title: Heteromeric acid-sensing ion channels (ASICs) composed of ASIC2b and ASIC1a display novel channel properties and contribute to acidosis-induced neuronal death.
abstract: Acid-sensing ion channel (ASIC) subunits associate to form homomeric or heteromeric proton-gated ion channels in neurons throughout the nervous system. The ASIC1a subunit plays an important role in establishing the kinetics of proton-gated currents in the CNS, and activation of ASIC1a homomeric channels induces neuronal death after local acidosis that accompanies cerebral ischemia. The ASIC2b subunit is expressed in the brain in a pattern that overlaps ASIC1a, yet the contribution of ASIC2b has remained elusive. We find that coexpression of ASIC2b with ASIC1a in Xenopus oocytes results in novel proton-gated currents with properties distinct from ASIC1a homomeric channels. In particular, ASIC2b/1a heteromeric channels are inhibited by the nonselective potassium channel blockers tetraethylammonium and barium. In addition, steady-state desensitization is induced at more basic pH values, and Big Dynorphin sensitivity is enhanced in these unique heteromeric channels. Cultured hippocampal neurons show proton-gated currents consistent with ASIC2b contribution, and these currents are lacking in neurons from mice with an ACCN1 (ASIC2) gene disruption. Finally, we find that these ASIC2b/1a heteromeric channels contribute to acidosis-induced neuronal death. Together, our results show that ASIC2b confers unique properties to heteromeric channels in central neurons. Furthermore, these data indicate that ASIC2, like ASIC1, plays a role in acidosis-induced neuronal death and implicate the ASIC2b/1a subtype as a novel pharmacological target to prevent neuronal injury after stroke.
authors.affiliation: Department of Neuroscience, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Sherwood
authors.forename: Kirsten G
authors.initials: KG
authors.lastname: Lee
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Gormley
authors.forename: Candice C
authors.initials: CC
authors.lastname: Askwith
mesh_terms: D062565:Acid Sensing Ion Channels; D000138:Acidosis / Q000378:metabolism* / Q000503:physiopathology; D000704:Analysis of Variance; D000818:Animals; D016923:Cell Death / Q000502:physiology*; D004594:Electrophysiology; D006624:Hippocampus / Q000378:metabolism* / Q000503:physiopathology; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D015222:Sodium Channels / Q000378:metabolism*; D014981:Xenopus
chemical_list: C568267:ASIC1 protein, mouse; C568265:ASIC2 protein, mouse; D062565:Acid Sensing Ion Channels; D009419:Nerve Tissue Proteins; D015222:Sodium Channels