論文

査読有り
2009年7月

Protein kinase C regulation of neuronal zinc signaling mediates survival during preconditioning

JOURNAL OF NEUROCHEMISTRY
  • Mandar A. Aras
  • ,
  • Hirokazu Hara
  • ,
  • Karen A. Hartnett
  • ,
  • Karl Kandler
  • ,
  • Elias Aizenman

110
1
開始ページ
106
終了ページ
117
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1111/j.1471-4159.2009.06106.x
出版者・発行元
WILEY-BLACKWELL PUBLISHING, INC

Sub-lethal activation of cell death processes initiate pro-survival signaling cascades. As intracellular Zn(2+) liberation mediates neuronal death pathways, we tested whether a sublethal increase in free Zn(2+) could also trigger neuroprotection. Neuronal free Zn(2+) transiently increased following preconditioning, and was both necessary and sufficient for conferring excitotoxic tolerance. Lethal exposure to NMDA led to a delayed increase in Zn(2+) that contributed significantly to excitotoxicity in non-preconditioned neurons, but not in tolerant neurons, unless preconditioning-induced free Zn(2+) was chelated. Thus, preconditioning may trigger the expression of Zn(2+)regulating processes, which, in turn, prevent subsequent Zn(2+)-mediated toxicity. Indeed, preconditioning increased Zn(2+)-regulated gene expression in neurons. Examination of the molecular signaling mechanism leading to this early Zn(2+) signal revealed a critical role for protein kinase C (PKC) activity, suggesting that PKC may act directly on the intracellular source of Zn(2+). We identified a conserved PKC phosphorylation site at serine-32 (S32) of metallothionein (MT) that was important in modulating Zn(2+)-regulated gene expression and conferring excitotoxic tolerance. Importantly, we observed increased PKC-induced serine phosphorylation in immunopurified MT1, but not in mutant MT1(S32A). These results indicate that neuronal Zn(2+) serves as an important, highly regulated signaling component responsible for the initiation of a neuroprotective pathway.

Web of Science ® 被引用回数 : 40

リンク情報
DOI
https://doi.org/10.1111/j.1471-4159.2009.06106.x
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/19453299
Web of Science
https://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=JSTA_CEL&SrcApp=J_Gate_JST&DestLinkType=FullRecord&KeyUT=WOS:000266923700010&DestApp=WOS_CPL