Jgp_201711826 1..5

In virtually all mammalian cells, the traditional roles of the Na/K pump include establishing and maintaining transcellular gradients of Na and K and modulating steady-state gradients of H and Ca. By regulating intracellular Na, [Na]i, the Na/K pump also makes a major contribution to cellular volume control, although some aspects of this modulation of osmolarity are not completely understood (Aronson et al., 2003). Additional roles of the Na/K pump arise from the fact that it is electrogenic: specifically, 3 Na are extruded from the cell for every 2 K that are taken up. The resulting small net outward current is functionally important, as is the dependence of this pump on [Na]i, which can change rapidly and substantially. In this issue of The Journal of General Physiology, Lu and Hilgemann reveal that [Na]i usually remains relatively constant in healthy adult ventricular myocytes and that the decline in Na/K pump current during continuous stimulation is caused by an inactivation mechanism. In many tissues, including epithelia, endothelia, and the atria and conduction system of the heart, the net outward current generated by the Na/K pump operating through a very high input resistance is sufficient to generate a hyperpolarizing influence of ∼5 mV. Moreover, the fundamental physicochemical properties of this ATP-requiring pump are such that it can contribute to the after-potential profile in a variety of nerve cells, especially following periods of intense firing (Rang and Ritchie, 1968; but see Wallén et al., 2007). Similarly, this pump current can result in a significant and quite long-lasting hyperpolarization and change in excitability after bouts of relatively high heart rate in the cardiac conduction system. This has been termed overdrive suppression in these cardiac Purkinje fibers (cf, Bocchi and Vassalle, 2008). A somewhat similar phenomenon may contribute to postrepolarization refractoriness in mammalian atrial myocytes in settings such as paroxysmal fibrillation (cf, Grandi et al., 2011). Many of these Na/K pump–induced (or regulated) phenomena can be explained by the pronounced dependence of the turnover rate of the predominant isoforms of this active transporter on the precise levels of [Na]i (Despa and Bers, 2007; Han et al., 2009). However, it is now known that several critical aspects of this regulation are based on the exact microanatomical localization and tethering of both the α and the β subunits of the predominant Na/K pump isoforms. In some cells, there is evidence that the Na/K pump is colocalized with other Na-dependent antiporters (e.g., Na/Ca exchangers) and that the integral membrane proteins may function interdependently (cf, Clancy et al., 2015).