Acid-sensing ion channel

Acid-Sensing Ion Channels (ASICs) are neuronal voltage-insensitive sodium channels activated by extracellular protons. ASIC proteins are a subfamily of the ENaC/Deg superfamily of ion channels. In mammalian genomes, the ASIC is encoded by five genes, ASIC1, ASIC2, ASIC3, ASIC4, and ASIC5. These genes have splice variants that encode for several isoforms that are marked by a suffix. For example, two major products of ASIC1 gene are called as ASIC1a and ASIC1b. 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. The structure of ASIC1a has also served as a model to understand the structure of the homologous epithelial sodium channel ENaC. 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.

ASICs are potential drug targets for treating a wide variety of conditions linked to both the CNS and PNS. 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.

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.

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