| TCID | Name | Domain | Kingdom/Phylum | Protein(s) |
|---|---|---|---|---|
|
1.A.6.1.1 | Epithelial Na+ channel, ENaC (regulates salt and fluid homeostasis and blood pressure; regulated by Nedd4 isoforms and SGK1, 2 and 3 kinases) (Henry et al., 2003; Pao 2012). Cd2+ inhibits α-ENaC by binding to the internal pore where it interacts with residues in TMS2 (Takeda et al., 2007). The channel is regulated by palmitoylation of the beta subunit which modulates gating (Mueller et al. 2010). ENaCs are more selective for Naa+ over other cations than ASICs (Yang and Palmer 2018). ENaC plays a role in chronic obstructive pulmonary diseases (COPD) (Zhao et al. 2014). The hetrodimeric complex can consist of αβγ or δβγ subunits, depending on the tissue (Giraldez et al. 2012). The α- and γ-subunits of the epithelial Na+ channel interact directly with the Na+:Cl- cotransporter, NCC, in the renal distal tubule with functional cosequences, and together they determine bodily salt balance and blood pressure (Mistry et al. 2016). ENaC is regulated by syntaxins (Saxena et al. 2006). The cryoEM structure has been solved (Noreng et al. 2018). Interactions between the epithelial sodium channel gamma-subunit and claudin-8 modulates paracellular sodium permeability in the renal collecting duct (Sassi et al. 2020). Tumer necrosis factor, TNF, of 233 aas, is the source of a modified cyclic peptide of 17 aas, solnatide or the TIP peptide, (CGQRETPEGAEAKPWYC), residues 177 - 195), that activates ENaC (Madaio et al. 2019; Martin-Malpartida et al. 2022). Acid-Sensing ion channels are inhibited by KB-R7943, a reverse Na+/Ca2+ exchanger (see TC# 1.D.208) (Sun et al. 2023). EGR-1 contributes to pulmonary edema by regulating the epithelial sodium channel in lipopolysaccharide-induced acute lung injury (Wang et al. 2023). Enhanced glycolysis causes extracellular acidification and activates acid-sensing ion channel 1a in hypoxic pulmonary hypertension (Tuineau et al. 2024). | Eukaryota |
Metazoa, Chordata | αβγ- or δβγ-ENaC heterotrimeric epithelial Na+ channel of Homo sapiens |
|
1.A.6.1.2 | Amiloride-sensitive cation channel, ASIC1/ASIC3 (also called ASIC1a, BNC1, MDEG, ACCN2 and BNAC2), which is an acid-sensitive (proton-gated) homo- or hetero-oligomeric cation (Na+ (high affinity), Ca2+, K+) channel. It it 98% identical to the human ortholog and associates with DRASIC tomediate touch sensation, being a mechanosensor (lead inhibited) channel (Wang et al., 2006). In pulmonary tissue (lung epithelial cells) it and CFTR interregulate each other (Su et al., 2006). ASIC3 is a sensor of acidic and primary inflammatory pain (Deval et al., 2008). Acid sensing ion channel-1b (ASIC1b), virtually identical to the rat and human orthologs, is stimulated by hypotonic stimuli (Ugawa et al., 2007; Deval et al., 2008). This protein is 98% idientical to the human ortholog Z(as noted above), which is an excitatory neuronal cation channel, involved in physiopathological processes related to extracellular pH fluctuation such as nociception, ischaemia, perception of sour taste and synaptic transmission. The spider peptide toxin psalmotoxin 1 (PcTx1) inhibits its proton-gated cation channel activity (Salinas et al. 2006). ASIC1a localizes to the proximal tubular and contributes to ischaemia/reperfusion (I/)R induced kidney injury (Song et al. 2019). Stomatin (STOM; TC# 8.A.21.1.1) is an inhibitor of ASIC3, and it is anchored to the ASIC3 channel via a site on the distal C-terminus of the channel to stabilizes the desensitized state via an interaction with TMS1 (Klipp et al. 2020). Sun et al. 2020 presented single-particle cryo-EM structures of human ASIC1a (hASIC1a) and the hASIC1a-Mamba1 complex at resolutions of 3.56 and 3.90 Å, respectively. The structures revealed the inhibited conformation of