Acid-sensing (proton-gated) ion channels (ASICs) | Ion channels

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Acid-sensing (proton-gated) ion channels (ASICs)

Acid-sensing (proton-gated) ion channels (ASICs) C

Unless otherwise stated all data on this page refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).

Overview

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Acid-sensing ion channels (ASICs, nomenclature as agreed by NC-IUPHAR [37]) 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 [48] and INaC [49] that have also been named BASICs, for bile acid-activated ion channels [60]. ASIC subunits contain two TM domains and assemble as homo- or hetero-trimers [5,33,36] to form proton-gated, voltage-insensitive, Na⁺ permeable, channels (reviewed in [35,59]). Splice variants of ASIC1 [termed ASIC1a (ASIC, ASICα, BNaC2α) [57], ASIC1b (ASICβ, BNaC2β) [15] and ASIC1b2 (ASICβ2) [52]; note that ASIC1a is also permeable to Ca²⁺] and ASIC2 [termed ASIC2a (MDEG1, BNaC1α, BNC1α) [32,47,58] and ASIC2b (MDEG2, BNaC1β) [42]] have been cloned. Unlike ASIC2a (listed in table), heterologous expression of ASIC2b alone does not support H⁺-gated currents. A third member, ASIC3 (DRASIC, TNaC1) [56], has been identified. A fourth mammalian member of the family (ASIC4/SPASIC) does not support a proton-gated channel in heterologous expression systems and is reported to downregulate the expression of ASIC1a and ASIC3 [1,26,34,41]. ASIC channels are primarily expressed in central and peripheral neurons including nociceptors 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). A neurotransmitter-like function of protons has been suggested, involving postsynaptically located ASICs of the CNS in functions such as learning and fear perception [27,38,65], responses to focal ischemia [61] and to axonal degeneration in autoimmune inflammation in a mouse model of multiple sclerosis [31], as well as seizures [66] and pain [11,21-22,24]. 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 [3,9,30,42].

Channels and Subunits

ASIC1 C Show summary »« Hide summary More detailed page

Target Id

684

Nomenclature

ASIC1

Previous and unofficial names

Genes

ASIC1 (Hs), Asic1 (Mm), Asic1 (Rn)

Ensembl ID

ENSG00000110881 (Hs), ENSMUSG00000023017 (Mm), ENSRNOG00000018789 (Rn)

UniProtKB AC

P78348 (Hs), Q6NXK8 (Mm), P55926 (Rn)

Endogenous activators

Extracellular H⁺ pEC₅₀ ~6.2 – 6.8 (ASIC1a) , ~5.1 – 6.2 (ASIC1b)

Channel blockers

Pi-hexatoxin-Hi1a pIC₅₀ ~9.3 (ASIC1a) [12]

psalmotoxin 1 pIC₅₀ 9.0 (ASIC1a)

Pi-theraphotoxin-Hm3a pIC₅₀ ~8.5 (ASIC1a) [29]

Zn²⁺ pIC₅₀ ~8.2 (ASIC1a)

mambalgin-1 pIC₅₀ ~7.3 (ASIC1a) [24], ~7.0 (ASIC1b) [6]

diminazene pIC₅₀ ~6.5 (ASIC1a & ASIC1b) [40]

A-317567 pIC₅₀ ~5.7 (ASIC1a) [28] - Rat

Pb²⁺ pIC₅₀ ~5.8 (ASIC1b) , ~5.4 (ASIC1a)

benzamil pIC₅₀ 5.0 (ASIC1a)

ethylisopropylamiloride pIC₅₀ 5.0 (ASIC1a)

nafamostat pIC₅₀ ~4.9 (ASIC1a)

amiloride pIC₅₀ 5.0 (ASIC1a) , 4.6 – 4.7 (ASIC1b)

ibuprofen pIC₅₀ ~3.5 (ASIC1a)

flurbiprofen pIC₅₀ 3.5 (ASIC1a) [54] - Rat

Ni²⁺ pIC₅₀ ~3.2 (ASIC1a)

