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 two 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]

1. Akopian AN, Chen CC, Ding Y, Cesare P, Wood JN. (2000) A new member of the acid-sensing ion channel family. Neuroreport, 11 (10): 2217-22. [PMID:10923674]

2. Alexander SP, Kelly E, Marrion N, Peters JA, Benson HE, Faccenda E, Pawson AJ, Sharman JL, Southan C, Davies JA et al.. (2015) The Concise Guide to PHARMACOLOGY 2015/16: Other ion channels. Br J Pharmacol, 172 (24): 5942-55. [PMID:26650442]

3. Alexander SP, Kelly E, Marrion NV, Peters JA, Faccenda E, Harding SD, Pawson AJ, Sharman JL, Southan C, Davies JA et al.. (2017) THE CONCISE GUIDE TO PHARMACOLOGY 2017/18: Other ion channels. Br J Pharmacol, 174 Suppl 1: S195-S207. [PMID:29055039]

4. Andrey F, Tsintsadze T, Volkova T, Lozovaya N, Krishtal O. (2005) Acid sensing ionic channels: modulation by redox reagents. Biochim Biophys Acta, 1745 (1): 1-6. [PMID:16085050]

5. Babinski K, Catarsi S, Biagini G, Séguéla P. (2000) Mammalian ASIC2a and ASIC3 subunits co-assemble into heteromeric proton-gated channels sensitive to Gd3+. J Biol Chem, 275 (37): 28519-25. [PMID:10842183]

6. Babinski K, Lê KT, Séguéla P. (1999) Molecular cloning and regional distribution of a human proton receptor subunit with biphasic functional properties. J Neurochem, 72 (1): 51-7. [PMID:9886053]

7. Baconguis I, Bohlen CJ, Goehring A, Julius D, Gouaux E. (2014) X-ray structure of acid-sensing ion channel 1-snake toxin complex reveals open state of a Na(+)-selective channel. Cell, 156 (4): 717-29. [PMID:24507937]

8. Baron A, Diochot S, Salinas M, Deval E, Noël J, Lingueglia E. (2013) Venom toxins in the exploration of molecular, physiological and pathophysiological functions of acid-sensing ion channels. Toxicon, 75: 187-204. [PMID:23624383]

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

10. Baron A, Schaefer L, Lingueglia E, Champigny G, Lazdunski M. (2001) Zn2+ and H+ are coactivators of acid-sensing ion channels. J Biol Chem, 276 (38): 35361-7. [PMID:11457851]

11. Baron A, Voilley N, Lazdunski M, Lingueglia E. (2008) Acid sensing ion channels in dorsal spinal cord neurons. J Neurosci, 28 (6): 1498-508. [PMID:18256271]

12. Blanchard MG, Rash LD, Kellenberger S. (2012) Inhibition of voltage-gated Na(+) currents in sensory neurones by the sea anemone toxin APETx2. Br J Pharmacol, 165 (7): 2167-77. [PMID:21943094]

13. Bohlen CJ, Chesler AT, Sharif-Naeini R, Medzihradszky KF, Zhou S, King D, Sánchez EE, Burlingame AL, Basbaum AI, Julius D. (2011) A heteromeric Texas coral snake toxin targets acid-sensing ion channels to produce pain. Nature, 479 (7373): 410-4. [PMID:22094702]

14. Brunner FS, Anaya-Rojas JM, Matthews B, Eizaguirre C. (2017) Experimental evidence that parasites drive eco-evolutionary feedbacks. Proc Natl Acad Sci USA, 114 (14): 3678-3683. [PMID:28320947]

15. Buta A, Maximyuk O, Kovalskyy D, Sukach V, Vovk M, Ievglevskyi O, Isaeva E, Isaev D, Savotchenko A, Krishtal O. (2015) Novel Potent Orthosteric Antagonist of ASIC1a Prevents NMDAR-Dependent LTP Induction. J Med Chem, 58 (11): 4449-61. [PMID:25974655]