hASIC1a upon Mamba1 binding. Mamba1 prefers to bind hASIC1a in a closed state and reduces the proton sensitivity of the channel, representing a closed-state trapping mechanism. Kinetic analyses of ASIC1a delineated conformational signaling from proton-sensing domains to the channel gate (Vullo et al. 2021). An arginine residue in the outer segment of hASIC1a TMS1 affects both proton affinity and channel desensitization (Chen et al. 2021). Acid-sensing ion channels (ASICs) are weakly sodium selective (sodium:potassium ratio approximately 10:1), while ENaCs show a high preference for sodium over potassium (>500:1). The pre-TMS1 and TMS1 regions of mASIC1a channels are major determinants of ion selectivity (Sheikh et al. 2021). ASIC1a shuttles between the membranous organellar fraction to the plasm membrane (Salinas Castellanos et al. 2022). Multiscale molecular dynamics simulations predict arachidonic acid binding sites in human ASIC1a and ASIC3 transmembrane domains (Ananchenko and Musgaard 2023). Rotundine inhibits the development and progression of colorectal cancer by regulating the expression of prognosis-related genes such as ASIC3 (ACCN3; SLNAC1, TNACT) in humans (Huang et al. 2023). Acid-sensing ion channel (ASIC)3 may be a therapeutic target for the control of glioblastoma cancer stem cells growth (Balboni et al. 2024). | Eukaryota |
Metazoa, Chordata | αβγENaC of Rattus norvegicus. DRASIC (O35240) ASIC3 (O55163) ASIC1 (P55926) |
|
1.A.6.1.3 | The epithelial Na+ channel, EnaC5 (involved in fluid and electrolyte homeostasis). The C-terminus of each subunit (α, β, and γ) contains a PPXY motif for interaction with the WW domains of the ubiquitin-protein ligases, Nedd4 and Nedd4-2. Disruption of this interaction, as in Liddle's syndrome where mutations delete or alter the PPXY motif of either the β or γ subunits, has been shown to result in increased ENaC activity and arterial hypertension. N4WBP5A (Nedd4-family interacting protein-2) plays a role (see 8.A.30; Konstas et al., 2002). Wiemuth & Grunder (2010) showed that an unknown ligand, interacting with an amino acyl residue in the extracellular domain, tunes Ca2+ inhibition in the rat protein, but not the mouse orthologue. | Eukaryota |
Metazoa, Chordata | ENaC5 of Rattus norvegicus (Q9R0W5) |
|
1.A.6.1.4 | ACD-1 (degenerin-like glial acid-sensitive channel) is constitutively open and impermeable to Ca2+, yet is required with neuronal DEG/ENaC channel, DEG-1 (1.A.6.2.1) for acid avoidance and chemotaxis to the amino acid lysine (Wang et al. 2008). | Eukaryota |
Metazoa, Nematoda | ACD-1 of Caenorhabditis elegans (P91102) |
|
1.A.6.1.5 | Neuronal acid-sensing cation channel-1, ASIC1 (>90% identical to ASIC1 of Rat (TC#1.A.6.1.2)). 3D structure (1.9Å resolution) has been solved (Jasti et al., 2007). Regulated by the glucocorticoid-induced kinase-1 isoform 1 (SGK1.1) (Arteaga et al., 2008). Residues in the second transmembrane domain of the ASIC1a that contribute to ion selectivity have been defined (Carattino and Della Vecchia, 2012). Outlines of the pore in open and closed conformations describe the gating mechanism (Li et al., 2011). Interactions between two extracellular linker regions control sustained channel opening (Springauf et al., 2011). Can form monomers, trimers and tetramers, but the tetramer may be the predominant species in the plasma membrane (van Bemmelen et al. 2015). The C-terminal tail projects into the cytosol by approximately 35 Å, and the N and C tails from the same subunits are closer than those of adjacent subunits (Couch et al. 2021). | Eukaryota |
Metazoa, Chordata | ASIC-1 of Gallus gallus (Q1XA76) |
|
1.A.6.1.6 | Acid sensing cation channel ASIC4.1 (senses and gated by extracellular pH) (forms homomers and heteromers with ASIC4.2) (Chen et al., 2007) | Eukaryota |
