REGULATION AND FUNCTIONAL-SIGNIFICANCE OF PHOSPHOLIPASE-D IN MYOCARDIUM

There is now clear evidence that receptor-dependent phospholipase D is present in myocardium. This novel signal transduction pathway provide s an alternative source of 1,2-diacylglycerol, which activates isoform s of protein kinase C. The members of the protein kinase C family resp ond differently to various combinations of Ca2+, phosphatidylserine, m olecular species of 1,2-diacylglycerol and other membrane phospholipid metabolites including free fatty acids. Protein kinase C isozymes are responsible for phosphorylation of specific cardiac substrate protein s that may be involved in regulation of cardiac contractility, hypertr ophic growth, gene expression, ischemic preconditioning and electrophy siological changes. The initial product of phospholipase D, phosphatid ic acid, may also have a second messenger role. As in other tissues, t he question how the activity of phospholipase D is controlled by agoni sts in myocardium is controversial. Agonists, such as endothelin-l, at rial natriuretic factor and angiotensin II that are shown to activate phospholipase D, also potently stimulate phospholipase C-P in myocardi um. PMA stimulation of protein kinase C inactivates phospholipase C an d strongly activates phospholipase D and this is probably a major mech anism by which agonists that promote phosphatidyl-4,5-bisphosphate hyd rolysis secondary activate phosphatidylcholine-hydrolysis. On the othe r hand, one group has postulated that formation of phosphatidic acid s econdary activates phosphatidyl-4,5-bisphosphate hydrolysis in cardiom yocytes. Whether GTP-binding proteins directly control phospholipase D is not clearly established in myocardium. Phospholipase D activation may also be mediated by an increase in cytosolic free Ca2+ or by tyros ine-phosphorylation.