16. Cadiou H, Studer M, Jones NG, Smith ES, Ballard A, McMahon SB, McNaughton PA. (2007) Modulation of acid-sensing ion channel activity by nitric oxide. J Neurosci, 27 (48): 13251-60. [PMID:18045919]

17. Chassagnon IR, McCarthy CA, Chin YK, Pineda SS, Keramidas A, Mobli M, Pham V, De Silva TM, Lynch JW, Widdop RE et al.. (2017) Potent neuroprotection after stroke afforded by a double-knot spider-venom peptide that inhibits acid-sensing ion channel 1a. Proc Natl Acad Sci USA, 114 (14): 3750-3755. [PMID:28320941]

18. Chen CC, England S, Akopian AN, Wood JN. (1998) A sensory neuron-specific, proton-gated ion channel. Proc Natl Acad Sci USA, 95 (17): 10240-5. [PMID:9707631]

19. Chen X, Kalbacher H, Gründer S. (2005) The tarantula toxin psalmotoxin 1 inhibits acid-sensing ion channel (ASIC) 1a by increasing its apparent H+ affinity. J Gen Physiol, 126 (1): 71-9. [PMID:15955877]

20. Chen X, Kalbacher H, Gründer S. (2006) Interaction of acid-sensing ion channel (ASIC) 1 with the tarantula toxin psalmotoxin 1 is state dependent. J Gen Physiol, 127 (3): 267-76. [PMID:16505147]

21. Chen X, Qiu L, Li M, Dürrnagel S, Orser BA, Xiong ZG, MacDonald JF. (2010) Diarylamidines: high potency inhibitors of acid-sensing ion channels. Neuropharmacology, 58 (7): 1045-53. [PMID:20114056]

22. Cheng YR, Jiang BY, Chen CC. (2018) Acid-sensing ion channels: dual function proteins for chemo-sensing and mechano-sensing. J Biomed Sci, 25 (1): 46. [PMID:29793480]

23. Chu XP, Close N, Saugstad JA, Xiong ZG. (2006) ASIC1a-specific modulation of acid-sensing ion channels in mouse cortical neurons by redox reagents. J Neurosci, 26 (20): 5329-39. [PMID:16707785]

24. Chu XP, Wemmie JA, Wang WZ, Zhu XM, Saugstad JA, Price MP, Simon RP, Xiong ZG. (2004) Subunit-dependent high-affinity zinc inhibition of acid-sensing ion channels. J Neurosci, 24 (40): 8678-89. [PMID:15470133]

25. de Weille JR, Bassilana F, Lazdunski M, Waldmann R. (1998) Identification, functional expression and chromosomal localisation of a sustained human proton-gated cation channel. FEBS Lett, 433 (3): 257-60. [PMID:9744806]

26. Deval E, Lingueglia E. (2015) Acid-Sensing Ion Channels and nociception in the peripheral and central nervous systems. Neuropharmacology, 94: 49-57. [PMID:25724084]

27. Deval E, Noël J, Gasull X, Delaunay A, Alloui A, Friend V, Eschalier A, Lazdunski M, Lingueglia E. (2011) Acid-sensing ion channels in postoperative pain. J Neurosci, 31 (16): 6059-66. [PMID:21508231]

28. Deval E, Noël J, Lay N, Alloui A, Diochot S, Friend V, Jodar M, Lazdunski M, Lingueglia E. (2008) ASIC3, a sensor of acidic and primary inflammatory pain. EMBO J, 27 (22): 3047-55. [PMID:18923424]

29. Diochot S, Baron A, Rash LD, Deval E, Escoubas P, Scarzello S, Salinas M, Lazdunski M. (2004) A new sea anemone peptide, APETx2, inhibits ASIC3, a major acid-sensitive channel in sensory neurons. EMBO J, 23 (7): 1516-25. [PMID:15044953]

30. Diochot S, Baron A, Salinas M, Douguet D, Scarzello S, Dabert-Gay AS, Debayle D, Friend V, Alloui A, Lazdunski M et al.. (2012) Black mamba venom peptides target acid-sensing ion channels to abolish pain. Nature, 490 (7421): 552-5. [PMID:23034652]

