Acid-sensing ion channels (ASICs, nomenclature as agreed by NC-IUPHAR [2-3,44]) are members of a Na⁺ channel superfamily that includes the epithelial Na⁺ channel (ENaC), the FMRF-amide activated channel (FaNaC) of invertebrates, the degenerins (DEG) of Caenorhabitis elegans, channels in Drosophila melanogaster and 'orphan' channels that include BLINaC [65] and INaC [67] that have also been named BASICs, for bile acid-activated ion channels [85]. ASIC subunits contain 2 TM domains and assemble as homo- or hetero-trimers [7,39,42,72,88-89] to form proton-gated, voltage-insensitive, Na⁺ permeable, channels that are activated by levels of acidosis occurring in both physiological and pathophysiological conditions with ASIC3 also playing a role in mechanosensation (reviewed in [22,41,44,64,84]) . Splice variants of ASIC1 [termed ASIC1a (ASIC, ASICα, BNaC2α) [79], ASIC1b (ASICβ, BNaC2β) [18] and ASIC1b2 (ASICβ2) [74]; note that ASIC1a is also permeable to Ca²⁺] and ASIC2 [termed ASIC2a (MDEG1, BNaC1α, BNC1α) [38,62,80] and ASIC2b (MDEG2, BNaC1β) [52]] have been cloned and differ in the first third of the protein. Unlike ASIC2a (listed in table), heterologous expression of ASIC2b alone does not support H⁺-gated currents. A third member, ASIC3 (DRASIC, TNaC1) [78] is one of the most pH-sensitive isoforms (along with ASIC1a) and has the fastest activation and desensitisation kinetics, however can also carry small sustained currents. ASIC4 (SPASIC) evolved as a proton-sensitive channel but seems to have lost this function in mammals [54]. Mammalian ASIC4 does not support a proton-gated channel in heterologous expression systems but is reported to downregulate the expression of ASIC1a and ASIC3 [1,32,40,50]. ASIC channels are primarily expressed in central (ASIC1a, -2a, 2b and -4) and peripheral neurons including nociceptors (ASIC1-3) where they participate in neuronal sensitivity to acidosis. They have also been detected in taste receptor cells (ASIC1-3)), photoreceptors and retinal cells (ASIC1-3), cochlear hair cells (ASIC1b), testis (hASIC3), pituitary gland (ASIC4), lung epithelial cells (ASIC1a and -3), urothelial cells, adipose cells (ASIC3), vascular smooth muscle cells (ASIC1-3), immune cells (ASIC1,-3 and -4) and bone (ASIC1-3) (ASIC distribution is well reviewed in [26,51]). A neurotransmitter-like function of protons has been suggested, involving postsynaptically located ASICs of the CNS in functions such as learning and fear perception [33,46,92], responses to focal ischemia [86] and to axonal degeneration in autoimmune inflammation in a mouse model of multiple sclerosis [37], as well as seizures [93] and pain [13,27-28,30,84]. Heterologously expressed heteromultimers form ion channels with differences in kinetics, ion selectivity, pH- sensitivity and sensitivity to blockers that resemble some of the native proton activated currents recorded from neurones [5,11,36,52]. In general, the known small molecule inhibitors of ASICs are non-selective or partially selective, whereas the venom peptide inhibitors have substantially higher selectivity and potency. Several clinically used drugs are known to inhibit ASICs, however they are generally more potent at other targets (e.g. amiloride at ENaCs, ibuprofen at COX enzymes) [59,63]. The information in the tables below are for the effects of inhibitors on homomeric channels, for information of known effect on heteromeric channels see the comments below.

