IUPHAR/BPS Guide to Pharmacology CITE
https://doi.org/10.2218/gtopdb/F118/2021.3

Acid-sensing (proton-gated) ion channels (ASICs) in GtoPdb v.2021.3



Stephan Kellenberger1 and Lachlan D. Rash2
  1. Université de Lausanne, Switzerland
  2. The University of Queensland, Australia


Abstract

Acid-sensing ion channels (ASICs, nomenclature as agreed by NC-IUPHAR [45, 2, 3]) 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 [66] and INaC [68] that have also been named BASICs, for bile acid-activated ion channels [86]. ASIC subunits contain 2 TM domains and assemble as homo- or hetero-trimers [43, 40, 7, 90, 89, 73] 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 [42, 85, 45, 65, 23]) . Splice variants of ASIC1 [termed ASIC1a (ASIC, ASICα, BNaC2α) [80], ASIC1b (ASICβ, BNaC2β) [19] and ASIC1b2 (ASICβ2) [75]; note that ASIC1a is also permeable to Ca2+] and ASIC2 [termed ASIC2a (MDEG1, BNaC1α, BNC1α) [63, 81, 39] and ASIC2b (MDEG2, BNaC1β) [53]] 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) [79] 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 [55]. 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, 41, 33, 51]. 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 [52, 27]). A neurotransmitter-like function of protons has been suggested, involving postsynaptically located ASICs of the CNS in functions such as learning and fear perception [34, 47, 93], responses to focal ischemia [87] and to axonal degeneration in autoimmune inflammation in a mouse model of multiple sclerosis [38], as well as seizures [94] and pain [85, 28, 29, 13, 31]. 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 [53, 5, 37, 11]. 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) [64, 60]. 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.

Contents

This is a citation summary for Acid-sensing (proton-gated) ion channels (ASICs) in the Guide to Pharmacology database (GtoPdb). It exists purely as an adjunct to the database to facilitate the recognition of citations to and from the database by citation analyzers. Readers will almost certainly want to visit the relevant sections of the database which are given here under database links.

GtoPdb is an expert-driven guide to pharmacological targets and the substances that act on them. GtoPdb is a reference work which is most usefully represented as an on-line database. As in any publication this work should be appropriately cited, and the papers it cites should also be recognized. This document provides a citation for the relevant parts of the database, and also provides a reference list for the research cited by those parts. For further details see [15].

Please note that the database version for the citations given in GtoPdb are to the most recent preceding version in which the family or its subfamilies and targets were substantially changed. The links below are to the current version. If you need to consult the cited version, rather than the most recent version, please contact the GtoPdb curators.

Database links

Acid-sensing (proton-gated) ion channels (ASICs)
https://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=118
    Channels and Subunits
            ASIC1
            https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=684
            ASIC2
            https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=685
            ASIC3
            https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=686

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