31. Diochot S, Salinas M, Baron A, Escoubas P, Lazdunski M. (2007) Peptides inhibitors of acid-sensing ion channels. Toxicon, 49 (2): 271-84. [PMID:17113616]

32. Donier E, Rugiero F, Jacob C, Wood JN. (2008) Regulation of ASIC activity by ASIC4--new insights into ASIC channel function revealed by a yeast two-hybrid assay. Eur J Neurosci, 28 (1): 74-86. [PMID:18662336]

33. Du J, Reznikov LR, Price MP, Zha XM, Lu Y, Moninger TO, Wemmie JA, Welsh MJ. (2014) Protons are a neurotransmitter that regulates synaptic plasticity in the lateral amygdala. Proc Natl Acad Sci USA, 111 (24): 8961-6. [PMID:24889629]

34. Dubé GR, Lehto SG, Breese NM, Baker SJ, Wang X, Matulenko MA, Honoré P, Stewart AO, Moreland RB, Brioni JD. (2005) Electrophysiological and in vivo characterization of A-317567, a novel blocker of acid sensing ion channels. Pain, 117 (1-2): 88-96. [PMID:16061325]

35. Er SY, Cristofori-Armstrong B, Escoubas P, Rash LD. (2017) Discovery and molecular interaction studies of a highly stable, tarantula peptide modulator of acid-sensing ion channel 1. Neuropharmacology, 127: 185-195. [PMID:28327374]

36. Escoubas P, De Weille JR, Lecoq A, Diochot S, Waldmann R, Champigny G, Moinier D, Ménez A, Lazdunski M. (2000) Isolation of a tarantula toxin specific for a class of proton-gated Na+ channels. J Biol Chem, 275 (33): 25116-21. [PMID:10829030]

37. Friese MA, Craner MJ, Etzensperger R, Vergo S, Wemmie JA, Welsh MJ, Vincent A, Fugger L. (2007) Acid-sensing ion channel-1 contributes to axonal degeneration in autoimmune inflammation of the central nervous system. Nat Med, 13 (12): 1483-9. [PMID:17994101]

38. García-Añoveros J, Derfler B, Neville-Golden J, Hyman BT, Corey DP. (1997) BNaC1 and BNaC2 constitute a new family of human neuronal sodium channels related to degenerins and epithelial sodium channels. Proc Natl Acad Sci USA, 94 (4): 1459-64. [PMID:9037075]

39. Gonzales EB, Kawate T, Gouaux E. (2009) Pore architecture and ion sites in acid-sensing ion channels and P2X receptors. Nature, 460 (7255): 599-604. [PMID:19641589]

40. Gründer S, Geissler HS, Bässler EL, Ruppersberg JP. (2000) A new member of acid-sensing ion channels from pituitary gland. Neuroreport, 11 (8): 1607-11. [PMID:10852210]

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

42. Jasti J, Furukawa H, Gonzales EB, Gouaux E. (2007) Structure of acid-sensing ion channel 1 at 1.9 A resolution and low pH. Nature, 449 (7160): 316-23. [PMID:17882215]

43. Jiang Q, Papasian CJ, Wang JQ, Xiong ZG, Chu XP. (2010) Inhibitory regulation of acid-sensing ion channel 3 by zinc. Neuroscience, 169 (2): 574-83. [PMID:20580786]

44. 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]

45. Krauson AJ, Rooney JG, Carattino MD. (2018) Molecular basis of inhibition of acid sensing ion channel 1A by diminazene. PLoS One, 13 (5): e0196894. [PMID:29782492]

46. Kreple CJ, Lu Y, Taugher RJ, Schwager-Gutman AL, Du J, Stump M, Wang Y, Ghobbeh A, Fan R, Cosme CV et al.. (2014) Acid-sensing ion channels contribute to synaptic transmission and inhibit cocaine-evoked plasticity. Nat Neurosci, 17 (8): 1083-91. [PMID:24952644]

