A critical role of TRPM2 in neuronal cell death by hydrogen peroxide

Shuji Kaneko, Seiko Kawakami, Yuji Hara, Minoru Wakamori, Etsuko Itoh, Toshiyuki Minami, Yuki Takada, Toshiaki Kume, Hiroshi Katsuki, Yasuo Mori, Akinori Akaike

Research output: Contribution to journalArticlepeer-review

160 Citations (Scopus)

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 Ca 2+-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, H 2O2-induced Ca2+ influx, and H 2O2-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 Ca 2+ influx, significantly inhibited H2O2-induced neuronal death. These results suggest that TRPM2 plays a pivotal role in H 2O2-induced neuronal death as redox-sensitive Ca 2+-permeable channels expressed in neurons.

Original languageEnglish
Pages (from-to)66-76
Number of pages11
JournalJournal of Pharmacological Sciences
Volume101
Issue number1
DOIs
Publication statusPublished - 2006
Externally publishedYes

Keywords

  • ADP-ribose
  • Calcium homeostasis
  • Cation channel
  • Cerebral cortex
  • TRP channel

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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