Fishing for holes in transporters: How protons breach the Na/K pump security gates

437 C o m m e n t a r y In this issue of the JGP, Vedovato and Gadsby show us that the native Na/K pumps of Xenopus laevis oocytes are even more complex machines than we realized. Readers of the JGP will be aware that Na/K pumps extrude three Na ions and import two K ions into cells with each pump cycle at the expense of one ATP being hydrolyzed to ADP. It now turns out that Na/K pumps develop a selective passageway for protons to cross the membrane during this normal cycle, even in the presence of physiological ion concentrations on both sides of the membrane. The proton-conducting pathway develops transiently when the pump enters into the specific state that releases the first of the three Na ions into the extracellular space and thereby generates electrical current. This Na-binding site, which is special because it cannot be occupied by a K ion, is called the " Na-selective binding site III. " When site III is not occupied by Na, protons can enter the pump's binding sites from the extracellular space and traverse site III to the cytoplasm. When the extracellular pH is lowered and membrane potential is negative, the proton flux through site III can be about as large as the Na and K fluxes generated by pump activity in oocytes. Therewith, the Na/K pump joins a list of hybrid membrane proteins that, on the one hand, engage in coupled transport via an alternating access mechanism, and, on the other hand, develop channel-like ion conductances in a state-dependent manner. This unexpected development raises new questions about the cellular function of Na/K pumps, especially in settings in which the extracellular or cytoplasmic space, or both, become acidified.