title: Structural domains underlying the activation of acid-sensing ion channel 2a.
abstract: The acid-sensing ion channels (ASICs) are a family of ion channels expressed throughout the mammalian nervous system. The principal activator of ASICs is extracellular protons, and ASICs have been demonstrated to play a significant role in many physiologic and pathophysiologic processes, including synaptic transmission, nociception, and fear. However, not all ASICs are proton-sensitive: ASIC2a is activated by acid, whereas its splice variant ASIC2b is not. We made a series of chimeric ASIC2 proteins, and using whole-cell electrophysiology we have identified the minimal region of the ASIC2a extracellular domain that is required for ASIC2 proton activation: the first 87 amino acids after transmembrane domain 1. We next examined the function of different domains within the ASIC2b N-terminus and identified a region proximal to the first transmembrane domain that confers tachyphylaxis upon ASIC2a. We have thus identified domains of ASIC2 that are crucial to channel function and may be important for the function of other members of the ASIC family.
authors.affiliation: Department of Pharmacology, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Laura-Nadine
authors.initials: LN
authors.lastname: Schuhmacher
authors.affiliation: Department of Pharmacology, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Shyam
authors.initials: S
authors.lastname: Srivats
authors.affiliation: Department of Pharmacology, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Ewan St John
authors.identifier: http://orcid.org/0000-0002-2699-1979
authors.initials: ES
authors.lastname: Smith
mesh_terms: D062565:Acid Sensing Ion Channels / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016466:CHO Cells; D003412:Cricetulus; D018408:Patch-Clamp Techniques; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013618:Tachyphylaxis
chemical_list: D062565:Acid Sensing Ion Channels; C568425:Asic2 protein, rat; D020033:Protein Isoforms; D011993:Recombinant Fusion Proteins