Psalmotoxin 1 (PcTx1) inhibits ASIC1a by increasing the affinity to H+ and promoting channel desensitization [19,36]. PcTx1 has little effect on ASIC2a, ASIC3 or ASIC1a expressed as a heteromultimer with either ASIC2a, or ASIC3 but does inhibit ASIC1a expressed as a heteromultimer with ASIC2b [69]. PcTx1 and π-Hm3a potentiate ASIC1b currents [20,35]. ASIC1-containing homo- and heteromers are inhibited by Mambalgins, toxins contained in the black mamba venom, which induce in ASIC1a an acidic shift of the pH dependence of activation [30]. π-Hi1a is highly selective for ASIC1a with very little activity at ASIC1b. It inhibits channel activation and is very slowly reversible [17]. APETx2 most potently blocks homomeric ASIC3 channels, but also ASIC2b+ASIC3, ASIC1b+ASIC3, and ASIC1a+ASIC3 heteromeric channels with IC₅₀ values of 117 nM, 900 nM and 2 μM, respectively. APETx2 has no effect on ASIC1a or ASIC2a+ASIC3, however, it does potentiate ASIC1b and ASIC2a homomers in the low micromolar range (1-10 μM) [29,31,48]. APETx2 however also inhibits voltage-gated Na⁺ channels [12,61]. IC₅₀ value for A-317567 was determined using high throughput electrophysiology on human ASIC3 expressed in HEK293 cells [47]. For some of the newer small molecule inhibitors it is not known whether they inhibit ion channels in addition to ASICs [15,53,58]. The effects of several compounds are pH-dependent, displaying higher potencies at more alkaline pH [15,53,58]. The pEC₅₀ values for proton activation of ASIC channels are influenced by numerous factors including extracellular di- and poly-valent ions, Zn²⁺, protein kinase C and serine proteases (reviewed in [44,84]). Rapid acidification is required for activation of ASIC1 and ASIC3 due to fast inactivation/desensitization. pEC₅₀ values for H⁺-activation of either transient, or sustained, currents mediated by ASIC3 vary in the literature and may reflect species and/or methodological differences [6,25,78]. The transient ASIC current component is Na⁺-selective (PNa/PK of about 10) [78,87] whereas the sustained current component that is observed with ASIC3 and some ASIC heteromers is non-selective between Na⁺ and K⁺ [25]. The reducing agents dithiothreitol (DTT) and glutathione (GSH) increase ASIC1a currents expressed in CHO cells and ASIC-like currents in sensory ganglia and central neurons [4,23] whereas oxidation, through the formation of intersubunit disulphide bonds, reduces currents mediated by ASIC1a [91]. ASIC1a is also irreversibly modulated by extracellular serine proteases, such as trypsin, through proteolytic cleavage [77]. Non-steroidal anti-inflammatory drugs (NSAIDs) are direct inhibitors of ASIC currents (reviewed in [9]). Extracellular Zn²⁺ potentiates proton activation of homomeric and heteromeric channels incorporating ASIC2a, but not homomeric ASIC1a or ASIC3 channels [10]. However, removal of contaminating Zn²⁺ by chelation reveals a high affinity block of homomeric ASIC1a and heteromeric ASIC1a+ASIC2 channels by Zn²⁺ indicating complex biphasic actions of the divalent [24]. Nitric oxide potentiates submaximal currents activated by H⁺ mediated by ASIC1a, ASIC1b, ASIC2a and ASIC3 [16]. The positive modulation of homomeric, heteromeric and native ASIC channels by the peptide FMRFamide and related substances, such as neuropeptides FF and SF, is reviewed in detail in [75]. Inflammatory conditions and particular pro-inflammatory mediators such as arachidonic acid induce overexpression of ASIC-encoding genes and enhance ASIC currents [28,56,70]. The sustained current component mediated by ASIC3 is potentiated by hypertonic solutions in a manner that is synergistic with the effect of arachidonic acid [28]. ASIC3 is partially activated by the lipids lysophosphatidylcholine (LPC) and arachidonic acid [57]. Mit-Toxin, which is contained in the venom of the Texas coral snake, activates several ASIC subtypes [13]. Selective activation of ASIC3 by GMQ at a site separate from the proton binding site is potentiated by mild acidosis and reduced extracellular Ca²⁺ [90].

