Interplay Between the Gamma Isoform of PKC and Calcineurin in Regulation of Vulnerability to Focal Cerebral Ischemia

Abstract

Protein phosphorylation and dephosphorylation mediated by protein kinases and protein phosphatases, respectively, represent essential steps in a variety of vital neuronal processes that could affect susceptibility to ischemic stroke. In this study, the role of the neuron-specific γ isoform of protein kinase C (γPKC) in reversible focal ischemia was examined using mutant mice in which the gene for γPKC was knockedout (γPKC-KO). A period of 150 minutes of unilateral middle cerebral artery and common carotid artery (MCA/CCA) occlusion followed by 21.5 hours of reperfusion resulted in significantly larger ( P < 0.005) infarct volumes (n = 10; 31.1 ± 4.2 mm3) in γPKC-KO than in wild-type (WT) animals (n = 12; 22.6 ± 7.4 mm3). To control for possible differences related to genetic background, the authors analyzed Balb/cJ, C57BL/6J, and 129SVJ WT in the MCA/CCA model of focal ischemia. No significant differences in stroke volume were detected between these WT strains. Impaired substrate phosphorylation as a consequence of γPKC-KO might be corrected by inhibition of protein dephosphorylation. To test this possibility, γPKC-KO mice were treated with the protein phosphatase 2B (calcineurin) inhibitor, FK-506, before ischemia. FK-506 reduced ( P < 0.008) the infarct volume in γPKC-KO mice (n = 7; 24.6 ± 4.6 mm3), but at this dose in this model, had no effect on the infarct volume in WT mice (n = 7; 20.5 ± 10.7 mm3). These results indicate that γPKC plays some neuroprotective role in reversible focal ischemia.