title: TRPM2 channel deficiency prevents delayed cytosolic Zn2+ accumulation and CA1 pyramidal neuronal death after transient global ischemia.
abstract: Transient ischemia is a leading cause of cognitive dysfunction. Postischemic ROS generation and an increase in the cytosolic Zn(2+) level ([Zn(2+)]c) are critical in delayed CA1 pyramidal neuronal death, but the underlying mechanisms are not fully understood. Here we investigated the role of ROS-sensitive TRPM2 (transient receptor potential melastatin-related 2) channel. Using in vivo and in vitro models of ischemia-reperfusion, we showed that genetic knockout of TRPM2 strongly prohibited the delayed increase in the [Zn(2+)]c, ROS generation, CA1 pyramidal neuronal death and postischemic memory impairment. Time-lapse imaging revealed that TRPM2 deficiency had no effect on the ischemia-induced increase in the [Zn(2+)]c but abolished the cytosolic Zn(2+) accumulation during reperfusion as well as ROS-elicited increases in the [Zn(2+)]c. These results provide the first evidence to show a critical role for TRPM2 channel activation during reperfusion in the delayed increase in the [Zn(2+)]c and CA1 pyramidal neuronal death and identify TRPM2 as a key molecule signaling ROS generation to postischemic brain injury.
authors.affiliation: Department fof Neurobiology, Institute of Neuroscience, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Zhejiang Province Key Laboratory of Neurobiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.
authors.forename: M
authors.initials: M
authors.lastname: Ye
authors.affiliation: 1] Department fof Neurobiology, Institute of Neuroscience, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Zhejiang Province Key Laboratory of Neurobiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China [2] School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: W
authors.initials: W
authors.lastname: Yang
authors.affiliation: School of Medicine, Faculty of Health and Medicine, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: J F
authors.initials: JF
authors.lastname: Ainscough
authors.affiliation: Department fof Neurobiology, Institute of Neuroscience, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Zhejiang Province Key Laboratory of Neurobiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.
authors.forename: X-P
authors.initials: XP
authors.lastname: Hu
authors.affiliation: School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: X
authors.initials: X
authors.lastname: Li
authors.affiliation: School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: A
authors.initials: A
authors.lastname: Sedo
authors.affiliation: Department fof Neurobiology, Institute of Neuroscience, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Zhejiang Province Key Laboratory of Neurobiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.
authors.forename: X-H
authors.initials: XH
authors.lastname: Zhang
authors.affiliation: Department fof Neurobiology, Institute of Neuroscience, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Zhejiang Province Key Laboratory of Neurobiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.
authors.forename: X
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department fof Neurobiology, Institute of Neuroscience, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Zhejiang Province Key Laboratory of Neurobiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department fof Neurobiology, Institute of Neuroscience, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Zhejiang Province Key Laboratory of Neurobiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.
authors.forename: X-M
authors.initials: XM
authors.lastname: Li
authors.affiliation: 1] School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK [2] School of Medicine, Faculty of Health and Medicine, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: D J
authors.initials: DJ
authors.lastname: Beech
authors.affiliation: School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: A
authors.initials: A
authors.lastname: Sivaprasadarao
authors.affiliation: Department fof Neurobiology, Institute of Neuroscience, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Zhejiang Province Key Laboratory of Neurobiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.
authors.forename: J-H
authors.initials: JH
authors.lastname: Luo
authors.affiliation: 1] School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK [2] Department of Physiology and Neurobiology, Xinxiang Medical University, Henan 453003, China.
authors.forename: L-H
authors.initials: LH
authors.lastname: Jiang
mesh_terms: D000818:Animals; D056547:CA1 Region, Hippocampal / Q000378:metabolism* / Q000473:pathology*; D016923:Cell Death; D003600:Cytosol / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000633:toxicity; D002546:Ischemic Attack, Transient / Q000150:complications / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D008569:Memory Disorders / Q000209:etiology / Q000517:prevention & control; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology; D050053:TRPM Cation Channels / Q000172:deficiency* / Q000378:metabolism; D015032:Zinc / Q000378:metabolism*
chemical_list: D050053:TRPM Cation Channels; C544443:TRPM2 protein, mouse; D006861:Hydrogen Peroxide; D015032:Zinc