H+,K+-atpase

The H+,K+-ATPases comprise a group of integral membrane proteins that belon g to the X+,K+-ATPase subfamily of P-type cation-transporting ATPases. Alth ough these H+,K+-ATPase isoforms share approximately 60-70% amino acid iden tity, they exhibit discrete kinetic and pharmacological properties when exp ressed in heterologous systems. HK alpha(2) has been categorized by its ins ensitivity to Sch-28080, an inhibitor of the gastric H+,K+-ATPase, and part ial sensitivity to ouabain, an inhibitor of the Na+,K+-ATPase. This functio nal profile contrasts with the pharmacological sensitivities ascribed to HK alpha(2) in transport studies in rat isolated medullary collecting ducts p erfused in vitro and in mouse medullary collecting duct cell lines. HK alph a(2) mRNA and protein abundance appears to be both tissue and site-specific ally upregulated in response to chronic hypokalemia. This regulatory respon se has been localized to the outer and inner medulla, To reconcile these ex pressed sensitivities to those reported in vitro in isolated tubules and ce lls in culture, it would be necessary to invoke modification of the pharmac ologic insensitivity of the colonic H+,K+-ATPase to Sch-28080. Although a ' unique' beta-subunit has been reported recently, this beta-subunit (beta(c) ) is identical at the amino acid level to the recently cloned beta(3)-Na+,K +-ATPase, Moreover, while HK alpha(2) can assemble indiscriminately with an y X+,K+-ATPase beta-subunit, HK alpha(2) has been reported to assemble stab ly with beta(1)- 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, F uthermore, recent studies have suggested that the H+,K+-ATPase is both Na+- dependent and localized to the apical membrane in the distal colon. Therefo re, 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 alpha- and/or beta-subunits could a ccount for these functional diversities. Curr Opin Nephrol Hypertens 8:597- 602. (C) 1999 Lippincott Williams & Wilkins.