal channel modulation by nitric oxide and reactive oxygen species (Ooi et al. 2013).

KCNQ5 of Mus musculus
(Q9JK45)

K⁺ voltage-gated channel, LQT-like subfamily; Kv7.1; KvLQT1; KCNQ1 (regulated by KCNE peptides which 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). 

.

KCNQ1 of Homo sapiens (P51787)

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).

SkCa2 of Homo sapiens

The intermediate conductance, Ca²⁺-activated K⁺ channel, hIK1, IKCa or KCa3.1 (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). 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). 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).

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).

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).

TSKCa of Psetta maxima (Turbot) (Pleuronectes maximus)

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).

KvAP of Aeropyrum pernix (Q9YDF8) 

Kv of Listeria monocytogenes (Q8Y5K1)

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, and Czirjak et al. (Czirjak et al. 2008) reported that 14-3-3 proteins which 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).

TRESK-1 of Mus musculus (AAQ91836)

Alkalinizatioin-activated Ca²⁺-selective channel, sperm-associated cation channel, CatSper, required for male fertility and the hyperactivated motility of spermatozoa. 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).  CatSper1 may be a target for immunocontraception (Li et al. 2009). CatSper channels regulate sperm motility (Vicente-Carrillo et al. 2017).

CatSper of Homo sapiens
CatSper1 (Q96P76)
CatSper3 (Q86XQ3)
CatSper4 (Q7RTX7)
CatSperβ (Q9H7T0)
CatSperγ (Q6ZRH7)
CatSperδ (Tmem146) (Q86XM0) 

Alkalinization-activated Ca²⁺-selective channel, 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) 

Voltage-sensitive K⁺ channel (P_Na⁺/P_K⁺ ≈ 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, K_v1.2 (Crystal structure known, Long et al., 2007; Chen et al. 2010). 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 K_V1/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).

K_v1.2 of Homo sapiens (P16389)

Voltage-gated K⁺ channel, Shab-related, K_v2.1 (858aas) (Crystal structure known, Long et al., 2007). Rat K_v2.1 and K_v2.2 (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 K_v2 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).

K_v2.1/K_v2.2 of Homo sapiens
(Q14721)
(Q92953)

Voltage-gated K⁺ channel, Kv1.1 or KCNA1. Regulated by syntaxin 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). Direct axon-to-myelin linkage by abundant K_V1/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 of Homo sapiens (Q09470)

Voltage-gated K⁺ channel subfamily C member 3, Kv3.3. 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).

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)

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).

Kcng3 or K_v10.1of Rattus norvegicus

The voltage-gated K⁺ channel subfamily D member 3, KCND3 or K_v4.3.  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

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-sensitive fast transient outward current K⁺ channel in neurons and muscle of flies and worms (Fawcett et al., 2006)

Shal2 of Drosophila melanogaster

Margatoxin-sensitive voltage-gated K⁺ channel, Kv1.3 (in plasma and mitochondrial membranes of T lymphocytes) (Szabò et al., 2005). K_v1.3 associates with the sequence similar (>80%) K_v1.5 protein in macrophage forming heteromers that like K_v1.3 homomers are r-margatoxin sensitive (Vicente et al., 2006). However, the heteromers have different biophysical and pharmacological properties. The K_v1.3 mitochondrial potassium channel is involved in apoptotic signalling in lymphocytes (Gulbins et al., 2010). Interactions between the C-terminus  of K_v1.5 and K_vβ regulate pyridine nucleotide-dependent changes in channel gating (Tipparaju et al., 2012).  Intracellular trafficking of the K_V1.3 K⁺ channel is regulated by the pro-domain of a matrix metalloprotease (Nguyen et al. 2013).  Direct binding of caveolin regulates K_v1 channels and allows association with lipid rafts (Pérez-Verdaguer et al. 2016). Addtionally, Na_vBeta1 interacts with the voltage sensing domain (VSD) of K_v1.3 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).

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), and (2) cytoplasmic Ca²⁺ binding proteins known as K⁺ channel interacting proteins (KChIPs; TC#5.B.1.1.7; 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).

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 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
(Q96KK3)

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)

K⁺ voltage-gated ether-a-go-go-related channel, H-ERG (KCNH2; Erg; HErg; Erg1) subunit K_v11.1 (long QT syndrome type 2) (Gong et al., 2006; Chartrand et al. 2010; McBride et al. 2013).  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).

H-ERG of Homo sapiens (Q12809)

K⁺ voltage-gated channel, rEAG1; K_v10.1; 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 of Rattus norvegicus (Q63472)

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).

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

K⁺- and Na⁺-conducting NaK channel (3-D structure solves with Na⁺ and K⁺) (Shi et al., 2006).  Exhibits tight structural and dynamic coupling between the selectivity filter and the channel scaffold (Brettmann et al. 2015).

NaK channel of Bacillus cereus (2AHYB) (Q81HW2)

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
(Q4VY51)

CASTOR of Lotus japonicus (Q5H8A6)

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

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

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).

MlotiK1 of Mesorhizobium loti (Q98GN8)

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

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 alginolytcus

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)

The 2 - 4 TMS K⁺ channel, LctB (Wolters et al. 1999).

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

Ca²⁺-activated K⁺ channel. 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).

Ca²⁺-activated K⁺ channel of Drosophila melanogaster

Large conductance Ca²⁺ - and voltage-activated K⁺ channel, α-subunit (subunit α1), BK, BK_Ca, 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 BK_Ca (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 BK_Ca 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). BK_Ca 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.

BK_Ca 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.

BK K⁺ channel of Caenorhabditis elegans (Q95V25)

rSlo2 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).

Slo3 of Mus musculus (O54982)

Human outward rectifying potassium channel, Slo2.1 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 anesthetics, such as isoflurane.  Inhibited upon stimulation of G-protein coupled receptors such as CHRM1 and GRIA1.  Orthologous to 1.A.1.3.4 (Garg et al. 2013).  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).

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

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).

AKT1 of Arabidopsis thaliana

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)

KDC1 of Daucus carota

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)

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).

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).

KAT1 of Arabidopsis thaliana (Q39128)

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)

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. Associated withfamiial sinus bradycardia (Boulton et al. 2017).

Hcn4 of Homo sapiens (Q9Y3Q4)

Hyperpolarization-activated cyclic nucleotide-gated (HCN) inward current carrying cationic channel, I(f), (HCN2/HCN4) (Ye and Nerbonne, 2009).

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).

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)

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.  Activated by cAMP, not by cGMP.  Highly specific for K+ over Na+.  Has a C-terminal cAMP-binding domain linked to the 6 TMS channel domain (Brams et al. 2014).

Channel of Spirochaeta thermophila

Cyclic nucleotide-gated cation (CNG) channel of 665 aas.

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) (P_Na⁺/P_K⁺ ≈ 0.3). The human orthologue (O88703) is 863 aas in length and catalyzes mixed monovalent cation currents K⁺:Na⁺= 4:1 (Lyashchenko and Tibbs et al., 2008). Biel et al. (2009) present a detailed review of hyperpolarization-activated cation-channels. Inhibited by nicotine and epibatidine which bind to the inner pore (Griguoli et al., 2010).

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).

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).

PAK11-MAC of Paramecium tetraurleia

Cyclic nuceotide-gated Na⁺ channel of 729 aas and 6 putative TMSs, CNGC19.  Constitutively expressed in roots but Induced in leaves and shoots under conditions of salt (NaCl) stress (Kugler et al. 2009).

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 of Arabidopsis thaliana

Putative cyclic AMP receptor protein (Crp), annotated in GenBank as a Crp homologue with a CAP_ED domain N-terminal and a helix-turn-hexix (HTH) domain C-terminal. This protein has two poorly hydrophobic peaks at ~ residue # 85 and 165, with a potential "P-loop" between these two peaks.  All of the cyclic nucleotide regulated channels in subfamily 2.A.1.5 have the two TMSs separated by about 80 residues with the P-loop inbetween.  Maybe the cAMP binding domains in the transcription factors and the channel proteins are derived from a common origin, and are therefore homologous.

Putative Crp homologue of Bifidobacterium longum

Cyclic nuceotide gated channel of 706 aas, CNGC18.  It is the essential Ca²⁺ channel for pollen tube guidance (Gao et al. 2016).

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 hyperpolarization-activated cyclic nucleotide-gated (HCN) channel of 767 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).

HPN1 of Strongylocentrotus purpuratus (Purple sea urchin)

Heterotetrameric (3A:1B) rod photoreceptor cyclic GMP-gated cation channel, CNGA1 (Zhong et al., 2002). 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 TMS4 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 structure, undergoing conformational rearrangements (Maity et al. 2015).

CNG of Homo sapiens
Subunit A1 (CNGA1)
Subunit B1 (CNGB1)

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) (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
(Q94AS9)

The non-selective cation transporter involved in germination, CNGC3 (Gobert et al., 2006; Zelman et al., 2012).

CNG3 of Arabidopsis thaliana (Q9SKD7)

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)

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).

Tok1 outward rectifier K⁺ channel of Saccharomyces cerevisiae

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 2PK1. Possesses two tandem Ca²⁺-binding EF-hand motifs, and cytosolic free Ca²⁺ (~300nM) activates (Czempinski et al., 1997).  Reviewed by González et al. 2014.

KCO1 of Arabidopsis thaliana
(Q8LBL1)

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

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

TWIK-1 inward rectifier K⁺ channel (Enyedi and Czirják, 2010).  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 pH_i 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).

TASK-2 of Homo sapiens

TREK-1 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).

TREK-1 of Mus musculus (P97438)

pH-dependent, voltage-insensitive, background potassium channel protein involved in maintaining the membrane potential, KCNK9 or TASK3 of 374 aas  (Huang et al. 2011).

KCNK9 or TASK3 of Homo sapiens

KCNK15 of Homo sapiens

KCNK3 K⁺ channel (TASK1, OAT1, TBAK1) (the K⁺ leak conductance). TASK1 and 3 may play a role 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).

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).

TREK-2 of Rattus norvegicus
(Q9JIS4)

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 (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
(Q96T54)

Sup-9 K⁺ channel (possibly regulated by unc-93; and may be a suppressor of unc-93. Another regulator of Sup-9 is Sup-10 (Q17374) (de la Cruz et al., 2003).

Sup-9 of Caenorhabditis elegans (O17185)

Twk-12 of Caenorhabditis elegans

AMPA-selective glutamate ionotropic channel receptor (GIC; AMPAR), kainate-subtype, GluR-K1; GluR1; GluR-A; GluA1; Gria1 of 906 aas (preferentially monovalent cation selective). Contributes to amygdala-dependent emotional learning and fear conditioning (Humeau et al., 2007). Transmembrane AMPAR regulatory protein (TARP) gamma-7 (TC#8.A.16.2.5) selectively enhances the synaptic expression of Ca²⁺-permeable (CP-AMPARs) and suppresses calcium-impermeable (CI-AMPAR) activities (Studniarczyk et al. 2013).  Thus, TARPs modulate the pharmacology and gating of AMPA-type glutamate receptors (Soto et al. 2014).  TARPs interact with the N-terminal domain of the AMPAR and control channel gating; residues in the receptor and the TARP involved in this interaction have been identified (Cais et al. 2014).  The auxilary protein, Shisa9 or CKAMP44 (UniProt acc# B4DS77), has a C-terminal PDZ domain that allows interaction with scaffolding proteins and AMPA glutamate receptors (Karataeva et al. 2014).  The transmembrane domain alone can tetramerize (Gan et al. 2016). The most potent and well-tolerated AMPA receptor inhibitors, used to treat epilepsy, act via a noncompetitive mechanism.  The crystal structures of the rat AMPA-subtype GluA2 receptor in complex with three noncompetitive inhibitors have been solved. The inhibitors bind to a binding site, completely conserved between rat and human, at the interface between the ion channel and linkers connecting it to the ligand-binding domains (Yelshanskaya et al. 2016). The endogenous neuropeptide, cyclopropylglycine, at a physiological concentration of 1 μM, enhances the transmembrane AMPA currents in rat cerebellar Purkinje cells (Gudasheva et al. 2016).

