title: Neuroprotection in ischemia: blocking calcium-permeable acid-sensing ion channels.
abstract: Ca2+ toxicity remains the central focus of ischemic brain injury. The mechanism by which toxic Ca2+ loading of cells occurs in the ischemic brain has become less clear as multiple human trials of glutamate antagonists have failed to show effective neuroprotection in stroke. Acidosis is a common feature of ischemia and is assumed to play a critical role in brain injury; however, the mechanism(s) remain ill defined. Here, we show that acidosis activates Ca2+ -permeable acid-sensing ion channels (ASICs), inducing glutamate receptor-independent, Ca2+ -dependent, neuronal injury inhibited by ASIC blockers. Cells lacking endogenous ASICs are resistant to acid injury, while transfection of Ca2+ -permeable ASIC1a establishes sensitivity. In focal ischemia, intracerebroventricular injection of ASIC1a blockers or knockout of the ASIC1a gene protects the brain from ischemic injury and does so more potently than glutamate antagonism. Thus, acidosis injures the brain via membrane receptor-based mechanisms with resultant toxicity of [Ca2+]i, disclosing new potential therapeutic targets for stroke.
authors.affiliation: Robert S Dow Neurobiology Laboratories, Legacy Research, Portland, OR 97232, USA. zxiong@downeurobiology.org
authors.forename: Zhi-Gang
authors.initials: ZG
authors.lastname: Xiong
authors.forename: Xiao-Man
authors.initials: XM
authors.lastname: Zhu
authors.forename: Xiang-Ping
authors.initials: XP
authors.lastname: Chu
authors.forename: Manabu
authors.initials: M
authors.lastname: Minami
authors.forename: Jessica
authors.initials: J
authors.lastname: Hey
authors.forename: Wen-Li
authors.initials: WL
authors.lastname: Wei
authors.forename: John F
authors.initials: JF
authors.lastname: MacDonald
authors.forename: John A
authors.initials: JA
authors.lastname: Wemmie
authors.forename: Margaret P
authors.initials: MP
authors.lastname: Price
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Welsh
authors.forename: Roger P
authors.initials: RP
authors.lastname: Simon
mesh_terms: D062565:Acid Sensing Ion Channels; D000138:Acidosis / Q000150:complications / Q000188:drug therapy / Q000378:metabolism*; D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy / Q000378:metabolism*; D019556:COS Cells; D002118:Calcium / Q000378:metabolism* / Q000633:toxicity; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015195:Drug Design; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism* / Q000633:toxicity; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009410:Nerve Degeneration / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology; D051381:Rats; D017470:Receptors, Glutamate / Q000187:drug effects / Q000378:metabolism; D026941:Sodium Channel Blockers / Q000494:pharmacology; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism*
chemical_list: C568266:ASIC1 protein, human; C568267:ASIC1 protein, mouse; D062565:Acid Sensing Ion Channels; D002121:Calcium Channel Blockers; D018691:Excitatory Amino Acid Antagonists; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D017470:Receptors, Glutamate; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D018698:Glutamic Acid; D002118:Calcium