Acid-sensing ion channel

Receptor ASIC1

Acid-Sensing Ion Channels (ASICs) are neuronal voltage-insensitive cationic channels activated by extracellular protons. ASIC proteins are a subfamily of the ENaC/Deg superfamily of ion channels. To date six proteins of the ASIC family have been identified that arise from four genes, ASIC1, ASIC2, ASIC3, and ASIC4. ASIC1a, 1b and 2a, 2b are splice variants. ASICs are trimeric and can be made up of different combinations of subunits. ASIC2b is non functional on its own but modulates channel activity when participating in heteromultimers. ASIC4 has no known function. All ASICs are expressed in the peripheral nervous system while ASIC1a, 2a, 2b, 3 and 4 are expressed in the central nervous system. ASICs are Na⁺ permeable with ASIC1a showing low Ca⁺⁺ permeability.

The crystal structure of chicken ASIC1a was solved in 2007.^[1] The structure of ASIC1a has also served as model to understand the structure of the homologous epithelial sodium channel ENaC.^[2] In contrast to ASIC1 structure that is a homotrimer, ENaC is assembled as a heterotrimer composed of three homologous subunits α, β, and γ or δ, β, and γ encoded by SCNN1A, SCNN1B, SCNN1G, and SCNN1D.^[2]

Physiology

ASICs are potential drug targets for treating a wide variety of conditions linked to both the CNS and PNS.^[3] Of particular interest to pain field is the ASIC3 subtype receptor, which is specifically expressed in nociceptors. This subtype exhibits a biphasic current upon proton activation, where the initial inward Na⁺ current is shortly followed by a sustained cationic current.

Pharmacology

ASICs are activated by protons (H⁺). The concentration of H+ required to open the channel varies with the channels subunit composition (pH from 7 to 5). A snake toxin (MitTx) was recently shown to directly activate ASIC channels and cause pain in mice.

The diuretic amiloride blocks ASICs by acting as pore blocker.

Two animal toxins have been shown to inhibit ASICs channel function. Psalmotoxin-1 (PcTx1) specifically inhibits ASIC1a homomultimeric channels with sub-nanomolar affinity. The sea anemone toxin APETx2 inhibits ASIC3-containing channels with IC₅₀<100 nM.

Results first reported in Nature in October 2012 suggest that a newly discovered class of three-finger peptides from the venom of the black mamba, named mambalgins by the researchers, suppress pain in mice without toxicity and with fewer side effects than morphine. The analgesic effects are believed to involve "blockade of heteromeric channels made of ASIC1a and ASIC2a subunits in central neurons and of ASIC1b-containing channels in nociceptors".^[4]^[5]

References

↑ Jasti J, Furukawa H, Gonzales EB, Gouaux E (September 2007). "Structure of acid-sensing ion channel 1 at 1.9 A resolution and low pH.". Nature 449 (7160): 316–323. doi:10.1038/nature06163. PMID 17882215.
1 2 Hanukoglu I, Hanukoglu A (Jan 2016). "Epithelial sodium channel (ENaC) family: Phylogeny, structure-function, tissue distribution, and associated inherited diseases.". Gene 579 (2): 95–132. doi:10.1016/j.gene.2015.12.061. PMID 26772908.
↑ Sluka KA, Winter OC, Wemmie JA (September 2009). "Acid-sensing ion channels: A new target for pain and CNS diseases". Curr Opin Drug Discov Devel 12 (5): 693–704. PMID 19736627.
↑ Diochot, S.; Baron, A.; Salinas, M.; Douguet, D.; Scarzello, S.; Dabert-Gay, A. S.; Debayle, D.; Friend, V. R.; Alloui, A.; Lazdunski, M.; Lingueglia, E. (2012). "Black mamba venom peptides target acid-sensing ion channels to abolish pain". Nature 490 (7421): 552–555. doi:10.1038/nature11494. PMID 23034652.
↑ Gallagher, James (3 October 2012). "Black mamba venom is 'better painkiller' than morphine". BBC News Health. BBC. Retrieved 3 October 2012.

Membrane transport protein: ion channels (TC 1A)

Ca²⁺: Calcium channel

Ligand-gated	Inositol trisphosphate receptor 1 2 3 Ryanodine receptor 1 2 3

Voltage-gated	L-type/Ca_vα 1.1 1.2 1.3 1.4 N-type/Ca_vα2.2 P-type/Ca_vα 2.1 Q-type/Ca_vα2.1 R-type/Ca_vα2.3 T-type/Ca_vα 3.1 3.2 3.3 α₂δ-subunits 1 2 β-subunits β1 β2 β3 β4 γ-subunits γ1 γ2 γ3 γ4 Cation channels of sperm 1 2 3 4 Two-pore channel 1 2

Na⁺: Sodium channel

Constitutively active	Epithelial sodium channel α β γ δ

Proton-gated	Amiloride-sensitive cation channel 1 2 3 4

Voltage-gated	Na_vα 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 7A Na_vβ 1 2 3 4

K⁺: Potassium channel

Calcium-activated	BK channel α1 β1 β2 β3 β4 SK channel SK1 SK2 SK3 IK channel IK1 K_Ca 1.1 2.1 2.2 2.3 3.1 4.1 4.2 5.1

Inward-rectifier	K_ATP K_ir 1.1 2.1 2.2 2.3 2.4 2.6 GIRK/K_ir 3.1 3.2 3.3 3.4 K_ir 4.1 4.2 5.1 6.1 6.2 7.1

Tandem pore domain	K2P 1 2 3 4 5 6 7 9 10 12 13 15 16 17 18

Voltage-gated	K_vα1-6 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 2.1 2.2 3.1 3.2 3.3 3.4 4.1 4.2 4.3 5.1 6.1 6.2 6.3 6.4 K_vα7-12 7.1 7.2 7.3 7.4 7.5 8.1 8.2 9.1 9.2 9.3 10.1 10.2 11.1/hERG 11.2 11.3 12.1 12.2 12.3 K_vβ 1 2 3 KCNIP 1 2 3 4 minK/ISK minK/ISK-like MiRP 1 2 3 Shaker gene

Miscellaneous

Cl⁻: Chloride channel	Calcium-activated chloride channels Anoctamin ANO1 Bestrophin 1 2 Chloride Channel Accessory 1 2 3 4 CFTR CLCN 1 2 3 4 5 6 7 KA KB CLIC 1 2 3 4 5 6 L1 CLNS 1A 1B

H⁺: Proton channel	HVCN1

M⁺: CNG cation channel	α 1 2 3 4 β 1 2 3 HCN FC 1 2 3 4

M⁺: TRP cation channel	TRPA (1) TRPC 1 2 3 4 4AP 5 6 7 TRPM 1 2 3 4 5 6 7 8 TRPML 1 2 3 TRPN TRPP 1 2 TRPV 1 2 3 4 5 6

H₂O (+ solutes): Porin	Aquaporin 0 1 2 3 4 5 6 7 8 9 Voltage-dependent anion channel 1 2 3 General bacterial porin family

Cytoplasm: Gap junction	Connexin: A GJA1 GJA3 GJA4 GJA5 GJA8 GJA9 GJA10 B GJB1 GJB2 GJB3 GJB4 GJB5 GJB6 GJB7 C GJC1 GJC2 GJC3 D GJD2 GJD3 GJD4) Innexin

By gating mechanism

Ion channel class	Ligand-gated Light-gated Voltage-gated Stretch-activated

see also disorders

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