Metazoa, Chordata | ASIC4.1 of Danio rerio (Q708S4) |
|
1.A.6.1.7 | Acid sensing cation channel ASIC4.2 (does not sense extracellular pH) (forms homomers and heteromers with ASIC4.1) (Chen et al., 2007). | Eukaryota |
Metazoa, Chordata | ASIC4.2 of Danio rerio (Q708S3) |
|
1.A.6.1.8 | Amiloride and acid-sensitive cation channels, ASIC2a and ASIC2b are splice variants of the same gene (ACCN1, ACCN, BNAC1, MDEG) product. Regions involved in acid (proton) sensing and confering tachyphylasis have been identified (Schuhmacher et al. 2015). ASIC2 isoforms have different subcellular distributions: ASIC2a targets the cell surface while ASIC2b resides in the ER. TMS1 and the proximal post-TMS1 domain (17 amino acids) of ASIC2a are critical for membrane targeting, and replacement of corresponding residues in ASIC2b by those of ASIC2a conferred proton-sensitivity as well as surface expression to ASIC2b (Kweon et al. 2016). This protein is 99% identical to the human ortholog with acc# Q16515. Rapid resensitization of ASIC2a is conferred by three amino acid residues near the N terminus (Lee et al. 2019). The human ortholog of ASIC1 (UniProt acc # P783480 is 98% identical to the mouse ortholog. ASIC1 plays a role in the occurrence and development of several types of tumors (Wang et al. 2022). | Eukaryota |
Metazoa, Chordata | ASIC1b of Mus musculus |
|
1.A.6.1.9 | Acid-sensing ion channel 2, ASIC2, of 520 aas and 2 TMSs. | Eukaryota |
Metazoa, Chordata | ASIC2 of Petromyzon marinus (Sea lamprey) |
|
1.A.6.1.10 | Acid-sensing ion channel 1, ACCN2 of 514 aas and 2 TMSs. | Eukaryota |
Metazoa, Chordata | ACCN2 of Lampetra fluviatilis (European river lamprey) (Petromyzon fluviatilis) |
|
1.A.6.1.11 | (Bile) acid-sensitive ion channel, BASIC (ASIC, ACCN5, HINAC), of 505 aas. Cation channel that gives rise to very low constitutive currents in the absence of activation. The activated channel exhibits selectivity for sodium, and is inhibited by amiloride (Schaefer et al. 2000). A cytoplasmic amphipathic α-helix controls activity (Schmidt et al. 2016). This system may be present in mitochondria ().
| Metazoa, Chordata | BASIC of Homo sapiens | |
|
1.A.6.1.12 | Duplicated ENaC with 990 aas and 4 TMSs in a 1 + 2 + 1 TMS arrangement. | Eukaryota |
Metazoa | Duplicated ENaC of Exaiptasia pallida |
|
1.A.6.1.13 | Acid-sensing ion channel 5 isoform X1 pf 639 aas and possibly 7 TMSs with 5 TMSs in an N-terminal domain not related to ASICs followed by two TMSs, one N-terminal and one C-terminal, all in the ASIC domain of the protein. | Eukaryota |
Metazoa, Rotifera | ASIC5 of Brachionus plicatilis |
|
1.A.6.1.14 | FMRFamide (peptide)-gated ionotropic receptor Na+ channel, NaC2-4 or NaC2, 3 and 5 (gated by neuropeptides Hydra-RFamides I and II; present in tentacles) (Golubovic et al. 2007). Three homologous subunits, NaC2, 3 and 5, assemble to form a more typical high affinity peptide-gated ion channel (Durrnagel et al., 2010). | Eukaryota |
Metazoa | NaC2-5 of Hydra magnipapillata: NaC2 - A8DZR6 NaC3 - A8DZR7 NaC4 - A8DZR8 NaC5 - D3UD58 |
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1.A.6.1.15 | Uncharacterized protein of 1029 aas and 4 TMSs, two near the N- and C-termini, and two more at residues 410 and 600. The region of homology with other members of the family are residues 570 to 1000, thus including the last two TMSs. | Eukaryota |
Metazoa, Arthropoda | UP of Cloeon dipterum |
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1.A.6.1.16 | Uncharacterized protein of 418 aas and 3 TMSs. | Eukaryota |
Metazoa, Arthropoda | UP of Allacma fusca |
