Molecular Regulation and Physiology of the H⁺,K⁺-ATPases in Kidney

Two H⁺, K⁺-adenosine triphosphatase (ATPase) proteins participate in K⁺ absorption and H⁺ secretion in the renal medulla. Both the gastric (HKα₁) and colonic (HKα₂) H⁺,K⁺-ATPases have been localized and characterized by a number of techniques, and are known to be highly regulated in response to acid-base and electrolyte disturbances. Both ATPases are dimers of composition α/β that localize to the apical membrane and both interact with the tetraspanin protein CD63. Although CD63 interacts with the carboxy-terminus of the α-subunit of the colonic H⁺,K⁺-ATPase, it interacts with the β-subunit of the gastric H⁺,K⁺-ATPase. Pharmacologically, both ATPases are distinct; for example, the gastric H⁺,K⁺-ATPase is inhibited by Sch-28080, but the colonic H⁺,K⁺-ATPase is inhibited by ouabain (a classic inhibitor of the Na⁺-pump) and is completely insensitive to Sch-28080. The α-subunit of the colonic H⁺,K⁺-ATPase is the only subunit of the X⁺,K⁺-ATPase superfamily that has 3 different splice variants that emerge by deletion or elongation of the amino-terminus. The messenger RNA and protein of one of these splice variants (HKα_2C) is specifically up-regulated in newborn rats and becomes undetectable in adult rats. Therefore, HKα₂, in addition to its role in potassium and acid-base homeostasis, appears to play a significant role in early growth and development. Finally, because chronic hypokalemia appears to be the most potent stimulus for upregulation of HKα₂, we propose that the HKα₂ participates importantly in the maintenance of chronic metabolic alkalosis.

Keywords: colonic H⁺,K⁺-ATPase, gastric H⁺,K⁺-ATPase, chronic hypokalemia, metabolic alkalosis, distal renal tubular acidosis, metabolic acidosis, renal medulla, type III K⁺-ATPase