47. Kuduk SD, Di Marco CN, Bodmer-Narkevitch V, Cook SP, Cato MJ, Jovanovska A, Urban MO, Leitl M, Sain N, Liang A et al.. (2010) Synthesis, structure-activity relationship, and pharmacological profile of analogs of the ASIC-3 inhibitor A-317567. ACS Chem Neurosci, 1 (1): 19-24. [PMID:22778804]

48. Lee JYP, Saez NJ, Cristofori-Armstrong B, Anangi R, King GF, Smith MT, Rash LD. (2018) Inhibition of acid-sensing ion channels by diminazene and APETx2 evoke partial and highly variable antihyperalgesia in a rat model of inflammatory pain. Br J Pharmacol, 175 (12): 2204-2218. [PMID:29134638]

49. Li WG, Yu Y, Zhang ZD, Cao H, Xu TL. (2010) ASIC3 channels integrate agmatine and multiple inflammatory signals through the nonproton ligand sensing domain. Mol Pain, 6: 88. [PMID:21143836]

50. Lin SH, Chien YC, Chiang WW, Liu YZ, Lien CC, Chen CC. (2015) Genetic mapping of ASIC4 and contrasting phenotype to ASIC1a in modulating innate fear and anxiety. Eur J Neurosci, 41 (12): 1553-68. [PMID:25828470]

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

52. Lingueglia E, de Weille JR, Bassilana F, Heurteaux C, Sakai H, Waldmann R, Lazdunski M. (1997) A modulatory subunit of acid sensing ion channels in brain and dorsal root ganglion cells. J Biol Chem, 272 (47): 29778-83. [PMID:9368048]

53. Liu Y, Ma J, DesJarlais RL, Hagan R, Rech J, Lin D, Liu C, Miller R, Schoellerman J, Luo J et al.. (2021) Molecular mechanism and structural basis of small-molecule modulation of the gating of acid-sensing ion channel 1. Commun Biol, 4 (1): 174. [PMID:33564124]

54. Lynagh T, Mikhaleva Y, Colding JM, Glover JC, Pless SA. (2018) Acid-sensing ion channels emerged over 600 Mya and are conserved throughout the deuterostomes. Proc Natl Acad Sci U S A, 115 (33): 8430-8435. [PMID:30061402]

55. Lynagh T, Romero-Rojo JL, Lund C, Pless SA. (2017) Molecular Basis for Allosteric Inhibition of Acid-Sensing Ion Channel 1a by Ibuprofen. J Med Chem, 60 (19): 8192-8200. [PMID:28949138]

56. Mamet J, Baron A, Lazdunski M, Voilley N. (2002) Proinflammatory mediators, stimulators of sensory neuron excitability via the expression of acid-sensing ion channels. J Neurosci, 22 (24): 10662-70. [PMID:12486159]

57. Marra S, Ferru-Clément R, Breuil V, Delaunay A, Christin M, Friend V, Sebille S, Cognard C, Ferreira T, Roux C et al.. (2016) Non-acidic activation of pain-related Acid-Sensing Ion Channel 3 by lipids. EMBO J, 35 (4): 414-28. [PMID:26772186]

58. Munro G, Christensen JK, Erichsen HK, Dyhring T, Demnitz J, Dam E, Ahring PK. (2016) NS383 Selectively Inhibits Acid-Sensing Ion Channels Containing 1a and 3 Subunits to Reverse Inflammatory and Neuropathic Hyperalgesia in Rats. CNS Neurosci Ther, 22 (2): 135-45. [PMID:26663905]

59. Osmakov DI, Khasanov TA, Andreev YA, Lyukmanova EN, Kozlov SA. (2020) Animal, Herb, and Microbial Toxins for Structural and Pharmacological Study of Acid-Sensing Ion Channels. Front Pharmacol, 11: 991. [PMID:32733241]

