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Cooperative calcium and zinc signaling underlies oxidant-induced neuronal injury

McCord, Meghan (2013) Cooperative calcium and zinc signaling underlies oxidant-induced neuronal injury. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Intracellular zinc release triggered by oxidative injury leads to cellular K+ efflux and neuronal apoptosis. Low intracellular K+ enables protease and nuclease activation during cell death processes. Our laboratory has demonstrated that the reduction in cytosolic K+ occurs via zinc-dependent phosphorylation of Kv2.1 by Src kinase and p38 MAPK, leading to the insertion of new Kv2.1 channels into the plasma membrane of dying neurons. As calcium dyshomeostasis is also observed in many models of neuronal injury, I tested the hypothesis that zinc- and Kv2.1-mediated apoptosis also depended on increased intracellular calcium. I observed that oxidant exposure triggered release of calcium from the endoplasmic reticulum, which led to the activation of the calcium/calmodulin-dependent protein kinase II (CaMKII). Molecular or pharmacological inhibition of CaMKII prevented both the oxidant-induced K+ current enhancement and, importantly, subsequent cell death. Further, I found that CaMKII regulated apoptosis by its direct association with the SNARE protein syntaxin, with syntaxin mediating the plasma membrane insertion of Kv2.1 via enhanced association with the phosphorylated channel. As such, Kv2.1/syntaxin binding was enhanced under conditions that promoted apoptosis, and inhibiting CaMKII prevented this interaction. Moreover, expression of a Kv2.1-derived peptide containing the channel’s c-terminal syntaxin binding site (C1a) was also sufficient to disrupt Kv2.1/syntaxin binding, preventing both the oxidant-induced K+ current enhancement and downstream apoptosis. Together, these findings support a novel role for calcium and CaMKII in an established zinc-mediated injury cascade. Further, they suggest that the metals work in concert to elicit the pro-apoptotic Kv2.1 channel activity necessary for oxidative stress-induced apoptosis. Finally, disruption of the pro-apoptotic syntaxin/Kv2.1 interaction may lead to novel therapeutic approaches for neurological disorders associated with oxidant-induced signaling.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairHastings,
Committee MemberLevitan, Edwinelevitan@pitt.eduELEVITAN
Committee MemberRomero, Guillermoggr@pitt.eduGGR
Committee MemberSeal, Rebeccarpseal@pitt.eduRPSEAL
Committee MemberSesti,
Thesis AdvisorAizenman, Eliasredox@pitt.eduREDOX
Date: 19 December 2013
Date Type: Publication
Defense Date: 9 December 2013
Approval Date: 19 December 2013
Submission Date: 18 December 2013
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 137
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Neurobiology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Kv2.1, apoptosis, coordinated regulation of potassium channel function
Date Deposited: 19 Dec 2013 19:43
Last Modified: 15 Nov 2016 14:16


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