Phospholemman and the Cardiac Sodium Pump

Abstract

See related article, pages 1376–1383 In excitable tissues, the activity of the plasmalemmal sodium/potassium ATPase (Na/K pump) is vital for the maintenance of normal electrical activity and ion gradients. In cardiac muscle, the transsarcolemmal sodium (Na) gradient established by the Na/K activity is essential not only for generating the rapid upstroke of the action potential but also for driving a number of ion exchange and transport processes that are crucial for normal cellular function, excitation contraction coupling, ion homeostasis and the control of cell volume. These Na-dependent membrane transporters include those responsible for the regulation of other ions (such as the sodium calcium exchanger (NCX), Na/H exchanger and Na-HCO3 cotransporter), as well as those involved in the movement of substrates and amino acids.1 By determining the set point for NCX, the Na/K pump controls the predominant mechanism of transmembrane calcium (Ca) flux, and hence indirectly controls intracellular Ca load and myocardial contractility. Interventions that influence either the activity of the Na/K pump, or indirectly the transmembrane sodium gradient, can therefore profoundly affect normal cardiac function. Phospholemman, a type 1 transmembrane protein, is the predominant quantitative site of phosphorylation by protein kinase A (PKA) and protein kinase C (PKC) in cardiac sarcolemma.2 PKA phosphorylates serine 68 and PKC phosphorylates serines 63 and 68 in phospholemman. For a long time following its cloning in 1991,3 the physiological role of phospholemman was unclear. Indeed, writing in this journal in 1998, researchers noted that “As a major target for hormone-stimulated phosphorylation in the heart, the physiological function of phospholemman is likely to be an important one”,4 however they were unable to suggest what this function may be. Various roles have now been proposed: 1) regulation of cell volume; …