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Zinc Signaling in Neuronal Tolerance

Aras, Mandar A. (2009) Zinc Signaling in Neuronal Tolerance. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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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.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Aras, Mandar A.maa35@pitt.eduMAA35
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairHorn, John Pjph@pitt.eduJPH
Committee MemberPitt, Bruce Rbrucep@pitt.eduBRUCEP
Committee MemberShuttleworth, C.
Committee MemberDeFranco, Donald Bdod1@pitt.eduDOD1
Committee MemberAizenman, Eliasredox@pitt.eduREDOX
Committee MemberAlbers, Kathryn Mkaa2@pitt.eduKAA2
Date: 1 September 2009
Date Type: Completion
Defense Date: 24 August 2009
Approval Date: 1 September 2009
Submission Date: 27 August 2009
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Neurobiology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: excitotoxicity; Kv2.1; metallothionein; PKC; preconditioning; zinc
Other ID:, etd-08272009-153115
Date Deposited: 10 Nov 2011 20:01
Last Modified: 15 Nov 2016 13:49


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