GluR-K1 of Rattus norvegicus

The homo- and heteromeric glutamate receptor, GLR3.3/3.4 (Desensitized in 3 patterns: (1) by Glu alone; (2) by Ala, Cys, Glu or Gly; (3) by Ala, Cys, Glu, Gly, Ser or Asn (Stephens et al., 2008).

GLR3.3/GLR3.4 receptor of Arabidopsis thaliana
GLR3.3 (Q9C8E7)
GLR3.4 (Q8GXJ4)

GriK2; GluK2; GluR6 glutamate receptor, ionotropic kainate 2. The 3-d structure is known (2XXY_A). The domain organization and function have been analyzed by Das et al. (2010).  Two auxiliary subunits, Neto1 and Neto2 (Neuropilin and tolloid-like proteins) alter the trafficking, channel kinetics and pharmacology of the receptors (Howe 2014).  They reduce inward rectification without altering calcium permeability (Fisher and Mott 2012). Interactions between the pore helix (M2) and adjacent segments of the transmembrane inner (M3) and outer (M1) helices may be involved in gating (Lopez et al. 2013). Mutations in the human GRIK2 (GLUR6) cause moderate-to-severe nonsyndromic autosomal recessive mental retardation (Motazacker et al. 2007). Kainate receptors regulate KCC2 (TC# 1.A.10.1.11) expression in the hippocampus (Pressey et al. 2017). GluR6, carrying the pore loop plus adjacent transmembrane domains of the prokaryotic, glutamate-gated, K⁺-selective GluR0 (TC# 1.A.10.2.1), adopted several electrophysiological properties of the donor pore uponpore transplantation (Hoffmann et al. 2006).

Grik2 of Rattus norvegicus (P42260)

The NMDA receptor. The crystal structure of the N-terminal domains (GluN1 and GluN2) have been determined (PDB#3QEL; Talukder and Wollmuth, 2011). The ligand-specific deactivation time courses of GluN1/GluN2D NMDA receptors have been measured (Vance et al., 2011).  NMDA receptors are Hebbian-like coincidence detectors, requiring binding of glycine and glutamate in combination with the relief of voltage-dependent magnesium block to open an ion conductive pore. Lee et al. 2014 presented X-ray structures of the Xenopus laevis GluN1-GluN2B NMDA receptor with the allosteric inhibitor, Ro25-6981, partial agonists and the ion channel blocker, MK-801. Receptor subunits are arranged in a 1-2-1-2 fashion, demonstrating extensive interactions between the amino-terminal and ligand-binding domains. The 3-TMS transmembrane domains harbour a closed-blocked ion channel, a pyramidal central vestibule lined by residues implicated in binding ion channel blockers and magnesium, and a approximately twofold symmetric arrangement of ion channel pore loops.

NMDA receptor of Xenopus laevis (Q91977)

Glu2 AMPA receptor (GluR-2; GluA2).  The 3-d structure is known at 3.6 Å resolution.  It shows a 4-fold axis of symmetry in the transmembrane domain, and a 2-fold axis of symmetry overall, although it is a homotetramer (Sobolevsky et al. 2009). A structure showing an agoniar-bound form of the rat GluA2 receptor revealed conformational changes that occur during gating (Yelshanskaya et al. 2014). GluR2 interacts directly with β3 integrin (Pozo et al., 2012).  In general, integrin receptors form macromolelcular complexes with ion channels (Becchetti et al. 2010).  TARPS are required for AMP receptor function and trafficking, but seven other auxiliary subunits have also been identified (Sumioka 2013). For example, AMPA receptors are regulated by S-SCAM through TARPs (Danielson et al. 2012).  The C-terminal domains of various TARPs (TC#8.A.16.2) play direct roles in the regulation of GluRs (Sager et al. 2011).  Whole-genome analyses have linked multiple TARP loci to childhood epilepsy, schizophrenia and bipolar disorders (Kato et al. 2010). Thus, TARPs emerge as vital components of excitatory synapses that participate both in signal transduction and in neuropsychiatric disorders. The architecture of a fully occupied GluR2-TARP complex has been illucidated by cryoEM, showing the homomeric GluA2 AMPA receptor saturated with TARP Υ2 subunits, showing how the TARPs are arranged with four-fold symmetry around the ion channel domain, making extensive interactions with the M1, M2 and M4 TMSs (Zhao et al. 2016).

GluR-2 of Homo sapiens (P42262)

Ionotropic receptor 25a, Ir25a.  Not involved in salt sensing (Zhang et al. 2013).  It resets the circadian clock in response to temperature (Chen et al. 2015).

Ir25a of Drosophila melanogaster

Glutamate ionotropic receptor homologue

Glutamate receptor in Daphnia pulex (water flea)

Olfactory ionotropic receptor, Ir93a of 842 aas

Ir93a of Panulirus argus (spiny lobster)

Ionotropic sodium channel; attractive, sodium gustatory sensory receptor for positive salt taste.  Not involved in salt avoidance which uses a distinct receptor (Zhang et al. 2013). 

Ir76b of Drosophila melanogaster

Calcium channel of 551 aas, Glr1 (Wheeler and Brownlee 2008).

Glr1 of Chlamydomonas reinhardtii

GIC, NMDA-subtype, Grin C2 (highly permeable to Ca²⁺-monovalent cations). A single residue in the GluN2 subunit controls NMDA receptor channel properties via intersubunit interactions (Retchless et al., 2012). Memantine (Namenda) is prescribed as a treatment for moderate to severe Alzheimer's Disease. Memantine functions by blocking the NMDA receptor, and the sites of interaction have been identified (Limapichat et al. 2013).  Genetic mutations in multiple NMDAR subunits cause various childhood epilepsy syndromes (Li et al. 2016).

NMDA receptor, Grin C2, of Homo sapiens

AMPA glutamate receptor 3 (GluR3) (non-selective monovalent cation channel and Ca²⁺  channel) (Ayalon et al., 2005; Midgett et al., 2012). Regulated by AMPA receptor regulatory proteins (TARPs) including stargazin and CNIH auxiliary subunits (Kim et al., 2010; Straub and Tomita, 2011; Jackson and Nicoll, 2011; Bats et al., 2012; Rigby et al. 2015). The domain architecture of a calcium-permeable AMPA receptor in a ligand-free conformation has been solved (Midgett et al., 2012). The TARP, stargazin, is elevated in the somatosensory cortex of Genetic Absence Epilepsy Rats (Kennard et al. 2011). TARPs alter the conformation of pore-forming subunits and thereby affect antagonist interactions (Cokić and Stein 2008).  The structural basis of AMPAR regulation by TARP gamma2, or stargazin (STZ) involves variable interaction stoichiometries of the AMPAR-TARP complex, with one or two TARP molecules binding one tetrameric AMPAR (Twomey et al. 2016).  The ion channel extracellular collar plays a role in gating and represents a hub for powerful allosteric modulation of AMPA receptor function (Yelshanskaya et al. 2017).

GluR3 of Homo sapiens (P42263)

The homomeric cation channel/glutamate receptor/kainate 1, GluR5 (weakly responsive to glutamate) (expressed in the developing nervous system) (Bettler et al., 1990).  The 3-d structures of the protein have been determined with agonists and antagonists.  The agonist, domoic acid, stabilizes the ligand-binding core of the iGluR5 complex in a conformation that is 11 degrees more open than the conformation observed when the full agonist, (S)-glutamate, is bound (Hald et al. 2007). Kainate receptors regulate KCC2 expression in the hippocampus (Pressey et al. 2017).

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GluR5 of Rattus norvegicus
(P22756)

The heteromeric monovalent cation/Ca²⁺ channel/glutamate (NMDA) receptor NMDAR1/NMDAR2A/NMDAR2B/NMDAR2C) (Monyer et al., 1992). Note: NR2B is the same as NR3, GluN2A, GRIN2A or subunit epsilon (Schüler et al., 2008). Mediates voltage- and Mg²⁺-dependent control of Na⁺ and Ca²⁺ permeability (Yang et al., 2010).  Mutations in the subunit, GRIN1, a 1464 aa protein, identified in patients with early-onset epileptic encephalopathy and profound developmental delay, are located in the transmembrane domain and the linker region between the ligand-binding and transmembrane domains (Yuan et al. 2014; Ohba et al. 2015).  Karakas and Furukawa 2014 determined the crystal structure of the heterotetrameric GluN1-GluN2B NMDA receptor ion channel at 4 Å resolution. The receptor is arranged as a dimer of GluN1-GluN2B heterodimers with the twofold symmetry axis running through the entire molecule composed of an amino terminal domain, a ligand-binding domain, and a transmembrane domain.  The GluN2 subunit regulates synaptic trafficking of AMPA in the neonatal mouse brain (Hamada et al. 2014).  GRIN1 and GRIN2A mutations are associated with severe intellectual disability with cortical visual impairment, epilepsy and oculomotor and movement disorders being discriminating phenotypic features (Lemke et al. 2016; Chen et al. 2017).The cryoEM structure of a triheteromeric receptor including GluN1 (glycine binding), GluN2A and GluN2B (both glutamate binding)has been solved with and without a GluN2B the allosteric antagonist, Ro 25-6981 (Lü et al. 2017). Ogden et al. 2017 implicated the pre-M1 region in gating, provided insight into how different subunits contribute to gating, and suggested that mutations in the pre-M1 helix, such as those that cause epilepsy and developmental delays, can compromise neuronal health.

NR1/NR2A or NR2B or NR2C of Rattus norvegicus
NR1 (Q05586)
NR2A (O08948)
NR2B (Q00960)
NR2C (Q62644)

The mouse glutamate receptor δ-2 subunit precursor (GluR δ-2, GluR delta subunit, or GluD2) (Uemura et al., 2004).  The 3-d structure in the synaptic junctional complex with presynaptic β-neurexin 1 (β-NRX1 or NRXN1A; Q9ULB1 = the human homologue) and the C1q-like synaptic organizer, cerebellin-1 (Cbln1; 193 aas, 1 or 2 TMSs; Q9R171 = the human homolgue) has been solved (Elegheert et al. 2016).

GluR δ2 of Mus musculus (Q61625)

Glutamate-gated ionotropic K⁺ channel receptor, GluR0 (5TMSs). X-ray structures are available (PDB: 1IIT) (Lee et al. 2005; Lee et al. 2008)  GluR6 (TC# 1.A.10.1.11), carrying the pore loop plus adjacent transmembrane domains of this prokaryotic, glutamate-gated, K⁺-selective GluR0, adopted several electrophysiological properties of the donor pore upon pore transplantation (Hoffmann et al. 2006).

GluR0 of Synechocystis sp. PCC6803

Probable Ionotropic glutamate receptor (GluR)

GluR homologue of Algoriphagus sp. PR1 (A3I049)

Probably Ionotropic glutamate receptor (GluR) 

GluR homologue of Chlorobium luteolum (Q3B5G3)

Probable Ionotropic glutamate receptor (GluR)

GluR homologue of Vibrio fischeri (B5FDH7)

Uncharacterized protein of 1003 aas and 5 - 7 TMSs

UP of Chlamydomonas reinhardtii (Chlamydomonas smithii)

The Wongabel virus U5 protein (putative viroporin) of 127 aas and 1 or 2 TMSs.

