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Protein kinase C regulation of neuronal zinc signaling mediates survival during preconditioning
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| Zeitschriftentitel: | Journal of Neurochemistry |
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| Personen und Körperschaften: | , , , , |
| In: | Journal of Neurochemistry, 110, 2009, 1, S. 106-117 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
Wiley
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| Schlagwörter: |
| Zusammenfassung: | <jats:title>Abstract</jats:title><jats:p>Sub‐lethal activation of cell death processes initiate pro‐survival signaling cascades. As intracellular Zn<jats:sup>2+</jats:sup> liberation mediates neuronal death pathways, we tested whether a sub‐lethal increase in free Zn<jats:sup>2+</jats:sup> could also trigger neuroprotection. Neuronal free Zn<jats:sup>2+</jats:sup> 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<jats:sup>2+</jats:sup> that contributed significantly to excitotoxicity in non‐preconditioned neurons, but not in tolerant neurons, unless preconditioning‐induced free Zn<jats:sup>2+</jats:sup> was chelated. Thus, preconditioning may trigger the expression of Zn<jats:sup>2+</jats:sup>‐regulating processes, which, in turn, prevent subsequent Zn<jats:sup>2+</jats:sup>‐mediated toxicity. Indeed, preconditioning increased Zn<jats:sup>2+</jats:sup>‐regulated gene expression in neurons. Examination of the molecular signaling mechanism leading to this early Zn<jats:sup>2+</jats:sup> signal revealed a critical role for protein kinase C (PKC) activity, suggesting that PKC may act directly on the intracellular source of Zn<jats:sup>2+</jats:sup>. We identified a conserved PKC phosphorylation site at serine‐32 (S32) of metallothionein (MT) that was important in modulating Zn<jats:sup>2+</jats:sup>‐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<jats:sup>2+</jats:sup> serves as an important, highly regulated signaling component responsible for the initiation of a neuroprotective pathway.</jats:p> |
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| Umfang: | 106-117 |
| ISSN: |
0022-3042
1471-4159 |
| DOI: | 10.1111/j.1471-4159.2009.06106.x |