title: A critical role of TRPM2 in neuronal cell death by hydrogen peroxide.
abstract: A brief exposure to hydrogen peroxide (H2O2) induces severe deterioration of primary cultured neurons in vitro. We have investigated a link between the H2O2-induced neuronal death and Ca2+-permeable TRPM2 channels regulated by ADP-ribose (ADPR). In cultured cerebral cortical neurons from fetal rat, TRPM2 proteins were detected at cell bodies and neurite extensions. Application of H2O2 to the cultured neurons elicited an increase in intracellular Ca2+ concentration ([Ca2+]i) caused by Ca2+ influx and the Ca2+-dependent neuronal death in a similar concentration range. Molecular cloning of TRPM2 cDNA from rat brain revealed several differences in amino acid sequences within the Nudix box region as compared with those of human and mouse TRPM2. ADPR-induced current responses, H2O2-induced Ca2+ influx, and H2O2-induced cell death were induced in human embryonic kidney cells heterologously expressing rat TRPM2. Treatment of cultured neurons with small interfering RNA against rat TRPM2,which efficiently suppressed immunoreactive TRPM2 content and the H2O2-induced Ca2+ influx,significantly inhibited H2O2-induced neuronal death. These results suggest that TRPM2 plays a pivotal role in H2O2-induced neuronal death as redox-sensitive Ca2+-permeable channels expressed in neurons.
authors.affiliation: Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Japan. skaneko@pharm.kyoto-u.ac.jp
authors.forename: Shuji
authors.initials: S
authors.lastname: Kaneko
authors.forename: Seiko
authors.initials: S
authors.lastname: Kawakami
authors.forename: Yuji
authors.initials: Y
authors.lastname: Hara
authors.forename: Minoru
authors.initials: M
authors.lastname: Wakamori
authors.forename: Etsuko
authors.initials: E
authors.lastname: Itoh
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Minami
authors.forename: Yuki
authors.initials: Y
authors.lastname: Takada
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Kume
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Katsuki
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Mori
authors.forename: Akinori
authors.initials: A
authors.lastname: Akaike
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism*; D016923:Cell Death / Q000502:physiology; D002460:Cell Line; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000196:embryology*; D020868:Gene Silencing; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity*; D007668:Kidney / Q000196:embryology / Q000378:metabolism; D008856:Microscopy, Fluorescence; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050053:TRPM Cation Channels / Q000502:physiology*
chemical_list: D034741:RNA, Small Interfering; D050053:TRPM Cation Channels; D006861:Hydrogen Peroxide; D002118:Calcium