Phospholipid N-methylation as a Signal Transduction Mechanism in Normal and Failing Hearts

The phospholipid N-methylation pathway comprises of three successive N-terminal methylations of phosphatidylethanolamine where S-adenosyl-L-methionine acts as the physiological donor. Under optimal conditions in cardiac membranes, the catalytic sites I, II, and III of methyltransferase have been identified which are responsible for the synthesis of the major product, phosphatidyl-N-monomethylethanolamine, phosphatidyl-N,N-dimethylethanolamine, and phosphatidylcholine, respectively. The characterization of the phosphatidylethanolamineN-methyltransferase system has shown that each of the catalytic sites exhibits different biochemical properties. The phospholipid N-methylation pathway has also been observed to regulate heart function by inducing localized structural, compositional, and functional changes in cardiac membranes under different pathological conditions of chronic nature. This review deals with the phosphatidylethanolamine N-methylation–mediated signal transduction mechanism involving modification of the Ca2+-transporting activities of the sarcolemmal and sarcoplasmic reticular membranes of the cardiomyocyte. In this regard, special attention is given to the status of this pathway and its relevance for the functioning of membrane-related Ca2+-transport systems in heart dysfunction due to different cardiac pathologies, such as diabetes-induced cardiomyopathy, catecholamine-induced cardiomyopathy, genetically linked cardiomyopathy, and adriamycin-induced cardiomyopathy. In addition, changes in phosphatidylethanolamine N-methylation in heart dysfunction due to cardiac hypertrophy, Ca2+-paradox hearts, and ischemic-reperfused hearts have been described. It is suggested that an increase in phosphatidylethanolamine N-methylation activity may play an adaptive role, whereas a depression may contribute towards contractile dysfunction. This revised version was published online in July 2006 with corrections to the Cover Date.