implications of proton import during Na + / K + exchange by native Na + / K + - ATPase pumps

Na/K-ATPase pumps expel three Na ions and import two K ions for each ATP hydrolyzed, generating the ion gradients across the membrane that are essential to the life of all animal cells. Each transport cycle comprises a sequence of conformational transitions that permit extracellular K ions to access the binding sites in phosphorylated pumps (E2P conformations; Fig. 1) and cytoplasmic Na ions to access the sites after dephosphorylation (E1 conformations; Fig. 1). Binding of the third Na ion triggers autophosphorylation, and binding of the second K ion prompts auto-dephosphorylation. This coupling of alternating ion access to ATP hydrolysis ensures forward, energetically uphill, progress of the Na/K transport cycle. The larger pumped Na efflux than K influx constitutes outward current, a direction tending to make the membrane potential more negative. However, because each step in the cycle is reversible (Fig. 1), if the normally transported intracellular Na and extracellular K are both scarce, the cycle can run backward, thus synthesizing ATP (Garrahan and Glynn, 1967b) and generating inward, depolarizing current (Bahinski et al., 1988; De Weer et al., 2001).