Labelled ligands

[¹²⁵I]psalmotoxin 1 pK_d 9.7 (ASIC1a)

Functional characteristics

ASIC1a: γ =14pS
P_Na/P_K = 5-13, P_Na/P_Ca =2.5
rapid activation rate (5.8-13.7 ms), rapid inactivation rate (1.2-4 s) @ pH 6.0, slow recovery (5.3-13s) @ pH 7.4
ASIC1b: γ =19 pS
P_Na/P_K =14.0, P_Na >> P_Ca
rapid activation rate (9.9 ms), rapid inactivation rate (0.9-1.7 s) @ pH 6.0, slow recovery (4.4-7.7 s) @ pH 7.4

Comment

ASIC1a and ASIC1b are activated by the heteromeric Texas coral snake toxin MitTx, with pEC₅₀ values of ~8 and ~7.6 respectively [11].

ASIC2 C Show summary »« Hide summary More detailed page

Target Id

685

Nomenclature

ASIC2

Previous and unofficial names

Genes

ASIC2 (Hs), Asic2 (Mm), Asic2 (Rn)

Ensembl ID

ENSG00000108684 (Hs), ENSMUSG00000020704 (Mm), ENSRNOG00000007019 (Rn)

UniProtKB AC

Q16515 (Hs), Q925H0 (Mm), Q62962 (Rn)

Endogenous activators

Extracellular H⁺ pEC₅₀ ~4.1 – 5.0

Channel blockers

diminazene pIC₅₀ ~6.1 [40]

amiloride pIC₅₀ 4.6

A-317567 pIC₅₀ ~4.5

nafamostat pIC₅₀ ~4.2

Cd²⁺ pIC₅₀ ~3.0

Functional characteristics

γ=10.4-13.4 pS
P_Na/P_K =10, P_Na/P_Ca = 20
rapid activation rate, moderate inactivation rate (3.3-5.5 s) @ pH 5

Comment

ASIC2 is also blocked by diarylamidines

ASIC3 C Show summary »« Hide summary More detailed page

Target Id

686

Nomenclature

ASIC3

Previous and unofficial names

Genes

ASIC3 (Hs), Asic3 (Mm), Asic3 (Rn)

Ensembl ID

ENSG00000213199 (Hs), ENSMUSG00000038276 (Mm), ENSRNOG00000008380 (Rn)

UniProtKB AC

Q9UHC3 (Hs), Q6X1Y6 (Mm), O35240 (Rn)

Endogenous activators

Extracellular H⁺ pEC₅₀ ~6.2 – 6.7 (transient component) , ~3.5 – 4.3 (sustained component)

Activators

GMQ pEC₅₀ ~3.0 (largly non-desensitizing; at pH 7.4)

arcaine pEC₅₀ ~2.9 (at pH 7.4)

agmatine pEC₅₀ ~2.0 (at pH 7.4)

Channel blockers

APETx2 pIC₅₀ 7.2 (transient component only)

diminazene pIC₅₀ ~6.5 [40]

A-317567 pIC₅₀ 6.0 [39]

nafamostat pIC₅₀ ~5.6 (transient component)

amiloride pIC₅₀ 4.2 – 4.8 (transient component only - sustained component enhanced by 200μM amiloride at pH 4)

Gd³⁺ pIC₅₀ 4.4

Zn²⁺ pIC₅₀ 4.2

diclofenac pIC₅₀ 4.0 (sustained component)

aspirin pIC₅₀ 4.0 (sustained component) [54]

salicylic acid pIC₅₀ 3.6 (sustained component)

Functional characteristics

γ=13-15 pS;
biphasic response consisting of rapidly inactivating transient and sustained components;
very rapid activation (<5 ms) and inactivation (0.4 s);
fast recovery (0.4-0.6 s) @ pH 7.4, transient component partially inactivated at pH 7.2

Comment

ASIC3 is activated by Mit-Toxin (pEC₅₀ ~6.1) [11].

