[Molecular and functional diversity of NA,K-ATPase and renal H,K-ATPases]

Potassium homeostasis is a determinant factor in the maintenance of many vital functions. Cell excitability, for instance, in striate and cardiac muscle, as well as in neurons, is dependent upon the ratio of potassium levels on either side of the plasmic membrane. Acute or chronic mechanisms of adjustment to disorders of bodily potassium balance exist in muscle, the kidney and distal colon. Na+K(+)-ATPase is involved in potassium transfers between the extracellular and intracellular compartments, in particular in muscle, enabling the creation of an appropriate trans-membrane K gradient. Na+K(+)-ATPase also participates in the development and maintenance of a transmembrane potassium electrochemical gradient necessary for potassium secretion processes in the kidney or distal colon. Colonic and renal H+K(+)-ATPases, so-called non-gastric H+K(+)-ATPases, are involved in the absorption of potassium from the gastrointestinal lumen or urinary fluid. They have an important role to play during chronic disorders, e.g. chronic bodily potassium depletion. Renal H+K(+)-ATPases and Na+K-ATPase are P-ATPases, consisting of a heterodimer of two alpha and beta sub-units. Several isoforms have been identified, on both a molecular and functional basis, for both the alpha and beta sub-unit. These two ATPases form part of the Na+K(+)-ATPase/H+K(+)-ATPase gene group. These pumps share many structural and functional similarities, but also particular functional specificities, probably involved in separate physiological roles for each isoform. Four isoforms of the alpha sub-unit and two isoforms of the beta sub-unit of Na+K(+)-ATPase have been identified. Sensitivity to ouabain, a Na+K(+)-ATPase inhibitor, differs according to the alpha isoform present in the alpha beta heterodimer. It is also involved in the catalytic cycle and influences pump potassium affinity. Several H+K(+)-ATPases have been identified from a molecular standpoint: gastric H+K(+)-ATPases and a colonic H+K(+)-ATPase found more recently. Recent studies have shown that both these H+K(+)-ATPases exist in the kidney. "Gastric" H+K(+)-ATPase is active along the entire length of the collecting tubule, in rats exposed to a normal potassium intake. In contrast, colonic H+K(+)-ATPase is active only in the cells of the external medullary collecting duct. This activity cannot be detected in animals on a standard diet but is very powerfully induced by potassium depletion. Activity is independent of steroidal status and of aldosterone in particular. Identification of a molecular homologue in the bladder of the amphibian Bufo marinus (the functional equivalent of the cortical collecting duct of mammals) has enabled the development of functional tests by activity in the oocyte of Xenopus laevis. The use this functional approach has shown that bladder H+K(+)-ATPase, just like that of rat distal colon, is sensitive to ouabain, an inhibitor considered up to now to be specific to Na+K(+)-ATPase. In contrast, this H+K(+)-ATPase shows little or no sensitivity to Sch 28080, a "classical" gastric H+K(+)-ATPase inhibitor. It thus seems that two H+K(+)-ATPases, different from a molecular standpoint, exist in rat kidney. They differ in terms of their cellular activity, regulation and functional properties. This is strongly suggestive of a specific role of each of them in potassium homeostasis, a role which remains to be defined. The use of genetically modified animals, as well as of physiological studies more focussed on this question, should provide clarification of the specific functional role of each isoform of the alpha and beta sub-units of renal H+K(+)-ATPases and Na+K(+)-ATPase. Extrapolation of these results to human pathophysiology is quite another challenge. Control of Na+K(+)-ATPase activity by endoouabain and its effects on cardiovascular pathophysiology must be identified. An H+K(+)-ATPase with molecular and functional characteristics similar to those of amphibian bladder and rat colon H+K(+)-A