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• W1519633796 abstract "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." @default.
• W1519633796 created "2016-06-24" @default.
• W1519633796 creator A5076478370 @default.
• W1519633796 date "2013-12-19" @default.
• W1519633796 modified "2023-09-27" @default.
• W1519633796 title "Cooperative calcium and zinc signaling underlies oxidantinduced neuronal injury" @default.
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