We have investigated the roles of protein kinase C (PKC) and mitogen-activated protein kinases (MAPK) in the phosphorylation and activation of cytosolic phospholipase A2 (cPLA2) in endothelin-1- (ET-1) stimulated cat iris sphincter smooth muscle (CISM) cells. We found that in these cells both PKC and p38 MAP kinases play a critical role in ET-1-induced cPLA2 phosphorylation and arachidonic acid (AA) release. Our findings indicate that stimulation of the endothelin-A- (ETA) receptor leads to: (1) activation of Gq protein which stimulates phospholipase C to hydrolyze the polyphosphoinositide PIP2 into diacylglycerol (DAG) and inositol trisphosphate (IP3), the DAG may then activate PKC to phosphorylate and activate cPLA2; and (2) activation of Gi protein, which, through a series of kinases, leads to the stimulation of p38 MAPK and subsequently to phosphorylation and activation of cPLA2. The ability of the activated ETA-receptor, which is coupled to both Gq and Gi proteins, to recruit and activate this complex signal transduction mechanism remains to be clarified.
Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, Georgia, U.S.A.
Address correspondence and reprint requests to Ata A. Abdel-Latif, Department of Biochemistry and Molecular Biology, Medical College of Georgia, 1120 Laney-Walker Blvd, Augusta, GA 30912-2100, U.S.A.
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