title: A key role for TRPM7 channels in anoxic neuronal death.
abstract: Excitotoxicity in brain ischemia triggers neuronal death and neurological disability, and yet these are not prevented by antiexcitotoxic therapy (AET) in humans. Here, we show that in neurons subjected to prolonged oxygen glucose deprivation (OGD), AET unmasks a dominant death mechanism perpetuated by a Ca2+-permeable nonselective cation conductance (IOGD). IOGD was activated by reactive oxygen/nitrogen species (ROS), and permitted neuronal Ca2+ overload and further ROS production despite AET. IOGD currents corresponded to those evoked in HEK-293 cells expressing the nonselective cation conductance TRPM7. In cortical neurons, blocking IOGD or suppressing TRPM7 expression blocked TRPM7 currents, anoxic 45Ca2+ uptake, ROS production, and anoxic death. TRPM7 suppression eliminated the need for AET to rescue anoxic neurons and permitted the survival of neurons previously destined to die from prolonged anoxia. Thus, excitotoxicity is a subset of a greater overall anoxic cell death mechanism, in which TRPM7 channels play a key role.
authors.affiliation: Toronto Western Hospital Research Institute, 11-416 MC-PAV, 399 Bathurst Street, Toronto, Ontario M5T-2S8 Canada.
authors.forename: Michelle
authors.initials: M
authors.lastname: Aarts
authors.forename: Koji
authors.initials: K
authors.lastname: Iihara
authors.forename: Wen-Li
authors.initials: WL
authors.lastname: Wei
authors.forename: Zhi-Gang
authors.initials: ZG
authors.lastname: Xiong
authors.forename: Mark
authors.initials: M
authors.lastname: Arundine
authors.forename: Waldy
authors.initials: W
authors.lastname: Cerwinski
authors.forename: John F
authors.initials: JF
authors.lastname: MacDonald
authors.forename: Michael
authors.initials: M
authors.lastname: Tymianski
mesh_terms: D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology; D002412:Cations / Q000378:metabolism; D016923:Cell Death / Q000502:physiology; D002460:Cell Line; D002470:Cell Survival / Q000502:physiology; D005947:Glucose / Q000172:deficiency; D006801:Humans; D020925:Hypoxia-Ischemia, Brain / Q000378:metabolism* / Q000503:physiopathology; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology*; D007473:Ion Channels / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000235:genetics; D007501:Iron / Q000378:metabolism; D008565:Membrane Proteins; D051379:Mice; D009410:Nerve Degeneration / Q000378:metabolism* / Q000503:physiopathology; D009498:Neurotoxins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000172:deficiency* / Q000235:genetics; D017346:Protein Serine-Threonine Kinases; D034622:RNA Interference; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species / Q000378:metabolism; D050053:TRPM Cation Channels
chemical_list: D002412:Cations; D007473:Ion Channels; D008565:Membrane Proteins; D009498:Neurotoxins; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D050053:TRPM Cation Channels; D016718:Arachidonic Acid; D007501:Iron; D011494:Protein Kinases; C421903:Trpm7 protein, mouse; D017346:Protein Serine-Threonine Kinases; C486583:TRPM7 protein, human; D005947:Glucose; D002118:Calcium