RECEPTOR-MEDIATED SIGNALING PATHWAYS ACTING THROUGH HYDROLYSIS OF MEMBRANE PHOSPHOLIPIDS IN CARDIOMYOCYTES

The aim is to summarize briefly the evidence for the existence and pos sible functions of receptor-mediated activity of phospholipases C and D in the myocardium. Muscarinic, alpha1-adrenergic, angiotensin II, en dothelin-1, thrombin, adenine nucleotide and opioid peptide receptors are all linked through GTP-binding proteins to phospholipase C which h ydrolyses phosphatidylinositol 4,5-bisphosphate (PIP2) in the myocardi um. Events that are not linked to receptors, such as mechanical loadin g (stretching) of cardiomyocytes, can also activate phospholipase C Th e high capacity for resynthesis of PIP2 maintains the pool of PIP2, ev en during maximal activation of phospholipase C. Activation of phospho lipase C by endothelin-1, alpha1-adrenoceptor and angiotensin II, is s ubject to different rates of homologous desensitization. Protein kinas e C is probably not involved in the desensitization of the response to endothelin-1. One of the products of the hydrolysis of PIP2, inositol 1,4,5-trisphosphate (IP), releases Ca2+ from the sarcoplasmic reticul um. This intracellular response seems to be causally related to positi ve inotropy. The phosphorylated product of IP3, inositol 1,3,4,5-tetra kisphosphate (IP4), is believed to play a role in the handling of intr acellular Ca2+, as well as in the inotropic response; however, its for mation is controversial. At present the oscillations in the level of i ntracellular Ca2+ underlying, for example, the positive inotropy induc ed by alpha1-adrenoceptors or endothelin are not clearly identified. T he other product of phospholipase C, 1,2-diacylglycerol, activates Ca2 +-dependent protein kinase C and potentially controls a wide array of cellular functions such as ion transport, myofibrillar Ca2+ sensitivit y, ''cross-talk'' between phospholipases C and D, gene expression, pro tein synthesis and hypertrophic cell growth. Alterations in the fatty acid composition, particularly the polyunsaturated fatty acids, modify the phosphoinositide response induced by hormones. Cultured cardiomyo cytes, incubated in sera containing the fatty acids 18:2n-6 or 20:5n-3 , but not 18:0 and 18:1n-9, show a decrease in the phospholipase C res ponses mediated by alpha1-adrenoceptors. The fatty acid composition of myocardial phosphatidyl inositol 4-monophosphate (PIP) and PIP2 diffe rs from that of phosphatidylinositol, which indicates that phosphatidy linositol kinases have a certain substrate specificity or have access to localized phosphatidylinositol molecules. The estimation of the lev el of stimulated 1,2-diacylglycerol is complicated by the contribution of the activity of receptor-mediated phospholipase D. The identificat ion of the molecular species of 1,2-diacylglycerol is crucial in estab lishing the roles and the sources of 1,2-diacylglycerol. The fatty aci ds covalently bound in the membrane phospholipids may also influence p hospholipases C and D. There may be a complementary role of phospholip ases C and D in maintaining the levels of 1,2-diacylglycerol for the r egulation of gene expression and hypertrophic cell growth induced by a lpha1-adrenergic agonists, endothelin-I, angiotensin II and mechanical stretch.