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Protein kinase C regulation of neuronal zinc signaling mediates survival during preconditioning
Author(s) -
Aras Mandar A.,
Hara Hirokazu,
Hartnett Karen A.,
Kandler Karl,
Aizenman Elias
Publication year - 2009
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2009.06106.x
Subject(s) - neuroprotection , microbiology and biotechnology , protein kinase c , excitotoxicity , phosphorylation , signal transduction , kinase , intracellular , programmed cell death , neurotoxicity , biology , serine , protein kinase a , chemistry , biochemistry , neuroscience , apoptosis , toxicity , organic chemistry
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 sub‐lethal 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.