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PKMζ Regulation of Na/K ATPase: A Potential Endogenous Neuro-protective Mechanism of Ischemic Preconditioning.
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Bergold, Peter
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Fall 2006
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2006-10-24
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Doctoral Dissertation
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In ischemic preconditioning, a sublethal ischemic insult protects neurons from subsequent ischemia. We studied ischemic preconditioning in organotypic hippocampal slice cultures, in which a preconditioning 5-minute hypoxia-hypoglycemia treatment protected against a 10-minute experimental ischemic (EI) treatment of hypoxia-hypoglycemia. Whereas the preconditioning treatment protected against EI given 24 hours later, it did not prevent neuronal loss when EI given 2 hours later. This model was used to identify two regulators of ischemic preconditioning; the atypical PKC isoform PKMζ and the Na/K ATPase. Two hours following preconditioning, when there was no neuroprotection, Na/K ATPase activity was unchanged from basal level. In contrast, Na/K ATPase activity as measured by 86Rb uptake was significantly increased 24 hours after the preconditioning treatment. Elevated Na/K ATPase activity 24 hours following preconditioning was accompanied by increased surface expression of the Na/K ATPase α 1 and α 2 isoforms. Similarly, levels of active PKM ζ were increased at 24 hours, but not 2 hours, after preconditioning. To examine the possibility of PKMζ regulation of Na/K ATPase, pharmacological occlusion experiments were performed, using marinobufagenin to inhibit α1, dihydroouabain to inhibit α2/3 and a ζ-pseudosubstrate peptide to inhibit PKMζ. These experiments showed that PKMζ regulated both the activity and surface expression of the α1 isoform of the Na/K ATPase. Finally, we used marinobufagenin, dihydroouabain and ζ-pseudosubstrate peptide to determine if PKMζ or the α1 and α2 Na/K ATPase isoforms protected neurons. All three compounds blocked neuroprotection following ischemic preconditioning. These data indicate key roles of PKMζ and Na/K ATPase in neuroprotection following ischemic preconditioning.
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Tian, D. (2006). PKMζ Regulation of Na/K ATPase: A Potential Endogenous Neuro-protective Mechanism of Ischemic Preconditioning. [Doctoral dissertation, SUNY Downstate Health Sciences University]. SUNY Open Access Repository. https://soar.suny.edu/handle/20.500.12648/16112
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Doctoral Dissertation