BPS/IUPHAR Guide to Pharmacology | GRAC IC FAMILIES | Acid-sensing (proton-gated) ion channels (ASICs)

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

Acid-sensing ion channels (ASICs, provisional nomenclature; [27,47]) 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 [34] and INaC [35]. ASIC subunits contain two TM domains and assemble as homo- or hetero-trimers [22,26] to form proton-gated, voltage-insensitive, Na⁺ permeable, channels (reviewed in [23]). Splice variants of ASIC1[provisionally termed ASIC1a (ASIC, ASICα, BNaC2α) [43], ASIC1b (ASICβ, BNaC2β) [8] and ASIC1b2 (ASICβ2) [39]; note that ASIC1a is also permeable to Ca²⁺] and ASIC2 [provisionally termed ASIC2a (MDEG1, BNaC1α, BNC1α) [21,33,44] and ASIC2b (MDEG2, BNaC1β) [28]] 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) [42], 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 down regulate the expression of ASIC1a and ASIC3 [1,16,24]. 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). The activation of ASIC1a within the central nervous system contributes to neuronal injury caused by focal ischemia [48] and to axonal degeneration in autoimmune inflammation in a mouse model of multiple sclerosis [20]. However, activation of ASIC1a can terminate seizures [51]. Peripheral ASIC3-containing channels play a role in post-operative pain [12]. Further proposed roles for centrally and peripherally located ASICs are reviewed in [47] and [27]. The relationship of the cloned ASICs to endogenously expressed proton-gated ion channels is becoming established [14-15,19,25,27,29,38,45-47]. Heterologously expressed heteromultimers form ion channels with altered kinetics, ion selectivity, pH- sensitivity and sensitivity to blockers that resemble some of the native proton activated currents recorded from neurones [3,6,19,28].

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

Subunits

ASIC1 Show »« Hide

Nomenclature

ASIC1

Other names

ASIC, BNaC2, ACCN2, hBNaC2, amiloride-sensitive cation channel 2, neuronal, Asic1, acid-sensing ion channel 1, brain sodium channel 2, proton gated cation channel ASIC1, ASIC1a, ASIC1 beta, ASICalpha

Genes

ASIC1 (Hs), Accn2 (Mm), Asic1 (Rn)

Ensembl ID

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

Endogenous activators
(EC₅₀)

H⁺ (extracellular) (ASIC1a) (~1.6x10^-7 – 6.3x10^-7 M)

H⁺ (extracellular) (ASIC1b) (~6.3x10^-7 – 8x10^-6 M)

Channel Blockers
(IC₅₀)

psalmotoxin 1 (ASIC1a) (9x10^-10 M)

Zn²⁺ (ASIC1a) (~7x10^-9 M)

Pb²⁺ (ASIC1b) (~1.5x10^-6 M)

A317567 (ASIC1a) (~2x10^-6 M)

Pb²⁺ (ASIC1a) (~4x10^-6 M)

amiloride (ASIC1a) (1x10^-5 M)

benzamil (ASIC1a) (1x10^-5 M)

EIPA (ASIC1a) (1x10^-5 M)

nafamostat (ASIC1a) (~1.3x10^-5 M)

amiloride (ASIC1b) (2.1x10^-5 – 2.3x10^-5 M)

flurbiprofen (ASIC1a) (3.5x10^-4 M)

ibuprofen (ASIC1a) (~3.5x10^-4 M)

Ni²⁺ (ASIC1a) (~6x10^-4 M)

Radioligands
(K_d)

[¹²⁵I]psalmotoxin 1 (ASIC1a) (2.13x10^-10 M)

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 also blocked by diarylamidines (IC₅₀ ~3 μM for ASIC1a)

ASIC2 Show »« Hide

Nomenclature

ASIC2

Other names

BNC1, BNaC1, MDEG, ACCN, ACCN1, ASIC2a, hBNaC1, amiloride-sensitive cation channel 1, neuronal, degenerin, ASIC2a/ASIC2b, BNC1k, MDEG1, MDEG2, Amiloride-sensitive cation channel 1 neuronal (degenerin), Amiloride-sensitive cation channel 1 neuronal (degenerin) two different splice products: MDEG1 and MDEG2, Amiloride-sensitive cation channel 1, neuronal (degenerin), acid-sensing ion channel 2, amiloride-sensitive brain sodium channel 2, amiloride-sensitive cation channel 1, amiloride-sensitive cation channel neuronal 1, brain sodium channel 1, mammalian degenerin homolog, BNaC1a

Genes

ASIC2 (Hs), Accn1 (Mm), Asic2 (Rn)