U5 of Wongabel virus

Putative viroporin of 118 aas and 1 or 2TMSs

Putative Viroporin of Joinjakaka virus

Putative viroporin of 90 aas and 1 TMS

Putative viroporin of Kotonkan virus

The small integral membrane protein 22 of 81 aas and 1 TM

Small integral membrane protein 22 of Stegastes partitus

Small integral membrane protein 5 isoform X1 of 119 aas and 1 TM

Small integral membrane protein 5 isoform X1  of Anolis carolinensis

Pex11 of 236 aas and possibly 3 TMSs (Mindthoff et al. 2015).

Pex11 of Saccharomyces cerevisiae

Pex11 of 247 aas.

Pex11 of Homo sapiens

Pex11 of 248 aas

Pex11 of Arabidopsis thaliana

Pex11 of 222 aas

Pex11 of Leishmainia major

Pex11 of 234 aas

Pex 11 of Drosophila melanogaster (Fruit fly)

Pex11C-like protein of 199 aas

Pex11C-like protein of Mombyx mori

Uncharacterized glycosomal protein of 220 aas

UP of Leishmania major

Putative Pex11 of 355 aas

Pex11 homologue of Aspergillus niger

Putative Pex11 homologue of 315 aas

Pex11 homologue of Cryptococcus neoformans (Filobasidiella neoformans)

Uncharacterized protein of 327 aas

UP of Bipolaris oryzae

Pex11 homologue of 290 aas

Pex11 homologue of Sphaerulina musiva (Poplar stem canker fungus) (Septoria musiva)

Uncharacterized protein of 188 aas

UP of Aphanomyces astaci

Uncharacterized protein of 317 aas

UP of Wallemia mellicola (Wallemia sebi

Uncharacterized protein of 410 aas

UP of Serpula lacrymans (Dry rot fungus)

Uncharacterized protein of 334 aas

UP of Rhodosporidium toruloides (Yeast) (Rhodotorula gracilis)

Uncharacterized protein of 228 aas

UP of Mucor circinelloides (Mucormycosis agent) (Calyptromyces circinelloides)

Uncharacterized glycosomal protein of 225 aas

UP of Leishmania braziliensis

Uncharacterized protein of 253 aas

UP of Leishmania braziliensis

Uncharacterized protein of 247 aas

UP of Trypanosoma cruzi

Uncharacterized protein of 252 aas

UP of Emiliania huxleyi

Uncharacterized protein of 252 aas

UP of Saprolegnia diclina

Uncharacterized protein of 421 aas

UP of Emiliania huxleyi

Pex11 of 240 aas

Pex11 of Tetrahymena thermophila

Uncharacterized protein of 289 aas

UP of Paramecium tetraurelia

Pex11 domain containing protein of 235 aas

Pex11 of Oxytricha trifallax

Peroxin Pex11 of 243 aas

Pex11 of Physcomitrella patens (Moss)

Uncharacterized protein of 244 aas

UP of Kazachstania africana (Yeast) (Kluyveromyces africanus)

Pex25 of 294 aas

Pex25 of Saccharomyces cerevisiae

Pex27 of 376 aas and 2 predicted TMSs.

Pex27 of Saccharomyces cerevisiae

Uncharacterized protein of 206 aas

UP of Thalassiosira oceanica (Marine diatom)

Uncharacterized protein of 360 aas

UP of Phaeodactylum tricornutum

Uncharacterized protein of 252 aas

UP of Pythium ultimum

The PB1-F2 protein of 90 aas, and possibly a weakly hydrophobic C-terminal TMS, exhibits viroporin activity, transporting monovalent cations and Ca²⁺ (Hyser and Estes 2015).

PB1-F2 of Influenza virus A

The Parainfluenza Virus 5 (Simian Virus 5) viroporin, SH, of 44 aas and 1 C-terminal TMS. Transports monovalent cations (Hyser and Estes 2015).

SH of Parainfluenza Virus 5 (Simian Virus 5)

SH protein of 44 aas and 1 C-terminal TMS. Transports monovalent cations (Hyser and Estes 2015).

SH of Parainfluenza Virus 5

The FlhA flagellar biosyththesis energizer Na⁺ channel of 692 aas and 8 TMSs.  Evidence for the Na⁺ channel activity of FlhA has been presented (Minamino et al. 2016).

FlhA of E. coli

The mixed lineage kinase domain-like (MLKL) protein of 471 aas and 5 TMSs; forms Mg²⁺-selective channels in the presence of Na⁺ and K⁺ (Xia et al. 2016).

MLKL of Homo sapiens

Mixed lineage kinase domain-like protein, MLKL, of 711 aas and 4 N-terminal TMSs.

MLKL of Balaenoptera acutorostrata scammoni (whale)

The Transmembrane and coiled-coil domains protein 1 (TMCO1) of 188 aas and 3 TMSs. It is an ER transmembrane protein that actively prevents Ca²⁺ stores from overfilling, acting as a "Cacium Load-activated Calcium channel" or "CLAC" channel. TMCO1 undergoes reversible homotetramerization in response to ER Ca²⁺ overloading and disassembly upon Ca²⁺ depletion to form a Ca²⁺-selective ion channel as demonstrated in liposomes (Wang et al. 2016). TMCO1 knockout mice reproduce the main clinical features of human cerebrofaciothoracic (CFT) dysplasia spectrum, a developmental disorder linked to TMCO1 dysfunction, and exhibit severe mishandling of ER Ca²⁺ in cells. Thus, TMCO1 provides a protective mechanism to prevent overfilling of ER stores with calcium ions (Wang et al. 2016).

TMCO1, a CLAC channel of Homo sapiens

TMCO1 of 183 aas and 3 TMSs

TMCo1 of Hydra vulgaris (Hydra) (Hydra attenuata)

TMCO1 or Anon-37B-2 of 177 aas and 3 TMSs.

TMCO1 of Drosophila melanogaster (Fruit fly)

TMCO1 of 177 aas and 3 TMSs

TMCO1 of Schistosoma japonicum (Blood fluke)

TMCO1 homologue of 201 aas and 3 TMSs

TMCO1 homologue of Toxoplasma gondii

Uncharacterized protein of 199 aas and 3 TMSs

UP of Zea mays (Maize)

Uncharacterized protein of 219 aas and 3 TMSs

UP of Eimeria tenella (Coccidian parasite)

Uncharacterized protein of 196 aas and 3 TMSs

UP of Arabidopsis thaliana

Uncharacterized TMCO1 homologue

UP of Chlamydomonas reinhardtii

TMCO1 homologue of 167 aas and 3 TMSs

TMCO1 homologue of Korarchaeum cryptofilum

Uncharacterized protein of 174 aas and 3 TM

UP of Thermococcus nautili

Uncharacterized protein

UP of Methanobrevibacter smithii

Uncharacterized protein of 301 aas and 4 TMSs

UP of Halorubrum saccharovorum

Uncharactized protein of 193 aas and 3 or 4 TMSs

UP of Ferroglobus placidus

Pore-forming Hemoglobin-α of 142 aas (Morrill and Kostellow 2016).

Hemoglobin-α of Homo sapiens

Pore-forming hemoglobin-β of 147 aas (Morrill and Kostellow 2016).

Hemoglobin-β of Homo sapiens

Pore-forming myoglobin of 154 aas (Morrill and Kostellow 2016).

Myoglobin of Homo sapiens

Pore-forming neuroglobin of 151 aas (Morrill and Kostellow 2016).

Neuroglobin of Homo sapiens

Pore-forming cytoglobin of 154 aas (Morrill and Kostellow 2016).

Cytoglobin of Homo sapiens

Ammonia transporter and regulatory sensor, AmtB (Blauwkamp and Ninfa, 2003; Khademi et al., 2004)

AmtB of E. coli (P69681)

High-affinity electrogenic ammonia/methylammonia transporter (allosterically activated by the C-terminus (Loqué et al., 2009).  NH_4⁺ is stable in the AmtB pore, reaching a binding site from which it can spontaneously transfer a proton to a pore-lining histidine residue (His168). The substrate diffuses down the pore in the form of NH₃, while the proton is cotransported through a highly conserved hydrogen-bonded His168-His318 pair (Wang et al. 2012).

Amt1 of Arabidopsis thaliana (P54144)

Ammonium transporter, AmtB or Amt1 of 463 aas and 9 TMSs.  Regulated by direct interaction with GlnK (Pedro-Roig et al. 2013).

AmtB of Haloferax mediterranei (Halobacterium mediterranei)

Ammonium uptake transporter, Amt1 of 458 aas and 11 TMSs.  62% identical to Amt1 of Pyropia yezoensis (Rhodophyta) which is 483 aas long with 11 TMSs and is induced by nitrogen deficiency (Kakinuma et al. 2016).

Amt1 of Chondrus crispus (Carrageen Irish moss) (Polymorpha crispa)

Ammonia-specific uptake carrier, Amt2. For AMT2 from Arabidopsis thaliana NH₄⁺ is the recruited substrate, but the uncharged form NH₃ is conducted.  AtAMT2 partially co-localizes with electrogenic AMTs and conducts methylamine with low affinity (Neuhäuser et al., 2009). This may explain the different capacities of AMTs to accumulate ammonium in the plant cell.

Amt2 of Arabidopsis thaliana

Ammonium/methyl ammonium uptake permease, AmtB (may need AmtB to concentrate [¹⁴C]methyl ammonium (Paz-Yepes et al., 2007))

AmtB of Synechococcus sp CC9311 (Q0IDE4)

Amt1;4 of Arabidopsis thaliana (Q9SVT8)

Amt2 NH₄⁺/CH₃-NH₃⁺ transporter, subject to allosteric activation by a C-terminal region (Loqué et al., 2009).

Amt2 of Archaeoglobus fulgidus (O28528)

Amt1;1, a proposed NH₄⁺:H⁺ sumporter (Ortiz-Ramirez et al., 2011)

Amt1;1 of Phaseolus vulgaris (E2CWJ2)

Ammonium transporter 2, AmtB

AmtB of Dictyostelium discoideum

Mep2 of Candida albicans (Q59UP8)

Rhesus (Rh) type C glycoprotein NH₃/NH₄⁺ transporter, RhCG (also called tumor-related protein DRC2) (Bakouh et al., 2004; Worrell et al., 2007). Zidi-Yahiaoui et al. (2009) have described characteristics of the pore/vestibule. The structure is known to 2.1 Å resolution (Gruswitz et al., 2010). Each monomer contains 12 transmembrane helices, one more than in the bacterial homologs. Reconstituted into proteoliposomes, RhCG conducts NH₃ to raise the internal pH. Models of the erythrocyte Rh complex based on the RhCG structure suggest that the erythrocytic Rh complex is composed of stochastically assembled heterotrimers of RhAG, RhD, and RhCE (Gruswitz et al., 2010).

RhCG of Homo sapiens (Q9UBD6)

Rhesus (Rh) type B glycoprotein NH₃/NH₄⁺ transporter, RhBG (~50% identical to type C) (Lopez et al., 2005; Worrell et al., 2008). Electrogenic NH₄⁺ transport is stimulated by alkaline pH_(out) but inhibited by acidic pH_(out) (Nakhoul et al., 2010). Regulated by Wnt/β-catenin signalling, a pathway frequently deregulated in many cancers and associated with tumorigenesis (Merhi et al. 2015).

RhBG of Homo sapiens (Q9H310)

Rhesus (Rh) complex (tetramer: RhAG₂, RhCE₁, RhD₁) (Exports ammonia from human red blood cells) (Conroy et al., 2005).  RhAG variants (I61R, F65S), associated with overhydrated hereditary stomatocytosis (OHSt), a disease affecting erythrocytes, are alterred for bidirectional ammonium transport (Deschuyteneer et al. 2013).

