Receptor-mediated signalling pathways acting through hydrolysis of membrane phospholipids in cardiomyocytes

Abstract

The aim is to summarize briefly the evidence for the existence and possible functions of receptor-mediated activity of phospholipases C and D in the myocardium. Muscarinic, alpha 1-adrenergic, angiotensin II, endothelin-1, thrombin, adenine nucleotide and opioid peptide receptors are all linked through GTP-binding proteins to phospholipase C which hydrolyses phosphatidylinositol 4,5-bisphosphate (PIP2) in the myocardium. Events that are not linked to receptors, such as mechanical loading (stretching) of cardiomyocytes, can also activate phospholipase C. The high capacity for resynthesis of PIP2 maintains the pool of PIP2, even during maximal activation of phospholipase C. Activation of phospholipase C by endothelin-1, alpha 1-adrenoceptor and angiotensin II, is subject to different rates of homologous desensitization. Protein kinase 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 (IP3), releases Ca2+ from the sarcoplasmic reticulum. This intracellular response seems to be causally related to positive inotropy. The phosphorylated product of IP3, inositol 1,3,4,5-tetrakisphosphate (IP4), is believed to play a role in the handling of intracellular Ca2+, as well as in the inotropic response; however, its formation is controversial. At present the oscillations in the level of intracellular Ca2+ underlying, for example, the positive inotropy induced by alpha 1-adrenoceptors or endothelin are not clearly identified. The other product of phospholipase C, 1,2-diacylglycerol, activates Ca(2+)-dependent protein kinase C and potentially controls a wide array of cellular functions such as ion transport, myofibrillar Ca2+ sensitivity, "cross-talk" between phospholipases C and D, gene expression, protein synthesis and hypertrophic cell growth. Alterations in the fatty acid composition, particularly the polyunsaturated fatty acids, modify the phosphoinositide response induced by hormones. Cultured cardiomyocytes, 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 responses mediated by alpha 1-adrenoceptors. The fatty acid composition of myocardial phosphatidyl inositol 4-monophosphate (PIP) and PIP2 differs from that of phosphatidylinositol, which indicates that phosphatidylinositol kinases have a certain substrate specificity or have access to localized phosphatidylinositol molecules. The estimation of the level of stimulated 1,2-diacylglycerol is complicated by the contribution of the activity of receptor-mediated phospholipase D. The identification of the molecular species of 1,2-diacylglycerol is crucial in establishing the roles and the sources of 1,2-diacylglycerol. The fatty acids covalently bound in the membrane phospholipids may also influence phospholipases C and D.(ABSTRACT TRUNCATED AT 400 WORDS)