FIGURE 18 Cellular models of Na+-coupled co-transport (A) and countertransport (B).

FIGURE 18 Cellular models of Na+-coupled co-transport (A) and countertransport (B).

gradient in turn provides the energy for many Na+-coupled secondary active co- and countertransport processes. (The terms symport and antiport are sometimes employed to describe co- and countertransport processes, respectively.)


All biologic membranes possess an assortment of pathways that permit the diffusion of water-soluble solutes, mainly ions (i.e., ''leak'' pathways) and carriers. These components, acting in concert, are responsible for the uptake of essential nutrients and building blocks by cells, the extrusion of the end products of some metabolic processes from cells, the maintenance of a near-constant (time-independent, or steady-state) intra-cellular composition and volume, and the establishment of transmembrane electrical potential differences.

In this section, we illustrate the interactions among carrier-mediated pumps and channel-mediated leaks by considering the processes responsible for the maintenance of the high intracellular concentrations of K+ and the low intracellular concentrations of Na+ characteristic of virtually all cells in higher animals. We have chosen this system as a prototype for other pump-leak systems, not only because of its ubiquity but also because of the essential role it plays in energizing a wide variety of other secondary active pumps, in essential bioelectric processes, and in the maintenance of cell volume.

The fact that cells from higher animals contain a high K+ concentration and a low Na+ concentration compared to the extracellular fluid was established in the 20th century shortly after analytic techniques for measuring these elements were developed. In the period from 1940 to 1952, Steinbach demonstrated that, when frog striated muscle is incubated in a K+-free solution, the cells simultaneously lose K+ and gain Na+, a process that could be reversed by the addition of K+ to the extracellular fluid. In the ensuing decade, abundant evidence accrued for the presence of carrier-mediated processes in biologic membranes that bring about the extrusion of Na+ from cells obligatorily coupled to the uptake of K+ by cells that are directly dependent on ATP; this mechanism is referred to as the (Na+-K+) pump. Furthermore, the stoichio-metry of this process is that three Na+ ions are extruded in exchange for two K+ ions for each ATP consumed.

In 1958, Skou identified an ATPase in a homogenate of crab nerve tissue whose hydrolytic activity was dependent on the simultaneous presence of Na+ and K+ in the assay medium. In addition, ATPase activity in the presence of Na+ and K+ could be inhibited by glycosides derived from the wild flower Digitalis purpurea (foxglove) (e.g., ouabain), known since 1953 to be potent inhibitors of the carrier-mediated transport mechanisms responsible for the active extrusion of Na+ from cells coupled to the active uptake of K+ (i.e., the [Na+-K+] pump).

During the past five decades, innumerable studies have incontrovertibly established that the (Na+-K+) pump and the (Na+, K+)-ATPase are one and the same. Furthermore, this (pump) ATPase has been isolated, purified, and reconstituted in active form in artificial lipid vesicles. It is now clear that it consists of two subunits: a and p. The a subunit has a molecular weight of approximately 100,000 Da, is minimally, if at all, glycosylated, and is the subunit that possesses the ATPase (catalytic) activity as well as the ability to bind Na+, K+, and digitalis glycosides such as ouabain. The p subunit has a molecular weight of about 55,000 Da, of which approximately two-thirds can be attributed to polypeptides and one-third to glycosylation; the P subunit has no ATPase activity, and its function may be to direct and insert (or anchor) the a subunit to the plasma membrane. Coassociation of the a and p subunits is necessary for pump activity.

The results of studies on the biochemical behavior of this ATPase are consistent with the very simplified sequence of events illustrated in Fig. 19. In the presence of intracellular Na+ and Mg2+, the (Na+, K+)-ATPase (E) is capable of hydrolyzing ATP to form the high-energy intermediate (E-P), which is capable of binding Na+. The interaction between (E-P) and extracellular K+ results in its hydrolysis, thereby reforming E and completing the cycle. Thus, the recycling of this enzymepump from the E stage through (several) high-energy outside


FIGURE 19 Simplified schematic of the partial reactions involved in coupled Na+ - K+ transport by (Na+, K+)-ATPase.


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