Ensembl ID

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

Endogenous activators
(EC₅₀)

H⁺ (extracellular) (~1x10^-5 – 8x10^-5 M)

Channel Blockers
(IC₅₀)

amiloride (2.8x10^-5 M)

A317567 (~3x10^-5 M)

nafamostat (~7x10^-5 M)

Cd²⁺ (~1x10^-3 M)

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 Show »« Hide

Nomenclature

ASIC3

Other names

DRASIC, TNaC1, ACCN3, amiloride-sensitive cation channel 3, testis, amiloride-sensitive cation channel 3, testis sodium channel 1, Asic3, acid sensing ion channel 3, acid-sensing ion channel 3, dorsal root ASIC, proton gated cation channel DRASIC

Genes

ASIC3 (Hs), Accn3 (Mm), Asic3 (Rn)

Ensembl ID

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

Endogenous activators
(EC₅₀)

H⁺ (extracellular) (transient component) (~2x10^-7 – 6.3x10^-7 M)

H⁺ (extracellular) (sustained component) (~5x10^-5 – 3.5x10^-4 M)

Activators
(EC₅₀)

GMQ (largly non-desensitizing; at pH 7.4) (~1x10^-3 M)

arcaine (at pH 7.4) (~1.2x10^-3 M)

agmatine (at pH 7.4) (~9.8x10^-3 M)

Channel Blockers
(IC₅₀)

APETx2 (transient component only) (6.3x10^-8 M)

nafamostat (transient component) (~2.5x10^-6 M)

A317567 (~1x10^-5 M)

amiloride (transient component only - sustained component enhanced by 200μM amiloride at pH 4) (1.6x10^-5 – 6.3x10^-5 M)

Gd³⁺ (4x10^-5 M)

Zn²⁺ (6.1x10^-5 M)

aspirin (sustained component) (9.2x10^-5 M)

diclofenac (sustained component) (9.2x10^-5 M)

salicylic acid (sustained component) (2.6x10^-4 M)

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 also blocked by diarylamidines

Comments Show »« Hide

psalmotoxin 1 (PcTx1) inhibits ASIC1a by modifying activation and desensitization by H⁺, but promotes ASIC1b opening. PcTx1 has little effect upon ASIC2a, ASIC3, or ASIC1a expressed as a heteromultimer with either ASIC2a, or ASIC3 [15,19] but does block ASIC1a expressed as a heteromultimer with ASIC2b [36]. spermine, which apparently competes with PcTx1 for binding to ASIC1a, selectively enhances the function of the channel [17]. Blockade of ASIC1a by PcTx1 activates the endogenous enkephalin pathway and has very potent analgesic effects in rodents [31]. 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, ASIC1b, ASIC2a, or ASIC2a+ASIC3 [14-15]. IC₅₀ values for A317567 are inferred from blockade of ASIC channels native to dorsal root ganglion neurones [18]. 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 [29]). 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 [4,11,42]. The transient and sustained current components mediated by rASIC3 are selective for Na⁺ [42]; for hASIC3 the transient component is Na⁺ selective (PNa/PK > 10) whereas the sustained current appears non-selective (PNa/PK = 1.6) [4,11]. 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 [2,9] whereas oxidation, through the formation of intersubunit disulphide bonds, reduces currents mediated by ASIC1a [50]. ASIC1a is also irreversibly modulated by extracellular serine proteases, such as trypsin, through proteolytic cleavage [41]. Non-steroidal anti-inflammatory drugs (NSAIDs) are direct blockers of ASIC currents at therapeutic concentrations (reviewed in [40]). Extracellular Zn²⁺ potentiates proton activation of homomeric and heteromeric channels incorporating ASIC2a, but not homomeric ASIC1a or ASIC3 channels [5]. However, removal of contaminating Zn²⁺ by chealation reveals a high affinity block of homomeric ASIC1a and heteromeric ASIC1a+ASIC2 channels by Zn²⁺ indicating complex biphasic actions of the divalent [10]. NO potentiates submaximal currents activated by H⁺ mediated by ASIC1a, ASIC1b, ASIC2a and ASIC3 [7]. Ammonium activates ASIC channels (most likely ASIC1a) in midbrain dopaminergic neurones: that may be relevant to neuronal disorders associated with hyperammonemia [32]. 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 [29]. Inflammatory conditions and particular pro-inflammatory mediators induce overexpression of ASIC-encoding genes, enhance ASIC currents [30], and in the case of arachidonic acid directly activate the channel [13,37]. The sustained current component mediated by ASIC3 is potentiated by hypertonic solutions in a manner that is synergistic with the effect of arachidonic acid [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⁺ [49].