Sub-lethal preconditioning stimuli can confer neuronal tolerance by triggering the activation of endogenous survival pathways that limit or resist subsequent injury. Recent evidence has demonstrated that neuroprotection is paradoxically dependent on the sub-lethal activation of cell death mediators. As intracellular Zn2+ accumulation has been closely associated with neuronal cell death pathways, I tested the hypothesis that neuronal tolerance is also dependent on sub-lethal Zn2+ signals. I found that preconditioning triggered an immediate transient rise in neuronal free Zn2+, while lethal excitotoxicity led to a delayed accumulation of the metal. The sub-lethal rise in Zn2+ was necessary and sufficient in attenuating subsequent Zn2+-dependent toxicity in preconditioned neurons. Chelating Zn2+ during the preconditioning stimulus restored the lethal excitotoxic accumulation in neuronal Zn2+ and abolished neuronal tolerance. These data suggested that preconditioning-induced Zn2+ could trigger mechanisms for preventing subsequent Zn2+-dependent cell death. Indeed, preconditioning triggered protein kinase C (PKC)-dependent Zn2+-regulated gene expression in neurons. Examination of the mechanism involved in modulating Zn2+-regulated gene expression revealed a surprisingly early role for PKC in directly modifying the intracellular source of Zn2+. A conserved PKC phosphorylation site was identified at serine 32 of the metal binding protein metallothionein, which was important in modulating Zn2+ regulated gene expression and ultimately conferring neuronal tolerance. In addition to modulating gene expression, Zn2+ signals may also be important in mediating the acute cellular response to stress. Here, I found a critical role for the transient Zn2+ rise in modulating changes in voltage-gated potassium channel activity and localization following ischemia. Together, these data strongly suggest that a transient rise in neuronal free Zn2+ is an important early signal in conferring neuronal tolerance and in mediating acute cellular adaptive responses to stress. Thus, Zn2+ is a previously unrecognized, highly regulated signaling component in the initiation of survival pathways in neurons.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-08272009-153115 |
| Date | 01 September 2009 |
| Creators | Aras, Mandar A. |
| Contributors | C. William Shuttleworth, John P. Horn, Bruce R. Pitt, Kathryn M. Albers, Donald B. DeFranco, Elias Aizenman |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-08272009-153115/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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