The RhAG/RhCE/RhD, complex of Homo sapiens
RhAG (Q02094)
RhCE (P18577)
RhD (Q02161)

The RH50 NH₃ channel (most like human Rh proteins TC# 1.A.11.4.1 and 2; 36-38% identity) (Cherif-Zahar et al., 2007). The Rh CO₂ channel protein (3-D structure ± CO₂ available) (3B9Z_A; 3B9Y_A) (Li et al., 2007; Lupo et al., 2007) (also transports methyl ammonia) (Weidinger et al., 2007).

RH50 of Nitrosomonas europaea (Q82X47)

Kidney rhesus glycoprotein p2 (Rhp 2). Transports NH₃ and methylammonium (Nakada et al., 2010).

Rhp2 of Triakis scyllium (D0VX38)

Rhesus-like glycoprotein A (Rh50-like protein RhgA)

RhgA of Dictyostelium discoideum

Ammonium transporter of 391 aas and 12 TMSs.  Shows limited seqences similarity with 9.B.124.1.7 (e^-5) (residues 1-5 align with residues 4 - 8 in 9.B.124.1.7).

Ammonium transporter of [Clostridium] papyrosolvens

Nuclear chloride channel-27, NCC27 or CLIC1 (Br^- > Cl^- > I^-) (241 aas).  CLIC1 has two charged residues, K37 and R29, in its single TMS which are important for the biophysical properties of the channel (Averaimo et al. 2013).  A putative Lys37-Trp35 cation-pi interaction stabilizes the active dimeric form of the CLIC1 TMS in membranes (Peter et al. 2013).  This channel may play a role in cancer (Peretti et al. 2014).  A positively charged motif at the C-terminus of the single TMS enhances membrane partitioning and insertion via electrostatic contacts.  It also functions as an electrostatic plug to anchor the TMS in membranes and is involved in orientating the TMS with respect to the cis and trans faces of the membrane (Peter et al. 2014).

CLIC1 or NCC27 of Homo sapiens

CLIC-5A of Homo sapiens (Q53G01)

The Janus protein, CLIC2. The 3-D structure of its water soluble form has been determined at 1.8 Å resolution (Cromer et al., 2007). CLIC2 interacts with the skeletal ryanodine receptor (RyR1) and modulates its channel activity (Meng et al., 2009).

CLIC2 of Homo sapiens (O15247)

Chloride intracellular channel protein 4, CLIC4.  Regulates the histamine H3 receptor (Maeda et al., 2008)) Discriminates poorly between anions and cations (Singh and Ashley, 2007). 76% identical to CLIC5.  May play a role in cancer (Peretti et al. 2014).

CLIC4 of Homo sapiens (Q9Y696)

Intracellular Cl^- channel-3 (CLIC3). The 3-d structure is known (3FY7). This protein is associated with pregnancy disorders (Murthi et al., 2012). 

CLIC3 of Homo sapiens (O95833)

Putative Glutathione S-transferase.  Pore formation has not been demonstrated in prokaryotes.

Probable glutathione S-transferase of Leptospira interrogans

The bacterial CLIC homologue, stringent starvation protein A, SspA (212 aas; 0 TMSs) [N-terminal Trx domain; C-terminal glutathione S-transferase (GST) domain].  May be involved in acid (Hansen et al. 2005) and sodium ion tolerance (Wu et al. 2014).

Stringent starvation protein A of E. coli (P0ACA3)

Glutathione S-transferase, YfcF of 214 aas.  Pore formation has not been demostrated.

YfcF of E. coli

Voltage-gated bovine epithelial Cl^- channel protein (Ca²⁺-activated), bEClC. In rats, two possible paralogues (rbCLCA1 and A2) are expressed in the CNS and peripheral organs (Yoon et al., 2006). CLCA1 may play a role in inflammatory airway diseases (Sala-Rabanal et al. 2015).

EClC of Bos taurus (NP_001070824)

The Ca-activated chloride channel-6 (Lee et al., 2011).

Ca-CLC-6 of Xenopus laevis (F7IYU6)

Putative lipoprotein of 1054 aas and 1-3 TMSs.

Putative lipoprotein of Leptospira biflexa

Ca⁺²-activated Cl^- channel, CLCA1 or CACC1 or 914 aas.  CLCA1 may play a role in inflammatory airway diseases (Sala-Rabanal et al. 2015).

CLCA1 of Homo sapiens

xCLCA3; xCLCA2 of 942 aas and 7 TMSs.  xCLCA3 contains a predicted signal sequence, multiple sites of N-linked glycosylation, N-myristoylation, PKA, PKC, and casein kinase II phosphorylation sites, five putative hydrophobic segments, and the HExxH metalloprotease motif. Additionally, the transmembrane prediction server yielded a preserved N-terminal CLCA domain and a von Willebrand factor type A domain with one transmembrane domain in the C-terminal region (Lee and Jeong 2016). xCLCA3 is expressed in a number of tissues, with strong expression in the brain, colon, small intestine, lung, kidney, and spleen, and poor expression in the heart and liver. xCLCA3 may be a candidate CLCA family member as well as a metalloprotease, rather than just an ion channel accessory protein.

xCLCA3 of Xenopus laevis (African clawed frog)

Hypothetical protein, HP

HP of Oryza sativa (B8AFH9)

Sll0103

Sll0103 of Synechocystis (Q55874)

The YfbK/CaClC homologue of 575aas and 0 TMSs.  YfbK has amyloidogenic regions due to asparagine- and glutamine-rich regions which is a common feature of many known amyloid proteins. This correlates with detergent-induced denaturation resistance (Antonets et al. 2016).

YfbK of E. coli (P76481)

Von Willebrand factor type A protein, vWFA. (905 aas; 2 N-terminal and 1 C-terminal TMSs)

vWFA of Chloroflexus aurantiacus (A9WIT9)

Bacterial homologue, BatB, of mammalian Ca-CLC channels (N- and C-terminal TMSs)

BatB of Myxococcus fulvus (F8CM01)

Uncharacterized protein of 252 aas and 2-3 TMSs

UP of E. coli

The Bax Inhibitor-1, BI-1.  Also called the testis-enhanced gene transcript (TEGT) protein or the transmembrane BAX inhibitor motif-containing protein 6 (TMBIM6).  It forms a pH-sensitive, cation-selective, Ca²⁺-permeable leak channel (Bultynck et al., 2011; Chang et al. 2014).  Residues that contribute to the ion-conducting pore and affect apoptosis, cell adhesion and migration independently have been identified (Carrara et al. 2015).

BI-1 or TEGT of Homo sapiens (P55061)

Uncharacterized protein of 304 aas and 7 TMSs.

UP of Trypanosoma cruzi marinkellei

Uncharacterized protein of 238 aas and 7 TMSs

UP of Babesia microti

Uncharacterized protein of 317 aas and 7 TMSs

UP of Emiliania huxleyi

Growth hormone-inducible membrane protein of 345 aas and 8 putative TMSs

GH-inducible membrahe protein of Anas platyrhynchos (Mallard) (Anas boschas)

The YccA protein, an inhibitor of FtsH. May share a similar mechanism of action as BI-1 in regulation apoptsis upon prolonged secretion stress (van Stelten et al., 2009).

YccA of E. coli (P0AAC6)

The YbhL (AceP) protein. Possibly a pmf-dependent acetate uptake transporter. [¹⁴C]Acetate uptake was inhibited by CCCP as well as cold acetate, serine, α-ketoglutarate, lactate, and succinate (M. Inouye, personal communication).

YbhL of E. coli (P0AAC4)

The 7 TMS proton-sensitive Ca²⁺ leak channel, YetJ.  The activity and high resolution 3-d structure have been determined (Chang et al. 2014).

YetJ of Bacillus subtilis (O31539)

Uncharacterized protein, YbhM, of 237 aas and 7 TMSs.  The ybhM gene is adjacent to the homologous ybhL gene (TC# 1.A.14.2.2), and another  homologous gene is inbetween these two; these two or three genes could function together as a single transporter. 

YbhM of E. coli

Protein of 234 aas and 7 TMSs encoded by a gene between and homologous to YbhL and YbhM. In the Pfam family Bax1-I.

Bax1-I protein of E. coli

Uncharacterized protein of 227 aas and 7 TMSs

UP of Streptococcus sanguinis

The NMDA receptor glutamate binding chain. Also called Protein lifeguard-1, putative MAPK-activating protein PMO2, and transmembrane BAX inhibitor motif-containing protein 3 (TMBIM3, GRINA, LFG1, NMDARA1). The human orthologue is Q7Z429.  Stimulation and block by spermine involve separate binding sites and distinct mechanisms (Jin et al. 2008).

NMDA receptor glutamate binding chain of Rattus sp. (Q63863)

Glutamate Receptor Gr2

Gr2 of Capsaspora owczarzaki (E9CCY6)

Golgi anti-apoptotic protein, GAAP of 237 aas.  Forms cation-selective channels; residues that contribute to ion-conduction and affect apoptosis, cell adhesion and migration independently have been identified (Carrara et al. 2015).

GAAP of Vaccinia virus, VacV (A2VCJ6)

Ionotropic glutamate receptor; N-methyl-D-aspartate-associated protein 1 (glutamate-binding).

Gr1 of Salmo salar (B5X2N0)

The BH3-only protein, Ynl205c (Büttner et al., 2011)

Ynl305c of Saccharomyces cerevisiae (P48558)

Protein lifeguard 4 (LFG4), also called Golgi anti-apoptotic protein (GAAP), Protein S1R, CGI-119, Transmembrane BAX inhibitor motif-containing protein 4, (TMBIM4) and Z-protein.  Forms cation-selective ion channels. Residues that contribute to the ion-conducting pore and affect apoptosis, cell adhesion and migration independently of each other have been identified (Carrara et al. 2015).  It's functions have been reviewed (Carrara et al. 2017).

TMBIM4 of Homo sapiens

7 TMS integral membrane protein

Uncharacterized membrane protein of Rhodopirellula baltica

Uncharacterized protein of 242 aas and 7 TMSs.

UP of Synechococcus elongatus (Anacystis nidulans R2)

Viral protein HWLF3 (342 aas; 7 TMSs)

HWLF3 of human cytomegalovirus, HHV-5 (Q03307)

Viral membrane protein US14 of 286 aas and 7 TMSs.

US14 of Panine herpesvirus 2 (Chimpanzee cytomegalovirus)

Viral US18 protein of 274 aas and 7 TMSs

US18 of Human cytomegalovirus (HHV-5) (Human herpesvirus 5)

Membrane protein US12A of 250 aas and 7 TMSs

US12A of Simian cytomegalovirus

Membrane protein US19 of 240 aas and 7 TMSs.

US19 of Human cytomegalovirus (HHV-5) (Human herpesvirus 5)

Sec62 of 274 aas and 2, 3 or 4  putative TMSs (Lyman and Schekman 1997).

Sec62 of Saccharomyces cerevisiae

Sec62 protein of 348 aas and 4 putative TMSs.

Sec62 of Paramecium tetraurelia

Translocation protein Sec62 of 276 aas and 3 or 4 putative TMSs.

Sec62 of Plasmodium vivax

Translocation protein Sec62 of 264 aas and 4 putative TMSs.

Sec62 of Arabidopsis thaliana (Mouse-ear cress)

Protein translocation protein, Sec62, of 265 aas and 2 - 4 putative TMSs.

Sec62 of Chlorella variabilis (Green alga)

NS channel protein-1 or Sec62 protein of 399aas and 2 TMSs.  Efficient secretion of small proteins in mammalian cells relies on Sec62-dependent posttranslational translocation (Lakkaraju et al. 2012).

