title: 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 gamma isoform of protein kinase C (gammaPKC) in reversible focal ischemia was examined using mutant mice in which the gene for gammaPKC was knocked-out (gammaPKC-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 gammaPKC-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 gammaPKC-KO might be corrected by inhibition of protein dephosphorylation. To test this possibility, gammaPKC-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 gammaPKC-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 gammaPKC plays some neuroprotective role in reversible focal ischemia.
authors.affiliation: Department of Neurology, The University of Texas--Houston, Medical School, 77030, USA.
authors.forename: J
authors.initials: J
authors.lastname: Aronowski
authors.forename: J C
authors.initials: JC
authors.lastname: Grotta
authors.forename: R
authors.initials: R
authors.lastname: Strong
authors.forename: M N
authors.initials: MN
authors.lastname: Waxham
mesh_terms: D000818:Animals; D001921:Brain / Q000201:enzymology*; D002545:Brain Ischemia / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D019703:Calcineurin / Q000378:metabolism*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000032:analysis / Q000378:metabolism; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D020022:Genetic Predisposition to Disease; D007166:Immunosuppressive Agents / Q000494:pharmacology; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D007527:Isoenzymes / Q000032:analysis / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation; D011493:Protein Kinase C / Q000032:analysis / Q000235:genetics* / Q000378:metabolism*; D016559:Tacrolimus / Q000494:pharmacology
chemical_list: D007166:Immunosuppressive Agents; D007527:Isoenzymes; C087857:protein kinase C gamma; D011493:Protein Kinase C; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019703:Calcineurin; D016559:Tacrolimus