Phospholemman (PLM), a member of the FXYD family of regulators of ion transport, is a major sarcolemmal substrate for protein kinases A and C in cardiac and skeletal muscle. In the heart, PLM co-localizes and co-immunoprecipitates with Na+-K+-ATPase, Na+/Ca2+ exchanger, and L-type Ca2+ channel. Functionally, when phosphorylated at serine68, PLM stimulates Na+-K+-ATPase but inhibits Na+/Ca2+ exchanger in cardiac myocytes. In heterologous expression systems, PLM modulates the gating of cardiac L-type Ca2+ channel. Therefore, PLM occupies a key modulatory role in intracellular Na+ and Ca2+ homeostasis and is intimately involved in regulation of excitation-contraction (EC) coupling. Genetic ablation of PLM results in a slight increase in baseline cardiac contractility and prolongation of action potential duration. When hearts are subjected to catecholamine stress, PLM minimizes the risks of arrhythmogenesis by reducing Na+ overload and simultaneously preserves inotropy by inhibiting Na+/Ca2+ exchanger. In heart failure, both expression and phosphorylation state of PLM are altered and may partly account for abnormalities in EC coupling. The unique role of PLM in regulation of Na+-K+-ATPase, Na+/Ca2+ exchanger, and potentially L-type Ca2+ channel in the heart, together with the changes in its expression and phosphorylation in heart failure, make PLM a rational and novel target for development of drugs in our armamentarium against heart failure. © 2010 Wiley Periodicals, Inc.
CITATION STYLE
Cheung, J. Y., Zhang, X. Q., Song, J., Gao, E., Rabinowitz, J. E., Chan, T. O., & Wang, J. F. (2010, August). Phospholemman: A novel cardiac stress protein. Clinical and Translational Science. https://doi.org/10.1111/j.1752-8062.2010.00213.x
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