NS channel translocation protein-1 or Sec62 of Homo sapiens

Formate uptake/efflux permease.  Catalyzes bidirectional transport, has a pentameric aquaporin-like (TC# 1.A.8) structure, and may function by a channel-type mechanism (Falke et al., 2009; Wang et al. 2009). The structure at 2.25 Å resolution has been determined (Wang et al., 2009).  Encoded in an operon with pyruvate-formate lyase, PflB.  A pyruvate:formate antiport mechanism has been suggested (Moraes and Reithmeier 2012).

FocA of E. coli (P0AC23)

Probable formate transporter 2 (Formate channel 2), FocB (Andrews et al. 1997).

FocB of Escherichia coli

Formate channel, FocA. Competition of formate by Thr90 from the Ω loop may open the channel (Waight et al., 2010).

FocA of Vibrio cholerae (F9A868)

Formate-specific channel protein, FdhC of 280 aas (Nölling and Reeve 1997).

FdhC of Methanobacterium thermoformicium

Nitrate uptake porter, NitA (Unkles et al., 1991; 2011)

NitA of Aspergillus (Emericella) nidulans

Probable formate uptake permease (Wood et al., 2003).

FdhC of Methanococcus maripaludis

Nitrite uptake porter of 355 aas, Nar1.

Nar1 of Chlamydomonas reinhardtii (Chlamydomonas smithii)

Nitrite channel transporter, NirC, of 382 aas. Structure/function studies including the x-ray structure of the Salmonella orthologue have been reported (Rycovska-Blume et al. 2015).

NirC of Thermofilum pendens

Nitrite/Nitrate exporter of 476 aas, Nar1 (Cabrera et al. 2014).

Nar1 of Pichia angusta (Yeast) (Hansenula polymorpha)

Nitrite uptake/efflux channel (Jia et al. 2009).

NirC of E. coli (P0AC26)

Uncharacterized transporter YwcJ

YwcJ of Bacillus subtilis

Hydrosulfide (hydrogen sulfide; HS^-), Fnt3 (Hsc) channel.  Also probably transports chloride, formate and nitrite. The 3-d crystal structure (2.2Å resolution in the closed state) is known (PDB# 3TE2) (Czyzewski and Wang, 2012). The Fnt3 gene is linked to the asrABC operon encoding the sulfite (SO₃^2-) reductase that gives HS^- as the product (Czyzewski and Wang 2012).

Hsc or Fnt3 HS^- channel of Clostridium difficile (Q186B7)

Nitrate transporter, NirC, of 268 aas and 6 TMSs.

NirC of Klebsiella oxytoca

Inner membrane protein, YfdC (310aas; 6 TMSs).  May be involved in surfactant resistance (Nakata et al. 2010).

YfdC of E. coli (P37327)

Putative FNT transporter of 346 aas

FNT transporter of Psychrobacter arcticus

FNT homologue  of 313 aas

FNT homologue of Salinarchaeum sp. Harcht-Bsk1

FNT homologue of 230 aas

FNT homologue of Acholeplasma palmae

FNT homologue of 213 aas

FNT homologue of Acholeplasma laidlawii

The plasma membrane Ca² -activated chloride (ICl_Ca) channel, TMEM16A (Anoctamin 1a; ANO1a) (Huang et al., 2012; Chen et al. 2011). The mouse orthologue (Q8BHY3), TMEM16A (956aas), is localized to the apical membranes of epithelia as well as intracellular membranes in many cell types. Knockout mice show diminished rhythmic contraction of gastric smooth muscle (Huang et al., 2009). ANO1 is also required for normal tracheal development (Ousingsawat et al., 2009). Expression is upregulated by epidermal growth factor (Mroz and Keely, 2012). Novel 5-substituted benzyloxy-2-arylbenzofuran-3-carboxylic acids are inhibitors (Kumar et al., 2012). TMEM16A channels contribute to the myogenic response in cerebral arteries (Bulley et al., 2012). Membrane stretch activates arterial myocyte TMEM16A channels, leading to membrane depolarization and vasoconstriction. A local Ca²⁺   signal generated by nonselective cation channels stimulates TMEM16A channels to induce myogenic constriction (Bulley et al., 2012).  Ca²⁺/calmodulin activates bicarbonate (anion) transport (Jung et al. 2012).  The protein exists in the membrane as a homodimer where the cytoplasmic N-terminus functions in dimerization (Tien et al. 2013).  TMSs 5-6 of the 8 TMSs may comprise parts of the pore-loop that controls Cl^- conductance (Adomaviciene et al. 2013).  ANO1 confers ICl_Ca in retinal neurons and acts as an intrinsic regulator of the presynaptic membrane potential during synaptic transmission (Jeon et al. 2013).  TMEM16A may be a primary driver of the "Grow" (tumor proliferation) or "Go" (metastasis) model for cancer progression, in which TMEM16A expression acts to balance tumor proliferation and metastasis via its promoter methylation (Shiwarski et al. 2014).  Regulation of TMEM16A/16B by Ca²⁺ is mediated by preassociated apo-calmodulin (Yang et al. 2014).as well asCaMKIIδ (Gui et al. 2015).  Because the Cl^- channel is the only active ion-selective conductance with a reversal potential that lies within the dynamic range of spiral ganglion neurons (SGN) action potentials, developmental alteration of [Cl^-], and hence the equilibrium potential for Cl^- (ECl), transforms the pre- to the posthearing phenotype (Zhang et al. 2015).  Four basic residues involved in ion selectivity and pore blocker sensitivity have been identified (Peters et al. 2015).  Channel activity is required for mucus secretion induced by interleukin-13 (Lin et al. 2015; Zhang et al. 2015). May interact cooperatively with TrpV1 (TC# 1.A.4.2.1) to form a thermal sensor (Kanazawa and Matsumoto 2014). Inhibitors have been described (Boedtkjer et al. 2015).  The first intracellular loop serves as a Ca²⁺ binding site and includes D439, E444 and E447 (Pang et al. 2015).  Inhibited by various 4-Aryl-2-amino thiazoles at concentrations as low as 1 mμM (Piechowicz et al. 2016).  ANO1 and TRPC6 (1.A.4.1.5) are present in the same macromolecular complex and localize in close spatial proximity in the myocyte plasma membrane.  TRPC6 channels probably generate a local intracellular Ca²⁺ signal that activates nearby ANO1 channels in myocytes to stimulate vasoconstriction (Wang et al. 2016).  ANO1 transports bicarbonate which functions in the regulation of pancreatic acinar cell pH (Han et al. 2016).  TMEM16A contains two ion conduction pores that are independently activated by Ca²⁺ binding to sites that are embedded within the transmembrane part of each subunit (Lim et al. 2016).  Interactions between the carboxy- terminus and the first intracellular loop in the TMEM16A homo-dimer regulate channel activity (Scudieri et al. 2016).  A STAT6-TMEM16A-ERK1/2 signal pathway and TMEM16A channel activity are required for the Interleukin-13 (IL-13)-induced TMEM16A mediated mucus production (Qin et al. 2016). Angiotensin II elicits a TMEM16A-mediated current, and TMEM16A participates in Ang II-induced basilar constriction via the RhoA/ROCK signaling pathway (Li et al. 2016). 2-acylamino-cycloalkylthiophene-3-carboxylic acid arylamides (AACTs) are inhibitors of TMEM16A, and 48 synthesized analogs (10ab-10bw) of the original AACT compound (10aa) have been synthesized and studied.  The most potent compound (10bm), which contains an unusual bromodifluoroacetamide at the thiophene 2-position, had an IC50 ~ 30 nM (Truong et al. 2017).

Anoctamin 1a of Homo sapiens (Q5XXA6)

Anoctamin, Anoh-2.  Present in mechanoreceptive neurons and spermatheca (Wang et al. 2013).

Anoh-2 of Caenorhabditis elegans

Ca-ClC Family homologue

Ca-ClC homologue of Paramecium tetraurelia (A0CAP8)

Ciliate CaClC homologue

CaClC homologue of Paramecium tetraurelia (A0CIB0)

Water mold Anoctamin-like protein

Anoctamin-like protein of Phytophthora infestans (D0NGF4)

Uncharacterized protein

Uncharacterized protein of Schizosaccharomyces japonicus

Anoctamin-like protein

Anoctamin-like protein of Oxytricha trifallax

TMEM16 (Ist2) ion channel/phospholipid scramblase (Malvezzi et al. 2013).

Ist2 of Aspergillus fumigatus (Neosartorya fumigata)

TMEM16 of 735 aas and 10 TMSs.  Operates as a Ca²⁺-activated lipid scramblase. Each subunit of the homodimer contains a hydrophilic membrane-traversing cavity that is exposed to the lipid bilayer as a potential site of catalysis. This cavity harbours a conserved Ca²⁺-binding site, located within the hydrophobic core of the membrane. Mutations of residues involved in Ca²⁺ coordination affect both lipid scrambling in N. haematococca TMEM16 and ion conduction in the Cl^- channel of TMEM16A. The structure reveals the general architecture of the family and its mode of Ca²⁺ activation (Brunner et al. 2014).

TMEM16 of Nectria haematococca (Fusarium solani subsp. pisi)

Increased sodium tolerance protein, Ist2, of 946 aas and 7 TMSs.  Ist2 is an endoplasmic reticulum (ER)-resident transmembrane protein that mediates associations between the plasma membrane (PM) and the cortical ER (cER) in baker's yeast (Kralt et al. 2015).

Ist2 of Saccharomyces cerevisiae

Anoctamin 1, isoform b (Gnathodiaphyseal dysplasia 1 protein homologue) (39% identical to Anoctamin 1a) (Planells-Cases and Jentsch, 2009).  See also Xu et al. 2015.

Anoctamin 1b of Homo sapiens (Q75UR0)

Anoctamin 3, ANO3 or KCNT1, of 981 aas and 9 TMSs.  Has calcium-dependent phospholipid scramblase activity, scrambling phosphatidylcholine and galactosylceramide. Seems to act as a potassium channel regulator and may inhibit pain signaling; can facilitate KCNT1/Slack channel activity by promoting its full single-channel conductance at very low sodium concentrations and by increasing its sodium sensitivity (Scudieri et al. 2012). Mutations cause  (i) epilepsy of infancy with migrating focal seizures (EIMFS; also known as migrating partial seizures in infancy), (ii) autosomal dominant nocturnal frontal lobe epilepsy, and (iii) other types of early onset epileptic encephalopathies (EOEEs) (Ohba et al. 2015).

ANO3 or KCNT1 of Homo sapiens

Ano5 (GDD1, TMEM16E) of 913 aas and 10 TMSs. Associated with bone fragility, limb girdle muscular dystrophy type 2L (LGMD2L), Miyoshi myopathy type 3 (MMD3), and gnathodiaphyseal dysplasia 1 (GDD1) in humans (Jin et al. 2017), but an Ano5 knock-out mutant in mice was not reported to exhibit such symptoms (Xu et al. 2015). The orthologue in mice is TC# 1.A.17.1.2.  TMEM16E may function as a phospholipid scramblase in intracellular membranes promoting sperm motility and function (Gyobu et al. 2016).

Ano5 of Homo sapiens

Subdued, a calcium-activated chloride channel of 1075 aas. Functions in conjunction with the thermo-TRPs in thermal nociception. Subdued channels may amplify the nociceptive neuronal firing that is initiated by thermo-TRP channels in response to thermal stimuli (Jang et al. 2015).

Subdued of Drosophila melanogaster

ANO-like protein of 921 aas and 9 predicted TMSs.

ANO-L family protein of Strongylocentrotus purpuratus (Purple sea urchin)

TMEM16B (Anoctamin-2, ANO2) anion channel.  Exists in the membrane as a homodimer where the cytoplasmic N-terminus functions in dimerization (Tien et al. 2013).  TMSs 5-6 may comprise parts of the pore-loop that controls Cl^- conductance (Adomaviciene et al. 2013).  TMEM16A and TMEM16B are differentially expressed during development in the olfactory epithelium of the mouse (Maurya and Menini 2014).

