H⁺,K⁺-ATPase

Abstract

The H⁺,K⁺-ATPases comprise a group of integral membrane proteins that belong to the X⁺,K⁺-ATPase subfamily of P-type cation-transporting ATPases. Although these H⁺,K⁺-ATPase isoforms share approximately 60-70% amino acid identity, they exhibit discrete kinetic and pharmacological properties when expressed in heterologous systems. HKα₂ has been categorized by its insensitivity to Sch-28080, an inhibitor of the gastric H⁺,K⁺-ATPase, and partial sensitivity to ouabain, an inhibitor of the Na⁺,K⁺-ATPase. This functional profile contrasts with the pharmacological sensitivities ascribed to HKα₂ in transport studies in rat isolated medullary collecting ducts perfused in vitro and in mouse medullary collecting duct cell lines. HKα₂ mRNA and protein abundance appears to be both tissue and site-specifically upregulated in response to chronic hypokalemia. This regulatory response has been localized to the outer and inner medulla. To reconcile these expressed sensitivities to those reported in vitro in isolated tubules and cells in culture, it would be necessary to invoke modification of the pharmacologic insensitivity of the colonic H⁺,K⁺-ATPase to Sch-28080. Although a ‘unique’ β-subunit has been reported recently, this β-subunit (β_c) is identical at the amino acid level to the recently cloned β₃-Na⁺,K⁺-ATPase. Moreover, while HKα₂ can assemble indiscriminately with any X⁺,K⁺-ATPase β-subunit, HKα₂ has been reported to assemble stably with β₁-Na⁺,K⁺-ATPase in the renal medulla and in the distal colon. It remains conceivable that subunit assembly could be tissue specific and might respond to different physiological and pathophysiological stimuli. Futhermore, recent studies have suggested that the H⁺,K⁺-ATPase is both Na⁺-dependent and localized to the apical membrane in the distal colon. Therefore, future studies will need to resolve these discrepancies by determining if a unique, yet undiscovered H⁺,K⁺-ATPase isoform exists in kidney, or if post-translational modifications of the α- and/or β-subunits could account for these functional diversities.