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1.A.6.1.17 | Broad-range thermal receptor 1 protein of 431 aas and 2 TMSs, N- and C-terminal. A nonvisual and extraocular sunlight detection mechanism occurs via the broad-range thermal receptor 1 (BRTNaC1, temperature range = 33 to 48 °C) in centipede antennae. BRTNaC1, a heat-activated cation-permeable ion channel, Heat activation of BRTNaC1 exhibits strong pH dependence controlled by two protonatable sites. Physiologically, temperature-dependent activation of BRTNaC1 upon sunlight exposure comes from a striking photothermal effect on the antennae, where a slightly acidic environment (pH 6.1) of the body fluid leads to the protonation of BRTNaC1 and switches on its high thermal sensitivity. Testosterone potently inhibits heat activation of BRTNaC1 and the sunlight avoidance behavior of centipedes. This suggests a sophisticated strategy for nonvisual sunlight detection in myriapods (Yao et al. 2023). | Eukaryota |
Metazoa, Arthropoda | BRTNaCl of Scolopendra subspinipes (centipede) |
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1.A.6.1.18 | Acid-sensing ion channel 1B-like of 524 aas and 3 TMSs. | Eukaryota |
Metazoa, Arthropoda | ASIC 1B of Daphnia pulex |
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1.A.6.2.1 | Degenerin-1 | Eukaryota |
Metazoa, Nematoda | Degenerin-1 of Caenorhabditis elegans (P24585) |
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1.A.6.2.2 | Touch-responsive mechanosensitive degenerin channel complex (Mec-4/Mec-10 form the cation/Ca2+-permeable channel; Mec-2 and Mec-6 regulate) (Bianchi, 2007; Chelur et al., 2002; ). Mec-6 is a chaparone protein required for functional insertion (Matthewman et al. 2018). Mec-10 plays a role in the response to mechanical forces such as laminar shear stress (Shi et al. 2016). MEC-4 or MEC-10 mutants that alter the channel's LSS response are primarily clustered between the degenerin site and the selectivity filter, a region that likely forms the narrowest portion of the channel pore (Shi et al. 2018). TMS2 forms the Ca2+ channel of Mec-4. A C-terminal domain affects trafficking of a neuronally expressed DEG/ENaC. Neuronal swelling occurs prior to commitment to necrotic death (Royal et al. 2005). | Eukaryota |
Metazoa, Nematoda | Mec-2, 4, 6, 10 mechanosensitive degenerin channel complex in Caenorhabditis elegans Mec-4 Mec-10 Mec-6 Mec-2 |
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1.A.6.2.3 | Degenerin channel, UNC-105. (Activated by degeneration or hypercontraction-causing mutations) (Bianchi, 2007; García-Añoveros et al., 1998) | Eukaryota |
Metazoa, Nematoda | UNC-105 of Caenorhabditis elegans (Q09274) |
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1.A.6.2.4 | Motility and anesthetic-sensitive degenerin, UNC-8 (Uncoordinated protein-8) Na+ (not Ca2+) channel (regulated by UNC-1 (a mammalian stomatin homologue)). UNC-1 and UNC-8 are found in cholesterol/sphingolipid rafts together with UNC-24 (Bianchi, 2007; Sedensky et al., 2004). UNC-8 is inhibited by μM concentrations of extracellular divalent cations mediated by the extracellular finger domain (Matthewman et al. 2018). | Eukaryota |
Metazoa, Nematoda | UNC-8 of Caenorhaditis elegans (Q21974) |
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1.A.6.2.5 | Mechanotransduction degenerin, DEL-1 (Bianchi, 2007). | Eukaryota |
Metazoa, Nematoda | DEL-1 of Caenorhabditis elegans (Q19038) |
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1.A.6.2.6 | Serum paraoxonase/arylesterase 1, PON 1 (Aromatic esterase 1) (A-esterase 1) (Serum aryldialkylphosphatase 1) | Eukaryota |
Metazoa, Chordata | PON1 of Homo sapiens |
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1.A.6.2.7 | Ion channel of 686 aas and 2 TMSs, one at the N-terminus and one at the C-terminus. The N-terminal half of this protein is cycsteine-rich and shows similarity with 9.B.87.1.12, while the C-terminal half shows extensive similarity with 1.A.6.2 proteins. | Eukaryota |
