Under resting conditions, Na+ slowly leaks into the cells and K+ leaks out of the cell because of electrochemical driving forces. Whenever an action potential is generated, additional Na+ enters the cell and K+ leaves the cell. While the number of ions moving across the sarcolemmal membrane in a single action potential is very small relative to the total number of ions, after many action potentials are generated, there would occur a significant change in the extracellular and intracellular concentration of these ions. To maintain the concentration gradients for Na+ and K+, it is necessary to transport Na+ out of the cell and K+ back into the cell. There is located on the sarcolemma an energy dependent (ATP-dependent) pump system Na+/K+-ATPase) that that performs this function. This pump is essential for the maintenance of Na+ and K+ concentrations across the membrane. If this pump stops working (as occurs under anoxic conditions when ATP is lost), or if the activity of the pump is inhibited (as occurs with cardiac glycosides such as digitalis), Na+ accumulates within the cell and intracellular K+ falls. This causes depolarization of the resting membrane potential. Furthermore, it is important to note that this pump is electrogenic in nature because it extrudes 3 Na+ for every 2 K+ entering the cell. By pumping more positive changes out of the cell than into the cell, the pump activity creates a negative potential within the cell. This potential may be up to -10 mV. Inhibition of this pump, therefore, causes depolarization resulting not only from changes in Na+ and K+ concentration gradients, but also from the loss of an electrogenic component of the membrane potential. Small increases in external K+ can stimulate the pump activity and thereby cause hyperpolarization, which is the opposite of what would be predicted by the Nernst equation for a small increase in external K+.
Because Ca++ enters the cell during action potentials, it is necessary to maintain its concentrations gradients. This is accomplished by calcium pumps and exchangers on the membrane.