Additional notes on the channels: Until recently they were thought to be vertebrate specific channels, however are now known to have evolved over 600 million years ago and appear to be conserved throughout the superphylum of animals known as deuterostomes (which includes vertebrates, tunicates, starfish, sea urchins, sea cucumbers and acorn worms) [54]. Recently an ion-conducting-independent signaling mechanism has been revealed for ASIC1a whereby the acidosis-activated channel recruits RIPK1 to its C-terminus resulting in RIPK1 phosphorylation and activation of necroptosis. This pathways is suggested to be the primary cause of ASIC-mediated neuronal cell death in ischemic stroke [81,83].

* Key recommended reading is highlighted with an asterisk

Baron A, Lingueglia E. (2015) Pharmacology of acid-sensing ion channels - Physiological and therapeutical perspectives. Neuropharmacology, 94: 19-35. [PMID:25613302]

Boscardin E, Alijevic O, Hummler E, Frateschi S, Kellenberger S. (2016) The function and regulation of acid-sensing ion channels (ASICs) and the epithelial Na(+) channel (ENaC): IUPHAR Review 19. Br J Pharmacol, 173 (18): 2671-701. [PMID:27278329]

* Cristofori-Armstrong B, Rash LD. (2017) Acid-sensing ion channel (ASIC) structure and function: Insights from spider, snake and sea anemone venoms. Neuropharmacology, 127: 173-184. [PMID:28457973]

* De Logu F, Geppetti P. (2019) Ion Channel Pharmacology for Pain Modulation. Handb Exp Pharmacol, 260: 161-186. [PMID:31820179]

Deval E, Gasull X, Noël J, Salinas M, Baron A, Diochot S, Lingueglia E. (2010) Acid-sensing ion channels (ASICs): pharmacology and implication in pain. Pharmacol Ther, 128 (3): 549-58. [PMID:20807551]

* Gründer S, Pusch M. (2015) Biophysical properties of acid-sensing ion channels (ASICs). Neuropharmacology, 94: 9-18. [PMID:25585135]

Hanukoglu I. (2017) ASIC and ENaC type sodium channels: conformational states and the structures of the ion selectivity filters. FEBS J, 284 (4): 525-545. [PMID:27580245]

* Kellenberger S, Schild L. (2015) International Union of Basic and Clinical Pharmacology. XCI. structure, function, and pharmacology of acid-sensing ion channels and the epithelial Na+ channel. Pharmacol Rev, 67 (1): 1-35. [PMID:25287517]

Lin SH, Sun WH, Chen CC. (2015) Genetic exploration of the role of acid-sensing ion channels. Neuropharmacology, 94: 99-118. [PMID:25582292]

Mathie A, Veale EL, Cunningham KP, Holden RG, Wright PD. (2021) Two-Pore Domain Potassium Channels as Drug Targets: Anesthesia and Beyond. Annu Rev Pharmacol Toxicol, 61: 401-420. [PMID:32679007]

Osmakov DI, Andreev YA, Kozlov SA. (2014) Acid-sensing ion channels and their modulators. Biochemistry Mosc, 79 (13): 1528-45. [PMID:25749163]

Rash LD. (2017) Acid-Sensing Ion Channel Pharmacology, Past, Present, and Future …. Adv Pharmacol, 79: 35-66. [PMID:28528673]

Rook ML, Musgaard M, MacLean DM. (2021) Coupling structure with function in acid-sensing ion channels: challenges in pursuit of proton sensors. J Physiol, 599 (2): 417-430. [PMID:32306405]

* Waldmann R, Champigny G, Bassilana F, Heurteaux C, Lazdunski M. (1997) A proton-gated cation channel involved in acid-sensing. Nature, 386 (6621): 173-7. [PMID:9062189]

Wang JJ, Liu F, Yang F, Wang YZ, Qi X, Li Y, Hu Q, Zhu MX, Xu TL. (2020) Disruption of auto-inhibition underlies conformational signaling of ASIC1a to induce neuronal necroptosis. Nat Commun, 11 (1): 475. [PMID:31980622]

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Subcommittee members: Stephan Kellenberger (Chairperson) Département de Sciences biomédicales Rue du Bugnon 27 Université de Lausanne CH-1011 Lausanne Switzerland Lachlan D. Rash School of Biomedical Sciences Faculty of Medicine The University of Queensland St Lucia, QLD 4072 Australia