Metazoa, Nematoda | Ion channel of Pristionchus pacificus |
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1.A.6.3.1 | Peptide neurotransmitter-gated ionotropic receptor | Eukaryota |
Metazoa, Mollusca | Phe-Met-Arg-Phe-NH2-activated Na+ channel of Helix aspersa |
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1.A.6.3.2 | FMRFamide (peptide)-gated sodium channel, FaNaC. The charge on aspartate-552 in TMS2 influcences the gating properties and potency of the channel (Kodani and Furukawa 2010; Kodani and Furukawa 2014). The FMRFamide-evoked current through AkFaNaC was depressed 2-3-fold by millimolar (1.8 mM) Ca2+ (Fujimoto et al. 2017). Both D552 and D556 were indispensable for the sensitivity of FaNaC to millimolar Ca2+. The Ca2+-sensitive gating was recapitulated by an allosteric model in which Ca2+-bound channels are more difficult to open. The desensitization of FaNaC was also inhibited by Ca2+ (Fujimoto et al. 2017). High-resolution cryo-EM structures of FaNaC in both apo and FMRFamide-bound states have been solved (Liu et al. 2023). AcFaNaC forms a chalice-shaped trimer and possesses several notable features, including two FaNaC-specific insertion regions, a distinct finger domain and non-domain-swapped TMS2 in the transmembrane domain (TMD). One FMRFamide binds to each subunit in a cleft located in the top-most region of the extracellular domain, with participation of residues from the neighboring subunit. Bound FMRFamide hass an extended conformation. FMRFamide binds tightly to A. californica FaNaC in an N terminus-in manner, which causes collapse of the binding cleft and induces large local conformational rearrangements. Such conformational changes are propagated downward toward the TMD via the palm domain, possibly resulting in outward movement of the TMD and dilation of the ion conduction pore (Liu et al. 2023). | Eukaryota |
Metazoa, Mollusca | FaNaC of Aplysia kurodai |
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1.A.6.3.3 | Uncharacterized protein of 577 aas and 2 TMSs, N- and C-terminal. | Eukaryota |
Metazoa, Platyhelminthes | UP of Taenia asiatica |
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1.A.6.3.4 | Uncharacterized protein of 616 aas and 2 TMSs, N- and C-terminal. | Eukaryota |
Metazoa, Platyhelminthes | UP of Hymenolepis diminuta |
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1.A.6.3.5 | Uncharacterized protein of 534 aas and 2 TMSs. | Eukaryota |
Metazoa, Annelida | UP of Helobdella robusta |
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1.A.6.4.1 | Ripped pocket (Rpk) fly gonad-specific Na+ channel (amiloride-sensitive) (Adams et al., 1998). | Eukaryota |
Metazoa, Arthropoda | Rpk of Drosophila melanogaster |
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1.A.6.4.2 | Pickpocket (Adams et al., 1998; Zhong et al., 2010). | Eukaryota |
Metazoa, Arthropoda | Pickpocket of Drosophila melanogaster (Q7KT94) |
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1.A.6.4.3 | Putative Na+ channel | Eukaryota |
Metazoa, Arthropoda | Putative Na+ channel of Drosophila melanogaster (O61365) |
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1.A.6.4.4 | Na+ channel protein, NaCh, of 522 aas with 2 or 3 TMSs in a 1 (N-terminal) + 1 or 2 TMSs (C-terminal). | Eukaryota |
Metazoa, Arthropoda | NaCh of Cyphomyrmex costatus |
|
1.A.6.4.5 | Uncharacterized protein of 509 aas and 2 TMSs, N- and C-terminal. | Eukaryota |
Metazoa, Arthropoda | UP of Laodelphax striatellus (small brown planthopper) |
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1.A.6.4.6 | Sodium channel protein Nach-like protein, NaCh, of 533 aas with the usual 2N- and C-terminal TMSs, but possibly as many as 6 smaller peaks of hydrophobicity (TMSs?) in between these two TMSs. | Eukaryota |
Metazoa, Arthropoda | NaCh of Vollenhovia emeryi |