Comments

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Psalmotoxin 1 (PcTx1) inhibits ASIC1a by increasing the affinity to H+ and promoting channel desensitization [16,30]. 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 [50]. PcTx1 and π-Hm3a potentiate ASIC1b currents [17,29]. 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 [24]. π-Hi1a is highly selective for ASIC1a with very little activity at ASIC1b. It inhibits channel activation and is very slowly reversible [14]. 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) [23,25,40]. APETx2 however also inhibits voltage-gated Na⁺ channels [10,45]. IC₅₀ value for A-317567 was determined using high throughput electrophysiology on human ASIC3 expressed in HEK293 cells [39]. 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 [37,59]). Rapid acidification is required for activation of ASIC1 and ASIC3 due to fast inactivation/desensitization. pEC₅₀values for H⁺-activation of either transient, or sustained, currents mediated by ASIC3 vary in the literature and may reflect species and/or methodological differences [4,20,56]. The transient ASIC current component is Na⁺-selective (PNa/PK of about 10) [56,62] whereas the sustained current component that is observed with ASIC3 and some ASIC heteromers is non-selective between Na⁺ and K⁺ [20]. 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 [2,18] whereas oxidation, through the formation of intersubunit disulphide bonds, reduces currents mediated by ASIC1a [64]. ASIC1a is also irreversibly modulated by extracellular serine proteases, such as trypsin, through proteolytic cleavage [55]. Non-steroidal anti-inflammatory drugs (NSAIDs) are direct inhibitors of ASIC currents (reviewed in [7]). Extracellular Zn²⁺ potentiates proton activation of homomeric and heteromeric channels incorporating ASIC2a, but not homomeric ASIC1a or ASIC3 channels [8]. 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 [19]. Nitric oxide potentiates submaximal currents activated by H⁺ mediated by ASIC1a, ASIC1b, ASIC2a and ASIC3 [13]. Ammonium ions activate ASIC channels (most likely ASIC1a) in midbrain dopaminergic neurones: that may be relevant to neuronal disorders associated with hyperammonemia [46]. 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 [53]. Inflammatory conditions and particular pro-inflammatory mediators such as arachidonic acid induce overexpression of ASIC-encoding genes and enhance ASIC currents [22,43,51]. The sustained current component mediated by ASIC3 is potentiated by hypertonic solutions in a manner that is synergistic with the effect of arachidonic acid [22]. ASIC3 is partially activated by the lipids lysophosphatidylcholine (LPC) and arachidonic acid [44]. Mit-Toxin, which is contained in the venom of the Texas coral snake, activates several ASIC subtypes [11]. Selective activation of ASIC3 by GMQ at a site separate from the proton binding site is potentiated by mild acidosis and reduced extracellular Ca²⁺ [63].

References

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NC-IUPHAR subcommittee and family contributors

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Subcommittee members:

Stephan Kellenberger (Chairperson)
Département de Pharmacologie et de Toxicologie
Rue du Bugnon 27
Université de Lausanne
CH-1005 Lausanne
Switzerland

Lachlan D. Rash
School of Biomedical Sciences
The University of Queensland
St Lucia, QLD 4072
Australia

Other contributors:

Laurent Schild
Département de Pharmacologie et de Toxicologie
Rue du Bugnon 27
Université de Lausanne
CH-1005 Lausanne
Switzerland

How to cite this family page

Database page citation (select format):

Concise Guide to PHARMACOLOGY citation:

Alexander SPH, Peters JA, Kelly E, Marrion NV, Faccenda E, Harding SD, Pawson AJ, Sharman JL, Southan C, Davies JA; CGTP Collaborators. (2017) The Concise Guide to PHARMACOLOGY 2017/18: Ligand-gated ion channels. Br J Pharmacol. 174 Suppl 1: S130-S159.