Acid Sensing Ion Channels

Acid-sensing ion channels (ASICs) are voltage-insensitive Na+ channels that are encoded by four different genes: ASIC1, ASIC2, ASIC3, and ASIC4 (97,157-159). ASIC1 and ASIC2 each have alternative splice variants termed "ASIC1a" and "ASIC1b" as well as ASIC2a and ASIC2b. Functional channels are made up of different ASIC subunits, most of which are expressed by primary afferent neurons, although to different degrees (160,161). Importantly, ASIC2b, which is inactive as a homomultimer, can form functional heteromultimers with other ASIC subunits, particularly ASIC3, which is exclusively expressed by small and large DRG cells (157,160-162) and, for this reason, is also termed "DRASIC." As their name implies, ASIC1, ASIC2 and ASIC3 are gated by a drop in the external pH below 6.9 (97,157-159). In addition, ASICs are mechanoreceptors (159,163), and studies involving deletion of the ASIC2 and ASIC3 genes point to a role in the transduction of low- and high-threshold mechanosensa-tion in the skin, respectively (164-166). ASIC1, to the contrary, does not contribute to cutaneous mechanotransduction, but plays a role in visceral mechanoreceptor function, given that ASIC1 gene knockout results in increased mechanosensitivity of gastroesophageal and colonic afferent neurons (167). Although an implication in visceral pain has remained unexplored, ASICs could conceivably participate in GI hypersensitivity to mechanical and chemical noxae (97). A role in GI pathology may also be envisaged from the upregulation of ASIC3, but not ASIC1 and ASIC2, in inflammatory bowel disease (168) and the stimulation of ASIC3 transcription by nerve growth factor and proinflammatory mediators such as 5-HT, interleukin-1, and bradykinin (169).

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