60. Osmakov DI, Kozlov SA, Andreev YA, Koshelev SG, Sanamyan NP, Sanamyan KE, Dyachenko IA, Bondarenko DA, Murashev AN, Mineev KS et al.. (2013) Sea anemone peptide with uncommon β-hairpin structure inhibits acid-sensing ion channel 3 (ASIC3) and reveals analgesic activity. J Biol Chem, 288 (32): 23116-27. [PMID:23801332]

61. Peigneur S, Béress L, Möller C, Marí F, Forssmann WG, Tytgat J. (2012) A natural point mutation changes both target selectivity and mechanism of action of sea anemone toxins. FASEB J, 26 (12): 5141-51. [PMID:22972919]

62. Price MP, Snyder PM, Welsh MJ. (1996) Cloning and expression of a novel human brain Na+ channel. J Biol Chem, 271 (14): 7879-82. [PMID:8626462]

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

64. 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]

65. Sakai H, Lingueglia E, Champigny G, Mattei MG, Lazdunski M. (1999) Cloning and functional expression of a novel degenerin-like Na+ channel gene in mammals. J Physiol (Lond.), 519 Pt 2: 323-33. [PMID:10457052]

66. Salinas M, Rash LD, Baron A, Lambeau G, Escoubas P, Lazdunski M. (2006) The receptor site of the spider toxin PcTx1 on the proton-gated cation channel ASIC1a. J Physiol, 570 (Pt 2): 339-54. [PMID:16284080]

67. Schaefer L, Sakai H, Mattei M, Lazdunski M, Lingueglia E. (2000) Molecular cloning, functional expression and chromosomal localization of an amiloride-sensitive Na(+) channel from human small intestine. FEBS Lett, 471 (2-3): 205-10. [PMID:10767424]

68. Schmidt A, Rossetti G, Joussen S, Gründer S. (2017) Diminazene Is a Slow Pore Blocker of Acid-Sensing Ion Channel 1a (ASIC1a). Mol Pharmacol, 92 (6): 665-675. [PMID:29025967]

69. Sherwood TW, Lee KG, Gormley MG, Askwith CC. (2011) Heteromeric acid-sensing ion channels (ASICs) composed of ASIC2b and ASIC1a display novel channel properties and contribute to acidosis-induced neuronal death. J Neurosci, 31 (26): 9723-34. [PMID:21715637]

70. Smith ES, Cadiou H, McNaughton PA. (2007) Arachidonic acid potentiates acid-sensing ion channels in rat sensory neurons by a direct action. Neuroscience, 145 (2): 686-98. [PMID:17258862]

71. Staruschenko A, Dorofeeva NA, Bolshakov KV, Stockand JD. (2007) Subunit-dependent cadmium and nickel inhibition of acid-sensing ion channels. Dev Neurobiol, 67 (1): 97-107. [PMID:17443775]

72. Sun D, Liu S, Li S, Zhang M, Yang F, Wen M, Shi P, Wang T, Pan M, Chang S et al.. (2020) Structural insights into human acid-sensing ion channel 1a inhibition by snake toxin mambalgin1. Elife, 9. DOI: 0.7554/eLife.57096 [PMID:32915133]

73. Ugawa S, Ishida Y, Ueda T, Inoue K, Nagao M, Shimada S. (2007) Nafamostat mesilate reversibly blocks acid-sensing ion channel currents. Biochem Biophys Res Commun, 363 (1): 203-8. [PMID:17826743]

74. Ugawa S, Ueda T, Takahashi E, Hirabayashi Y, Yoneda T, Komai S, Shimada S. (2001) Cloning and functional expression of ASIC-beta2, a splice variant of ASIC-beta. Neuroreport, 12 (13): 2865-9. [PMID:11588592]

75. Vick JS, Askwith CC. (2015) ASICs and neuropeptides. Neuropharmacology, 94: 36-41. [PMID:25592215]

76. Voilley N, de Weille J, Mamet J, Lazdunski M. (2001) Nonsteroid anti-inflammatory drugs inhibit both the activity and the inflammation-induced expression of acid-sensing ion channels in nociceptors. J Neurosci, 21 (20): 8026-33. [PMID:11588175]

