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

ABSTRACT: 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.

SUBMITTER: Aras MA

PROVIDER: S-EPMC2719843 | biostudies-literature | 2009 Jul

REPOSITORIES: biostudies-literature

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

Aras Mandar A MA Hara Hirokazu H Hartnett Karen A KA Kandler Karl K Aizenman Elias E

Journal of neurochemistry 20090422 1

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 excitotoxici ...[more]

PMID: 19453299

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

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

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