The renal H+-K+-ATPases: physiology, regulation, and structure

Abstract

The H(+)-K(+)-ATPases are ion pumps that use the energy of ATP hydrolysis to transport protons (H(+)) in exchange for potassium ions (K(+)). These enzymes consist of a catalytic alpha-subunit and a regulatory beta-subunit. There are two catalytic subunits present in the kidney, the gastric or HKalpha(1) isoform and the colonic or HKalpha(2) isoform. In this review we discuss new information on the physiological function, regulation, and structure of the renal H(+)-K(+)-ATPases. Evaluation of enzymatic functions along the nephron and collecting duct and studies in HKalpha(1) and HKalpha(2) knockout mice suggest that the H(+)-K(+)-ATPases may function to transport ions other than protons and potassium. These reports and recent studies in mice lacking both HKalpha(1) and HKalpha(2) suggest important roles for the renal H(+)-K(+)-ATPases in acid/base balance as well as potassium and sodium homeostasis. Molecular modeling studies based on the crystal structure of a related enzyme have made it possible to evaluate the structures of HKalpha(1) and HKalpha(2) and provide a means to study the specific cation transport properties of H(+)-K(+)-ATPases. Studies to characterize the cation specificity of these enzymes under different physiological conditions are necessary to fully understand the role of the H(+)-K(+) ATPases in renal physiology.

Fig. 1.

Physiological model of the renal H⁺-K⁺-ATPase. The renal H⁺-K⁺-ATPase secretes H⁺ and recycles K⁺ via apical K⁺ channels during K⁺ repletion and reabsorbs K⁺ via basolateral K⁺ channels during K⁺ depletion.

Fig. 2.

Molecular model of HKα₁. HKα₁ is shown bound to ADP-Mg²⁺. The model is colored from dark blue at the NH₂ terminus to red at the COOH terminus. The A or actuator domain is shown in light blue, the N or nucleotide binding domain in green, and the P or phosphorylation domain in white. The 10 transmembrane helices in the membrane domain are labeled M1–M10. For more detail, see Ref. .