Journal
BRAIN RESEARCH
Volume 1184, Issue -, Pages 345-353Publisher
ELSEVIER
DOI: 10.1016/j.brainres.2007.09.073
Keywords
ischemic tolerance; diazoxide; protein kinase C; organotypic slice culture; cell death; signal transduction
Categories
Funding
- NINDS NIH HHS [NS05820, R01 NS054147, R01 NS054147-01A1, NS045676, R01 NS045676, R29 NS034773, R01 NS034773, R01 NS045676-01A2, R01 NS034773-06A2, NS34773, NS054147, P01 NS005820, P01 NS005820-35A10027] Funding Source: Medline
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Neuroprotection against cerebral ischemia conferred by ischemic preconditioning (IPC) requires translocation of epsilon protein kinase C (epsilon PKC). A major goal in our laboratory is to define the cellular targets by which ePKC confers protection. We tested the hypothesis that epsilon PKC targets the mitochondrial K-ATP(+) channel (mtK(ATP)(+)) after IPC. Our results demonstrated a rapid translocation of epsilon PKC to rat hippocampal mitochondria after IPC. Because in other tissues epsilon PKC targets mtK(ATP)(+) channels, but its presence in brain mitochondria is controversial, we determined the presence of the K-ATP(+) channel-specific subunits (Kir6.1 and Kir6.2) in mitochondria isolated from rat hippocampus. Next, we determined whether mtK(ATP)(+) channels play a role in the IPC induction. In hippocampal organotypic slice cultures, IPC and lethal ischemia were induced by oxygen-glucose deprivation. Subsequent cell death in the CA1 region was quantified using propidium iodide staining. Treatment with the K-ATP(+) channel openers diazoxide or pinacidil 48 h prior to lethal ischemia protected hippocampal CA1 neurons, mimicking the induction of neuroprotection conferred by either IPC or epsilon PKC agonist-induced preconditioning. Blockade of mtK(ATP)(+) channels using 5-hydroxydecanoic acid abolished the neuroprotection due to either IPC or epsilon PKC preconditioning. Both ischemic and epsilon PKC agonist-mediated preconditioning resulted in phosphorylation of the mtK(ATP)(+) channel subunit Kir6.2. After IPC, selective inhibition of epsilon PKC activation prevented Kir6.2 phosphorylation, consistent with Kir6.2 as a phosphorylation target of epsilon PKC or its downstream effectors. Our results support the hypothesis that the brain mtK(ATP)(+) channel is an important target of IPC and the signal transduction pathways initiated by epsilon PKC. (c) 2007 Elsevier B.V. All rights reserved.
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