Phospholemman: its role in normal cardiac physiology and potential as a druggable target in disease.

Phospholemman (PLM) is a member of the FXYD ('fix-it') family of proteins many of which have now been identified as tissue-specific regulators of the Na/K ATPase. PLM (FXYD1) is the primary sarcolemmal substrate for PKC and PKA in the heart. We have recently identified PLM as a novel accessory protein that forms part of the cardiac Na/K ATPase pump complex. PLM regulates Na/K pump activity in a way analogous to the regulation of SERCA by phospholamban-that is un-phosphorylated PLM exerts a tonic inhibition on the Na/K pump, while phosphorylated PLM relieves this inhibition and stimulates pump activity. This process is likely to be fundamentally important in the normal physiological regulation of the cell particularly at high heart rates and, as briefly reviewed in this article, is also likely to offer novel therapeutic targets for the treatment of diseases such as cardiac hypertrophy and heart failure.