There are contradictory reports in the literature the possibility that sodium pump units are translocated to the plasma membrane has been highlighted by some workers studying the skeletal muscle Na +-K +-ATPase regulation ( 1, 2, 15– 18, 22, 26, 27, 31, 34, 36) but not observed by others ( 8, 9, 29).Įarly researchers proposed a “translocation hypothesis” to describe the mechanism by which sodium pump units were recruited to the plasma membrane from an intracellular compartment to explain the effect of insulin treatment on ouabain binding to intact frog muscles ( 15).
One mechanism to control the skeletal muscle sodium pump activity is through regulation of Na +-K +-ATPase cell surface abundance. The catalytic α-subunit of Na +-K +-ATPase and PLM are substrates for protein kinases ( 5, 8), and the pump phosphorylation is an important molecular mechanism for the short-term control of its activity in response to hormonal stimulation. The short-term sodium pump regulation includes elevation in the intracellular Na + concentration, increased sensitivity to intracellular Na + concentration, and covalent modification of the Na +-K +-ATPase subunits.
In skeletal muscle, on a long-term basis, thyroid hormone and exercise training lead to an increase in the Na +-K +-ATPase subunit expression and pump activity ( 8). In view of the fundamental importance of Na +-K +-ATPase, its regulation can be achieved by multiple mechanisms, including changes in the intrinsic activity, subcellular distribution, and cellular abundance. Interaction of PLM with sodium pump units modulates activity of Na +-K +-ATPase ( 5). The phospholemman (PLM, FXYD1) forms a complex with α/β-dimers in heart and skeletal muscle. The functional unit of the sodium pump is an α/β-heterodimer. Small amounts of the α 3-subunit are also detected in skeletal muscle ( 8).
Skeletal muscle contains one of the largest pools of Na +-K +-ATPase in the body and expresses α (α 1 and α 2)- and β (β 1 and β 2)-subunits. Skeletal muscle is a primary storage site for dietary K +, and the sodium pump plays a major role in the removal of this ion from the circulation under physiological conditions (i.e., after a meal or exercise bout), thereby preventing the development of hyperkalemia and muscle fatigue ( 28). Thus the maintenance of the intracellular K + concentration is a dynamic and fundamental process involving Na +-K +-ATPase ( 8). Hydrolysis of ATP by Na +-K +-ATPase fuels the coupled transport of K + into the cell and Na + out of the cell. In addition to these general functions, Na +-K +-ATPase promotes membrane repolarization and reuptake of extracellular potassium in excitable cells, including skeletal muscle ( 8). Na +- k +- atpase is a membrane cation pump that is critically involved in the maintenance of intracellular sodium and potassium concentrations and participates in the maintenance of cell volume and electrochemical gradients.
An understanding of the molecular regulation of Na +-K +-ATPase in skeletal muscle will have important clinical implications for the understanding of the development of complications associated with the metabolic syndrome, such as cardiovascular diseases or increased muscle fatigue in diabetic patients. Furthermore, the methodological caveats of major approaches to study the sodium pump translocation in skeletal muscle are discussed. This review summarizes more than 30 years work on the skeletal muscle sodium pump translocation paradigm. Due to the contradictory reports in the literature, the very existence of the translocation of Na +-K +-ATPase to the skeletal muscle cell surface is questionable. The molecular mechanism of this phenomenon is poorly understood. Insulin and muscle contractions stimulate Na +-K +-ATPase activity in skeletal muscle, at least partially via translocation of sodium pump units to the plasma membrane from intracellular stores. The skeletal muscle sodium pump plays a major role in the removal of K + ions from the circulation postprandial, or after a physical activity bout, thereby preventing the development of hyperkalemia and fatigue.