77. Vukicevic M, Weder G, Boillat A, Boesch A, Kellenberger S. (2006) Trypsin cleaves acid-sensing ion channel 1a in a domain that is critical for channel gating. J Biol Chem, 281 (2): 714-22. [PMID:16282326]

78. Waldmann R, Bassilana F, de Weille J, Champigny G, Heurteaux C, Lazdunski M. (1997) Molecular cloning of a non-inactivating proton-gated Na+ channel specific for sensory neurons. J Biol Chem, 272 (34): 20975-8. [PMID:9261094]

79. 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]

80. Waldmann R, Champigny G, Voilley N, Lauritzen I, Lazdunski M. (1996) The mammalian degenerin MDEG, an amiloride-sensitive cation channel activated by mutations causing neurodegeneration in Caenorhabditis elegans. J Biol Chem, 271 (18): 10433-6. [PMID:8631835]

81. 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]

82. Wang W, Duan B, Xu H, Xu L, Xu TL. (2006) Calcium-permeable acid-sensing ion channel is a molecular target of the neurotoxic metal ion lead. J Biol Chem, 281 (5): 2497-505. [PMID:16319075]

83. Wang YZ, Wang JJ, Huang Y, Liu F, Zeng WZ, Li Y, Xiong ZG, Zhu MX, Xu TL. (2015) Tissue acidosis induces neuronal necroptosis via ASIC1a channel independent of its ionic conduction. Elife, 4. [PMID:26523449]

84. Wemmie JA, Taugher RJ, Kreple CJ. (2013) Acid-sensing ion channels in pain and disease. Nat Rev Neurosci, 14 (7): 461-71. [PMID:23783197]

85. Wiemuth D, Assmann M, Gründer S. (2014) The bile acid-sensitive ion channel (BASIC), the ignored cousin of ASICs and ENaC. Channels (Austin), 8 (1): 29-34. [PMID:24365967]

86. Xiong ZG, Chu XP, Simon RP. (2007) Acid sensing ion channels--novel therapeutic targets for ischemic brain injury. Front Biosci, 12: 1376-86. [PMID:17127388]

87. Yang L, Palmer LG. (2014) Ion conduction and selectivity in acid-sensing ion channel 1. J Gen Physiol, 144 (3): 245-55. [PMID:25114023]

88. Yoder N, Gouaux E. (2020) The His-Gly motif of acid-sensing ion channels resides in a reentrant 'loop' implicated in gating and ion selectivity. Elife, 9. DOI: 10.7554/eLife.56527 [PMID:32496192]

89. Yoder N, Yoshioka C, Gouaux E. (2018) Gating mechanisms of acid-sensing ion channels. Nature, 555 (7696): 397-401. [PMID:29513651]

90. Yu Y, Chen Z, Li WG, Cao H, Feng EG, Yu F, Liu H, Jiang H, Xu TL. (2010) A nonproton ligand sensor in the acid-sensing ion channel. Neuron, 68 (1): 61-72. [PMID:20920791]

91. Zha XM, Wang R, Collier DM, Snyder PM, Wemmie JA, Welsh MJ. (2009) Oxidant regulated inter-subunit disulfide bond formation between ASIC1a subunits. Proc Natl Acad Sci USA, 106 (9): 3573-8. [PMID:19218436]

92. Ziemann AE, Allen JE, Dahdaleh NS, Drebot II, Coryell MW, Wunsch AM, Lynch CM, Faraci FM, Howard 3rd MA, Welsh MJ et al.. (2009) The amygdala is a chemosensor that detects carbon dioxide and acidosis to elicit fear behavior. Cell, 139 (5): 1012-21. [PMID:19945383]

93. Ziemann AE, Schnizler MK, Albert GW, Severson MA, Howard MA, Welsh MJ, Wemmie JA. (2008) Seizure termination by acidosis depends on ASIC1a. Nat Neurosci, 11 (7): 816-22. [PMID:18536711]

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