Phospholemman: a novel cardiac stress protein.
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(+)/Ca(2+) exchanger, and L-type Ca(2+) channel. Functionally, when phosphorylated at serine(68), PLM stimulates Na(+)-K(+)-ATPase but inhibits Na(+)/Ca(2+) exchanger in cardiac myocytes. In heterologous expression systems, PLM modulates the gating of cardiac L-type Ca(2+) channel. Therefore, PLM occupies a key modulatory role in intracellular Na(+) and Ca(2+) 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(+)/Ca(2+) 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(+)/Ca(2+) exchanger, and potentially L-type Ca(2+) 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. Clin Trans Sci 2010; Volume 3: 189-196.
Cheung
Joseph Y
JY
Department of Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania, USA. joseph.cheung@jefferson.edu
Zhang
Xue-Qian
XQ
Song
Jianliang
J
Gao
Erhe
E
Rabinowitz
Joseph E
JE
Chan
Tung O
TO
Wang
Jufang
J
D000818:Animals; D006321:Heart / Q000502:physiology*; D006333:Heart Failure / Q000503:physiopathology*; D006801:Humans; D008565:Membrane Proteins / Q000502:physiology*; D010750:Phosphoproteins / Q000502:physiology*; D012508:Sarcolemma / Q000502:physiology*; D013312:Stress, Physiological / Q000502:physiology*
D008565:Membrane Proteins; D010750:Phosphoproteins; C069141:phospholemman