Contrasting functional and regulatory profiles of the renal H+,K+-ATPases.
The H+,K+-ATPases belong to the X+,K+-ATPase subfamily of P-type cation-transporting ATPases. While these H+,K+-ATPase isoforms share approximately 60%-70% amino acid identity, they exhibit discrete kinetic and pharmacological properties. The colonic alpha isoform (HKalpha2) is insensitive to Sch-28080, an inhibitor of the gastric H+,K+-ATPase, and is sensitive to high concentrations of ouabain. This profile contrasts with the sensitivities attributed to HKalpha2 in transport studies. HKalpha2 mRNA and protein abundance appear to be both site-specifically upregulated in response to chronic hypokalemia, and have been localized to the outer and inner medulla. To reconcile expressed sensitivities with those reported in vitro in isolated tubules and cells in culture, it requires transformation of the expressed insensitivity of the colonic H+,K+-ATPase to Sch-28080. Although a "unique" beta subunit has been reported recently, this beta subunit ("betac"), is identical at the amino acid level to the recently cloned beta3-Na+,K+-ATPase. Moreover, while HKalpha2 can assemble indiscriminately with any X+,K+-ATPase beta subunit, HKalpha2 has been reported to assemble stably with beta1-Na+,K+-ATPase in the renal medulla and in the distal colon. It is conceivable that subunit assembly could be tissue-specific and might respond to different physiological and pathophysiological stimuli. Recent studies have suggested that the H+,K+-ATPase is both Na+-dependent and localized to the apical membrane in the distal colon. Future studies will be needed to resolve these discrepancies by determining if a unique, yet undiscovered H+,K+-ATPase isoform exists in the kidney, or if posttranslational modifications of the alpha and/or beta-subunits could account for these functional diversities.
Codina
J
J
Department of Internal Medicine, The University of Texas, Houston Medical School, 77030, USA.
Wall
S M
SM
DuBose
T D
TD
D000222:Adaptation, Physiological; D000818:Animals; D017506:H(+)-K(+)-Exchanging ATPase / Q000378:metabolism*; D006801:Humans; D007008:Hypokalemia / Q000378:metabolism*; D007679:Kidney Medulla / Q000201:enzymology*; D008565:Membrane Proteins / Q000378:metabolism; D012680:Sensitivity and Specificity
D008565:Membrane Proteins; D017506:H(+)-K(+)-Exchanging ATPase