TMEM16B of Homo sapiens (Q9NQ90)

Anoctamin-6 (ANO6: TMEM16F) Ca²⁺-dependent phospholipid scramblase (flippase) (Suzuki et al., 2010; Chauhan et al. 2016). Defects cause Scott syndrome. It is an essential component of the outwardly rectifying chloride channel (Martins et al., 2011; Keramidas and Lynch 2012).  It has also been reported to be an anion channel with delayed Ca²⁺ activation (Adomaviciene et al. 2013) as well as a Ca²⁺-activated cation channel with activity that is required for lipid scrambing (Yang et al. 2012).  However, Suzuki et al. (2013) showed that TMEM16F is a Ca²⁺-dependent phospholipid scramblase that exposes phosphatidylserine (PS) to the cell surface but lacks calcium-dependent chloride channel activity.  TMEM16C, 16D, 16G and 16J also had Ca²⁺-dependent scramblase but not channel activity (Suzuki et al. 2013).  The pore region resonsible for Cl^- transport in TMEM16A is also responsible for phospholipid scramblase activity (Suzuki et al. 2014).  Anoctamin-6 (Ano6) plays an essential role in C2C12 myoblast proliferation, probably by regulating the ERK/AKT signaling pathway (Zhao et al. 2014).  It regulates baeline phosphatidyl serine exposure and cell viability in human embryonic kidney cells (Schenk et al. 2016).

Anoctamin-6 of Homo sapiens (Q4KMQ2)

Uncharacterized protein

Uncharacterized protein of Batrachochytrium dendrobatidis

Anoctamin-like protein

amoctamin-like protein of Dictyostelium purpureum

Uncharacterized protein

unchacterized protein of Aureococcus anophagefferens

Anoctamin, Anoh-1 of 822 aas.  Functions in a sensory mode-specific manner.  Present inamphid sensory neurons to detect external chemical and nociceptive cues (Wang et al. 2013).

Anoh-1 of Caenorhabditis elegans

DUF590 family protein

DUF590 protein of Dicyostelium discoideum (Q54BH1)

TMEM16 homologue of 701 aas.

TMEM16 homologue of Naegleria gruberi (Amoeba)

Anoctamin homologue of 689 aas

Anoctamin of Guillardia theta

DUF590 homologue of 487 aas

DUF590 homologue of Entamoeba nuttalli

DUF590 protein of 914 aas

DUF590 protein of Allomyces macrogynus

Uncharacterized protein of 569 aas and 8 predicted TMSs.

UP of Dictyostelium fasciculatum (Slime mold)

Uncharacterized protein of 2464 aas and 11 TMSs.  Contains a trypsin-like serine protease domain (residues 100 - 400), a rabaptin (chromosome segregation) domain (residues 900 - 1200), an anoctamin domain (residues 1500 - 2000) and an AAA ATPase-containing von Willebrand factor type A domain (residues 2200 - 2500).

UP of Thalassiosira pseudonana (Marine diatom) (Cyclotella nana)

Uncharacterized protein of 1080 aas

UP of Ostreococcus lucimarinus

Anoctamin homologue of 1265 aas

Anoctamin homologue of Tetrahymena thermophila

Uncharacterized protein of 995 aas and 8 TMSs.

UP of Tetrahymena thermophila

Uncharacterized protein of 842 aas and 9 TMSs.

UP of Thalassiosira pseudonana (Marine diatom) (Cyclotella nana)

Uncharacterized protein of 835 aas and 9 TMSs.

UP of Phytophthora parasitica (Potato buckeye rot agent)

Uncharacterized protein of 1231 aas and 9 TMSs

UP of Aureococcus anophagefferens (Harmful bloom alga)

Uncharacterized protein of 945 aas and 8 TMSs

UP of Ectocarpus siliculosus (Brown alga)

Uncharacterized protein of 1437 aas

UP of Emiliania huxleyi

Uncharacterized protein of 1150 aas

UP of Capsaspora owczarzaki

DUF590/putative methyltransferase of 1221 aas and 10 TMSs.

DUF490 homologue of Oxytricha trifallax

DUF590 homologue of 1026 aas and 10 TMSs

DUF590 homologue of Paramecium tetraurelia (ciliate)

TMC2, like TMC1, plays a role in hearing and gravity detection (Kawashima et al., 2011).  Required for normal function of cochlear hair cells, possibly as a Ca²⁺ channel (Kim and Fettiplace 2013).  TMC1 and TMC2 are both components of hair cell transduction channels and contribute to permeation properties (Pan et al. 2013; Kawashima et al. 2014).  Both TMC1 and 2 interact with Protocadherin 15 (Maeda et al. 2014). TMC1 and TMC2 are components of the stereocilia mechanoelectrical transduction channel complex (Kurima et al. 2015).

TMC2 of Mus musculus (Q8R4P4)

Transmembrane channel 6, TMC6/EVER1 of 805 aas.  Mutations give rise to epidermodysplasia verruciformis (EV), a rare genodermatosis, characterized by increased sensitivity to infection by the beta-subtype of human papillomaviruses (beta-HPVs), causing persistent, tinea versicolor-like dermal lesions (Horton and Stokes 2014).

TMC6 of Homo sapiens

Transmembrane channel 8, TMC8/EVER2/EVIN2 of 726 aas.  Mutations give rise to epidermodysplasia verruciformis (EV), a rare genodermatosis characterized by increased sensitivity to infection by the beta-subtype of human papillomaviruses (beta-HPVs) ass well as increased incidence of cancer, causing persistent, tinea versicolor-like dermal lesions (Horton and Stokes 2014).  This is due to release of Zn²⁺ and Ca²⁺ from the endoplasmic reticulum (Sirianant et al. 2014).  The channel-like domain has been identified (Miyauchi et al. 2016).

TMC8 of Homo sapiens

Transmembrane channel protein 3, Tmc3 of 1130 aas (Kurima et al. 2003; Beurg et al. 2014).

Tmc3 of Mus musculus

Tmc1/Tmc2a or Tmc2b/protocadherin 15a (Pcdh15a). The complex is part of a mechanotransduction system (Maeda et al. 2014). Its trafficing to the plasma membrane depends on the transmembrane O-methyltransferase (TOMT/LRTOMT; 259 aas, 1 N-terminal TMS) (Erickson et al. 2017).

Tmc1/Tmc2/Pcdh15 complex of Danio rerio (Zebrafish) (Brachydanio rerio)

Tmc4 of 712 aas and 10 TMSs (Mancina et al. 2016).

TMC4 of Homo sapiens

Transmembrane channel-like protein-B, Tmc8 (EVER2).  Occurs in the endoplasmic reticulum where it functions to release Ca²⁺ and Zn²⁺ and supresses Cl^- currents (Sirianant et al. 2014). 

Tmc8 of Mus musculus (Q7TN58)

Hypothetical protein, HP

HP of Salpingoeca sp. (F2U2C0)

Hypothetical protein, HP

HP of Capsaspora owczarzaki (E9C7I1)

Transmembrane channel-like protein 7, TMC7

TMC7 of Acromyrmex echinatior (F4X8H9)

Transmembrane channel-like protein-1, Tmc1. Also called Transmembrane cochlear-expressed protein-1, Beethoven protein and deafness protein.  Required for normal function of cochlear hair cells, possibly as a Na⁺/K⁺/Ca²⁺ channel (Kim and Fettiplace 2013).  TMC1 and TMC2 are both components of hair cell transduction channels and contribute to permeation properties (Pan et al. 2013; Kawashima et al. 2014).  Channel activity has been demonstrated for the C. elegans orthologue, and the mouse Tmc1.  The C. elegans Tmc1 is probably a Na⁺-activated Na⁺-selective mechanosensor. The C. elegans Tmc2 may be a Na⁺/K⁺ channel.  The mouse Tmc1 is functional and replaces Tmc2 when expressed in C. elegans (WR Schafer, personal communication).  Ca²⁺ currents are blocked by the peptide toxin GsMTx-4 (Beurg et al. 2014).  Tmc1 and Tmc2, expressed in cochlear and vestibular hair cells, are required for hair cell mechanoelectric transduction (Nakanishi et al. 2014); mutations disrupt mechanoelectric transduction and are a cause of autosomal dominant and recessive forms of nonsyndromic hearing loss (Gao et al. 2015).  Using the mutant mouse model (Tmc1; Beethoven) for progressive hearing loss in humans (DFNA36) this mutation has been shown to affect the MET channel pore, reducing its Ca²⁺ permeability and its affinity for the permeant blocker, dihydrostreptomycin (Corns et al. 2016).  Evidence for TMC1 beiing the hair cell mechanosensitive channel has been evaluated (Fettiplace 2016).  The human orthologue (UniProt acc # Q8TDI8) is 96% identical.

Tmc1 of Mus musculus

The sodium sensor/cation conductance channel activated by high extracellular Na⁺, Tmc-1 (Tmc1) (Chatzigeorgiou et al. 2013).  It functions in salt taste chemosensation and salt avoidance and is an ionotropic sensory receptor.  Wang et al. 2016 showed that C. elegans TMC-1 mediates nociceptor responses to high pH, not sodium, allowing the nematode to avoid strongly alkaline environments in which most animals cannot survive (Spalthoff and Göpfert 2016).

Tmc-1 of Caenorhabditis elegans

Tmc2 channel of 1203 aas and 9 - 11 TMSs; functions in touch neurons as a mechanosensitive touch sensor (Chatzigeorgiou et al. 2013; WR Schafer, personal communication).  May function as a Na⁺/K⁺ channel.

Tmc2 of Caenorhabditis elegans

Tmc receptor/channel of 1932 aas. Plays a role in Drosophila proprioception and the sensory control of larval locomotion (Guo et al. 2016).

Tmc of Drosophila melanogaster

Uncharacterized protein, DUF221, of 703 aas

UP of Zea mays

The non-rectifying, plasma membrane, calcium-permeable, stress-gated, cation channel 1 (CSC1) of 771 aas (Hou et al. 2014).  Activated by hyperosmotic shock.  Permeable to Ca²⁺, K⁺ and Na⁺.  Inactivation or closure is Ca²⁺-dependent.  The N-terminal region contains 3 TMSs, the first of which may be a cleavable signal peptide., and the C-terminal region contains 6 TMSs corresponding to the DUF221 domain.  Arabidopsis contains at least 15 CSCs ((Hou et al. 2014).  Some plant homologues are transcriptionally upregulated in response to vaious abiotic and biotic stresses involving mechanical perturbation (Kiyosue et al. 1994).

CSC1 of Arabidopsis thaliana

Osmotically-gated calcium conductance channel of 782 aas. CSC1 (Hou et al. 2014). Activated under hyperosmotic conditions. There are four paralogues in S. cerevisiae. 

CSC1 of Saccharomyces cerevisiae

The osmosensitive calcium-permeable cation channel, CSC1 of 806 aas.  Activated by hyperosmolarity and Ca²⁺ (Hou et al. 2014).

CSC1 of Homo sapiens

Uncharacterized protein of 901 aas

UP of Spironucleus salmonicida

Uncharacterized protein of 1267 aas and 12 TMSs

UP of Dictyostelium discoideum (Slime mold)

Uncharacterized protein of 1548 aas and 12 TMSs.

UP of Thalassiosira pseudonana (Marine diatom) (Cyclotella nana)

Uncharacterized protein of 1172 aas

UP of Phytomonas sp. isolate EM1

Uncharacterized protein of 1258 aas and 11 TMSs.

UP of Agaricus bisporus (White button mushroom)

Uncharacterized protein of 816 aas containe a DUF221 domain

UP of Danio rerio

Uncharacterized transmembrane protein 63B of 832 aas with a DUF221 domain.

