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).