UP of Homo sapiens

Uncharacterized transmembrane protein 63B of 832 aas with a DUF221 domain.

UP of Acanthamoeba castellanii

Uncharacterized protein of 853 aas with a DUF221 domain.

UP of Botryotinia fuckeliana

Phosphate metabolism protein 7, Phm7

Phm7 of Saccharomyces cerevisiae

Sporulation-specific protein 75, Spo75

Spo75 of Saccharomyce cerevisiae

RSN-1-like protein of 957 aas

RSN-1-like protein of Saccharomyces kudriavzevii

Early response to dehydrate stress protein, ERD4 of 785 aas

ERD4 of Arabidopsis thaliana

Uncharacterized protein of 878 aas and 7 putative TMSs.

UP of Oxytricha trifallax

Uncharacterized protein of 707 aas and 10 TMSs

UP of Plasmodiophora brassicae

TMC-like protein 8 of 890 aas and 8 TMSs

TMC homologue of Oxytricha trifallax

Uncharacterized protein of 834 aas and 7 TMSs

UP of Oxytricha trifallax

Uncharacterized protein of 912 aas and 10 TMSs

UP of Phytophthora parasitica (Potato buckeye rot agent)

Uncharacterized protein of 620 aas and 9 TMSs

UP of Ectocarpus siliculosus (Brown alga)

Uncharacterized protein of 865 aas and 10 TMSs

UP of Guillardia theta

TMC protein of 890 aas and 10 TMSs

TMC protein of Tetrahymena thermophila

Uncharacterized protein of 1057 aas and 8 TMSs.

UP of Tetrahymena thermophila

Uncharacterized protein of 867 aas and 10 TMSs.

UP of Saprolegnia diclina

Uncharacterized protein of 836 aas and 12 TMSs.

UP of Giardia intestinalis (Giardia lamblia)

Uncharacterized protein of 637 aas and 8 TMSs.

UP of Spironucleus salmonicida

Uncharacterized protein of 646 aas and 8 TMSs.

UP of Emiliania huxleyi (Pontosphaera huxleyi)

Tic110 channel protein. The x-ray structure (4.2Å resolution) of Tic110B and C from Cyanidioschyzon merolae is known (Tsai et al., 2013). The C-terminal half of Tic110 posesses a rod-shaped helix-repeat structure that is too flattened and elongated to be a channel. The structure is most similar to the HEAT-repeat motif that functions as scaffolds for protein-protein interactions (Tsai et al., 2013).

Tic110 of Cyanidioschyzon merolae (M1V6H9)

Matrix protein, M2, an acid activated drug-sensitive proton channel.  Transport involves binding to the four His-37s and transfer to water molecules on the inside of the channel (Acharya et al., 2010).  Functional properties and structure are known (Hong and Degrado 2012). The cytoplasmic tail facilitates proton conduction (Liao et al. 2015).  It is a dimer of dimers (Andreas et al. 2015).  The four TMSs flanking the channel lumen alone seem to determine the proton conduction mechanism (Liang et al. 2016). His-37 forms a planar tetrad in the configuration of the bundle accepting and translocating the incoming protons from the N terminal side, exterior of the virus, to the C terminal side, inside the virus (Kalita and Fischer 2017).

M2 of influenza virus type A

Matrix protein M2 of 96 aas and 1 TMS.  Forms a proton-selective ion channel that is necessary for the efficient release of the viral genome during virus entry. After attaching to the cell surface, the virion enters the cell by endocytosis. Acidification of the endosome triggers M2 ion channel activity. The influx of protons into the virion interior is believed to disrupt interactions between the viral ribonucleoprotein (RNP), matrix protein 1 (M1), and lipid bilayers, thereby freeing the viral genome from interaction with viral proteins and enabling RNA segments to migrate to the host cell nucleus, where influenza virus RNA transcription and replication occur. Also plays a role in viral proteins secretory pathway.

M2 of Influenza A virus (A/flat-faced bat/Peru)

Matrix protein 2, M2, of 80 aas and 1 TMS

M2 of Influenza A virus (A/swine)

M2 protein of 95 aas and 1 TMS, AM2.  This protein shows 28% identity, 50% similarity and 10% gaps with BM2 (TC# 1.B.58.1.1) with residues 8 - 65 aligning with residues 26 - 81.

AM2 of Influenza A virus (A/herring gull/Newfoundland)

Protein of 489 aas with C-terminal region resembling the M2 protein (33% identity with no gaps).

Protein of Apis mellifera filamentous virus

ATP-activated inward rectifier K⁺ channel, IRK1 (also called ROMK or KIR1.1) (regulated by Sur1, allowing ATP sensitivity; also activated by phosphatidylinositol 4,5-bisphosphate (PIP) with affinity to PIP controlled by protein kinase A phosphorylation (which increases affinity for PIP)) and protein kinase C phosphorylation (which decreases affinity for PIP (Zeng et al., 2003). Alternariol (AOH), the most important mycotoxin produced by Alternaria species, which are the most common mycoflora infecting small grain cereals worldwide, causes loss of cell viability by inducing apoptosis. AOH-induced apoptosis through a mitochondria-dependent pathway is characterized by p53 activation, an opening of the mitochondrial permeability transition pore (PTP), loss of mitochondrial transmembrane potential (ΔΨm), a downstream generation of O₂^- and caspase 9 and 3 activation (Bensassi et al., 2012). Pharmacological inhibition of renal ROMK causes diuresis and natriuresis in the absence of kaliuresis (Garcia et al. 2013).

IRK1 of Homo sapiens (P48048)

G-protein-activated inward rectifying K⁺ channel, Kir3.2 or GIRK (Inanobe et al., 2011; Yokogawa et al. 2011).  Important in regulating heart rate and neuronal excitability.  Activated by binding of the βγ-subunit complex to the cytoplasmic pore gate (Yokogawa et al. 2011).

Kir3.2 of Homo sapiens (P48051)

Inward rectifying potassium channel 16, Kir5.1. (Potassium channel subfamily J member 16), KCNJ16.  Involved in pH and fluid regulation.  Forms heteromers with Kir4.1/KCNJ10 or Kir2.1/KCNJ2.

G protein-activated inward rectifying K⁺ channel 1 (Kir3.1; IRK3; GIRK1). Regulates the heartbeat in humans. Phosphatidylinositol bisphosphate (PIP2) activates by opening the intracelluar G-loop gate (Meng et al., 2012).  Along the ion permeation pathway, three relatively narrow regions (the selectivity filter, the inner helix bundle crossing, and the cytosolic G loop) may serve as gates to control ion permeation (Meng et al. 2016). Cholesterol up-regulates neuronal GIRK channel activity (Bukiya et al. 2017). Changes in the levels of cholesterol and PI(4,5)P2 may act in concert to provide fine-tuning of Kir3 channel function (Bukiya et al. 2017).

Kir3.1 (IRK3) of Homo sapiens (P48549)

ATP-sensitive inward rectifying K  channel 8, Kir6.1. Acts with Sur2B (3.A.1.208.23). Channel activity is inhibited in oxidative stress via S-glutathionylation (Yang et al., 2011). Oxidative sensitivity is dependent on Cys176 (Yang et al., 2011).  These proteins comprise part of the glucose sensing mechanism (Rufino et al. 2013).

Kir6.1 of Homo sapiens (Q15842)

Inward rectifying potassium (K⁺) (IRK) channel of 426 aas and 2 TMSs, AgaP.

AgaP of Anopheles gambiae (African malaria mosquito)

Kir1 (AgaP) K⁺ channel of 444 aas and 2 TMSs.

Kir1 of Anopheles gambiae (African malaria mosquito)

Inward rectifying K⁺ channel, Kir4.1 of 379 aas.  Inhibited by chloroethylclonidine which binds in the channel (Rodríguez-Menchaca et al. 2016). Also inhibited by chloropuine which inhibits by an open pore blocking mecnanism (Marmolejo-Murillo et al. 2017).

Kir4.1 of Homo sapiens

KCNJ11 or Kir6.2 or KATP of 390 aas; 96% identical to the rat homologue, TC# 1.A.2.1.7. Congenital hyperinsulinism (CHI) is characterized by persistent insulin secretion despite severe hypoglycemia. Mutations in the pancreatic ATP-sensitive K⁺ (K(ATP)) channel proteins sulfonylurea receptor 1 (SUR1) and Kir6.2, encoded by ABCC8 and KCNJ11, respectively, is the most common cause of the disease. Many mutations in SUR1 render the channel unable to traffic to the cell surface, thereby reducing channel function. Many studies have shown that for some SUR1 trafficking mutants, the defects could be corrected by treating cells with sulfonylureas or diazoxide (Yan et al. 2007). Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it. Their voltage dependence is regulated by the concentration of extracellular potassium; as external potassium is raised, the voltage range of the channel opening shifts to more positive voltages. The inward rectification is mainly due to the blockage of outward current by internal magnesium (Tammaro and Ashcroft 2007). Kir6.2 is an ATP-sensitive potassium (K_ATP) channel coupling cell metabolism to electrical activity by regulating K⁺ fluxes across the plasma membrane. Channel closure is facilitated by ATP, which binds to the pore-forming subunit (Kir6.2). Conversely, channel opening is potentiated by phosphoinositol bisphosphate (PIP₂), which binds to Kir6.2 and reduces channel inhibition by ATP.  The PIP₂ binding site has been identified (Haider et al. 2007).  KATP channels are metabolic sensors that couple cell energetics to membrane excitability. In pancreatic beta-cells, channels formed by SUR1 and Kir6.2 regulate insulin secretion and are the targets of antidiabetic sulfonylureas. Martin et al. 2017 used cryo-EM to elucidate the structural basis of channel assembly and gating. The structure, determined in the presence of ATP and the sulfonylurea, glibenclamide, at ~6 Å resolution, revealed a closed Kir6.2 tetrameric core with four peripheral SUR1s, each anchored to a Kir6.2 by its N-terminal transmembrane domain (TMD0). Intricate interactions between TMD0, the loop following TMD0, and Kir6.2 near the proposed PIP2 binding site, and where ATP density is observed, suggest that SUR1 may contribute to ATP and PIP2 binding to enhance Kir6.2 sensitivity to both. The SUR1-ABC core is found in an unusual inward-facing conformation whereby the two nucleotide binding domains are misaligned along a two-fold symmetry axis, revealing a possible mechanism by which glibenclamide inhibits channel activity (Martin et al. 2017).

Kir6.2 of Homo sapiens

G-protein enhanced inward rectifier K channel 2, IRK2 (Kir2.1) (Andersen-Tawil Syndrome (ATS-1) protein; the V302M mutation causing the syndrome, alters the G-loop cytoplasmic K conduction pathway) (Bendahhou et al., 2003; Ma et al., 2007). (Blocked by chloroquine which binds in the cytoplasmic pore domain (Rodriguez-Menchaca et al., 2008)). Forms heteromultimers with Kir3.1 and Kir3.4 (Ishihara et al., 2009). A C-terminal domain is critical for the sensitivity of Kir2.1 to cholesterol (Epshtein et al., 2009). Flecainide increases Kir2.1 currents by interacting with cysteine 311, decreasing the polyamine-induced rectification (Caballero et al., 2010).  The inhibitory cholesterol binding site has been identified (Fürst et al. 2014).  Polyamines and Mg²⁺ block ion flux synergistically (Huang and Kuo 2016).

IRK2 of Homo sapiens (P63252)

G-protein activated IRK5 channel. The p75 neurotrophin receptor mediates cell death by activating GIRK channels through phosphatidylinositol 4,5-bisphosphate (Coulson et al., 2008). Cholesterol up-regulates neuronal GIRK channel activity (Bukiya et al. 2017).

IRK5 of Homo sapiens (P48544)

Cranial nerve inward rectifying K⁺ channel, Kir2.4 (IRK4) (Töpert et al., 1998)

Kir2.4 of Rattus norvegicus (O70596)

Kidney/pancreas/muscle ATP-senstive, ER/Golgi K⁺ channel, KATP or ROMK (Kir6.2) (Boim et al., 1995) (three alternatively spliced isoforms are called ROMK1-3). Involved in congenital hyperinsulinism (Lin et al., 2008). Regulated by Ankyrin-B (Li et al., 2010). ATP activates ATP-sensitive potassium channels composed of mutant sulfonylurea receptor 1 (SUR1) and Kir6.2 with diminished PIP2 sensitivity (Pratt and Shyng, 2011). This channel protects the myocardium from hypertrophy induced by pressure-overloading (Alvin et al., 2011). Domain organization studies show which domains in Sur and Kir6.2 interact (Wang et al. 2012).  KATP channels consisting of Kir6.2 and SUR1 couple cell metabolism to membrane excitability and regulate insulin secretion in pancreatic beta cells, and mutations in the former protein can compensate for mutations in the latter (Zhou et al. 2013).  Mutations cause inactivation of channel function by disrupting PIP2-dependent gating (Bushman et al. 2013). Thus, these proteins comprise part of the glucose sensing mechanism (Rufino et al. 2013).  A single point mutation can confer voltage sensitivity (Kurata et al. 2010).  Its involvement in type II diabetes has been reviewed by Bonfanti et al. 2015. KATP channels (Kir6.2/SUR1) in the brain and endocrine pancreas  couple metabolic status to the membrane potential. In beta-cells, increases in cytosolic [ATP/ADP] inhibit KATP channel activity, leading to membrane depolarization and exocytosis of insulin granules. Mutations in ABCC8 (SUR1) or KCNJ11 (Kir6.2) can result in gain or loss of channel activity and cause neonatal diabetes (ND) or congenital hyperinsulinism (CHI), respectively.  Nucleotide binding without hydrolysis switches SUR1 to stimulatory conformations.  Increased affinity for ATP gives rise to ND while decreased affinty gives rise to CHI (Ortiz and Bryan 2015).  Kir6.2 can associate with either SUR1 (TC# 3.A.1.208.4) or SUR2A (TC# 3.A.1.208.23) to form heteroctamers, leading to different locations and consequences (Principalli et al. 2015).

ROMK of Rattus norvegicus (P70673)

The inward-rectifier k+ channel, Kir2.2 at the 3-d structure at 3.1 Å resolution is available (Tao et al., 2009). (70%v identical to Kir2.1 (TC # 1.A.2.1.2)). The structural basis of PIP2 activation of Kir2.2 has been presented (Hansen et al., 2011).

Kir2.2 of Homo sapiens (Q14500)

Prokaryotic K⁺-selective Kir channel KirBac1.1 (selectivity: K⁺ = Rb⁺ = Cs⁺ >> Li, Na⁺ or NMGM) (Enkvetchakul et al., 2004), inward rectifying (Cheng et al., 2009). The inhibitory cholesterol binding site has been identified (Fürst et al. 2014).

KirBac1.1 OF Burkholderia pseudomallei (IP7BA; gi33357898)

The KirBac3.1 K⁺ channel (a dimer of dimers with gating visualized by atomic force microscopy, Jaroslawski et al., 2007) (regulated by binding lipids, G-proteins, nucleotides, and ions (H⁺, Ca²⁺, and Mg²⁺)). The 3-D structure is available (1XL6_A).  The inhibitory cholesterol binding site has been identified (Fürst et al. 2014).

KirBac3.1 of Magnetospirillum magnetotacticum  (D9N164)

ATP-sensitive inward rectifying Kir K channel (Choi et al. 2010).

Kir K⁺ channel of Chromobacterium violaceum

Putative K⁺ channel

K⁺ channel of Synechocystis PCC 6803

Inward rectifier potassium channel 

K⁺ channel of Burkholderia xenovorans

NIP3L (NIP3-like protein X; Adenovirus E1B 19kDa-binding protein B5). 

NIP3L of Homo sapiens (O60238)

BCL2/adenovirus E1B 19 kDa protein-interacting protein 3  homologue of 215 aas and 1 C-terminal TMS.

BCL2 of Aquila chrysaetos canadensis

BCL2/Adenovirus E1B interacting protein, NIP3

NIP3 of Caenorhabditis elegans (Q09969)

NIP2-like protein of 195 aas and 1 C-terminal TMS

NIP3 of Trichinella spiralis (Trichina worm)

Apoptosis regulator Bcl-X(L) of 233 aas.  Also called Bcl2-like protein 1, isoform 1. Membrane insertion of the soluble form has been characterized (Vargas-Uribe et al. 2013).  The cytosolic domain of Bcl-2 forms small pores in the mitochondrial outer membrane (Peng et al. 2009).

Bcl-X(L) of Homo sapiens

The mitochondrial apoptosis-inducing channel-forming protein, BAX.  The C-terminal helix mediates membrane binding and pore formation (Garg et al. 2012). BAX pores are large enough to allow cytochrome c release and it activates the mitochondrial permeabilty transition pore; both play a role in programmed cell death, but the latter is quantitatively more important (Gómez-Crisóstomo et al. 2013). Bax functions like a holin when expressed in bacteria (Pang et al. 2011).  Bax (and likely Bak) dimers assemble into oligomers with an even number of molecules that fully or partially delineate pores of different sizes to permeabilize the mitochondrial outer membrane (MOM) during apoptosis (Cosentino and García-Sáez 2016). The membrane domain of Bax interacts with other members of the Bcl-2 family to form hetero-oligomers (Andreu-Fernández et al. 2017).

BAX of Homo sapiens (Q07812)

The mitochondrial apoptosis-inducing channel-forming protein, BAK. 3-D structures are known (2IMT_A).  Functions like a holin when expressed in bacteria (Pang et al. 2011).  Formation of the apoptotic pore involves a flexible C-terminal domain (Iyer et al. 2015). Bax (and likely Bak) dimers assemble into oligomers with an even number of molecules that fully or partially delineate pores of different sizes to permeabilize the mitochondrial outer membrane (MOM) during apoptosis (Cosentino and García-Sáez 2016). BAK is a C-tail-anchored mitochondrial outer membrane protein (Setoguchi et al. 2006). BAK plays a role in peroxisomal permeability, similar to mitochondrial outer membrane permeabilization (Hosoi et al. 2017).

BAK of Homo sapiens (Q16611). 

The BH3-only (Mcl-1) protein (mediates apoptosis). (3-d strucure known)

BH3-only of Homo sapiens (B4DG83)

Pro-survival Bcl-w protein.  Binds the BH3-only protein Bop to inhibit Bop-induced apoptosis (Zhang et al. 2012).  The structure is known (PDB# 1MK3).

Bcl-w of Homo sapiens

Bcl-XL of 289 aas.  The BH4 domain of Bcl-XL, but not that of Bcl-2, selectively targets VDAC1 and inhibits apoptosis by decreasing VDAC1-mediated Ca²⁺ uptake into mitochondria (Monaco et al. 2015). The ER-mitochondrion interface is a critical cell-signaling junction whereby Bcl-xL dynamically interacts with type 3 inositol 1,4,5-trisphosphate receptors (IP3R3) to coordinate mitochondrial Ca²⁺ transfer and alters cellular metabolism in order to increase the cells' bioenergetic capacity, particularly during periods of stress (Williams et al. 2016). Bcl-XL is a C-tail-anchored mitochondrial outer membrane protein (Setoguchi et al. 2006).

Bcl-XL of Xenopus laevis (African clawed frog)

Large mechanosensitive ion channel: MscL; catalyzes efflux of ions (slightly cation selective), osmolytes and small proteins. Protein-lipid interactions are important for gating, dependent on TMS tilting (Iscla et al., 2011b).  The carboxyl-terminal cytoplasmic helices assemble into a pentameric bundle that resembles cartilage oligomeric matrix protein, and these are required for the selective formation of the pentamer (Ando et al. 2015). Lysophospholipids can increase the size of particles that can be transported (Foo et al. 2015).

MscL of E. coli (P0A742)

Osmotic adaptation channel that influences sporulation and secondary metabolite production, Sco3190 (MscL) (Wang et al. 2007).

Sco3190 of Streptomyces coelicolor. 

Large conductance mechanosensitive channel protein, MscL, of 101 aas and 2 TMSs. When the membrane is stretched, MscL responds to the increase of membrane tension and opens a nonselective pore to about 30 A wide, exhibiting a large unitary conductance of approximately 3 nS. The structures of this archaeal MscL, trapped in the closed and expanded intermediate states, has been solved (Li et al. 2015). The comparative analysis of these two new structures reveals significant conformational rearrangements in the different domains of MscL. The large changes observed in the tilt angles of the two transmembrane helices (TMS1 and TMS2) fit well with the helix-pivoting model. Meanwhile, the periplasmic loop region transforms from a folded structure, containing an omega-shaped loop and a short beta-hairpin, to an extended and partly disordered conformation during channel expansion. Moreover, a significant rotating and sliding of the N-terminal helix (N-helix) is coupled to the tilting movements of TMS1 and TMS2. The dynamic relationships between the N-helix and TMS1/TMS2 suggest that the N-helix serves as a membrane-anchored stopper that limits the tilts of TM1 and TM2 in the gating process (Li et al. 2015).

MscL of Methanosarcina acetivorans

MscL protein of 171 aas and 2 or 3 TMSs.

MscL of Chondrus crispus (Carrageen Irish moss) (Polymorpha crispa)

MscL (activated by arachidonate (Balleza et al., 2010), 45% identical to MscL of Bacillus subtilis (1.A.22.1.3)).

MscL of Rhizobium etli (Q2KCQ1)

The pentameric MscL channel (Iscla et al., 2011).  The high resolution structure of a proposed closed but expanded tetrameric intermediate state has been determined (Liu et al. 2009).

MscL of Staphylococcus aureus (P68805)

MscL; rescues cells form osmotic downshift (Bucarey et al., 2012).

MscL of Micromonospora aurantica  (D9T6D3)

Large-conductance mechanosensitive channel, MscL

MscL of Synechococcus sp.

Large-conductance mechanosensitive channel, MscL

MscL of Leuconostoc citreum

Large-conductance mechanosensitive channel, MscL

MscL of Renibacterium salmoninarum

Minor K⁺-dependent MscS-type mechanosensitive channel protein, designated KefA, AefA or MscK, (Edwards et al. 2012).

KefA (AefA) of E. coli

Mini conductance (300 pS) mechanosensitive channel, YjeP or MscM (1107aas; 13 TMSs in a 1 + 12 TMS arrangement).  Encoded in an operon with phosphatidyl serine decarboxylase (Moraes and Reithmeier 2012). Protects against hypoosmotic shock (Edwards et al. 2012).

YjeP of E. coli (P39285)

Uncharacterized protein of 571 aas and 6 TMSs.

UP of Bdellovibrio exovorus

Major MscS channel protein, YggB. Seven residues, mostly hydrophobic, in the first and second transmembrane helices are lipid-sensing residues (Malcolm et al., 2011).  X-ray structures are available (Lai et al. 2013).  The cytoplasmic cage domain senses macromolecular crowding (Rowe et al. 2014). A gating mechanism has been proposed (Malcolm et al. 2015).  The thermodynamics of K⁺ leak have been studied (Koprowski et al. 2015).  In the MscS crystal structure (PDB 2OAU ), a narrow, hydrophobic opening is visible in the crystal structure, and a vapor lock, created by hydrophobic seals consisting of L105 and L109, is the barrier to water and ions (Rasmussen et al. 2015). The voltage dependence of inactivation occurs independently of the positive charges of R46, R54, and R74 (Nomura et al. 2016).