The gastric H, K-ATPase system also functions as the Na, K-ATPase and Ca-ATPase in altered states

Tushar Ray

doi:10.12688/f1000research.2-165.v1

Abstract

This article offers an explanation for the apparent lack of Na, K-ATPase activity in parietal cells although ouabain has been known to inhibit gastric acid secretion since 1962. The gastric H, K-ATPase (proton-pump) seems to be acting in altered states, thus behaving like a Na, K-ATPase (Na-pump) and/or Ca-ATPase (Ca-pump) depending on cellular needs. This conclusion is based on the following findings. First, parietal cell fractions do not exhibit Na, K-ATPase activity at pH 7.0 but do at pH 8.5. Second, the apical plasma membrane (APM) fraction exhibits a (Ca or Mg)-ATPase activity with negligible H, K-ATPase activity. However, when assayed with Mg alone in presence of the 80 k Da cytosolic proton-pump activator (HAF), the APM fraction reveals remarkably high H, K-ATPase activity, suggesting the observed low affinity of Ca (or Mg)-ATPase is an altered state of the latter. Third, calcium (between 1 and 4 µM) shows both stimulation and inhibition of the HAF-stimulated H, K-ATPase depending on its concentration, revealing a close interaction between the proton-pump activator and local Ca concentration in gastric H, K-ATPase function. Such interactions suggest that Ca is acting as a terminal member of the intracellular signaling system for the HAF-regulated proton-pump. It appears that during resting state, the HAF-associated H, K-ATPase remains inhibited by Ca (>1 µM) and, prior to resumption of acid secretion the gastric H, K-ATPase acts temporarily as a Ca-pump for removing excess Ca from its immediate environment. This conclusion is consistent with the recent reports of immunochemical co-localization of the gastric H, K-ATPase and Ca-ATPase by superimposition in parietal cells, and a transitory efflux of Ca immediately preceding the onset of acid secretion. These new perspectives on proton-pump function would open new avenues for a fuller understanding of the intracellular regulation of the ubiquitous Na-pump.

Highlights

At the peak of acid secretion gastric juice has a pH close to 0.1 compared to blood. Based on this the parietal cells transport protons against a concentration gradient of over a million fold mediated by the gastric H, K-ATPase system
Major developments in the field occurred following the single topology scheme for the Na, K-ATPase reaction proposed by Post and Albers in the early 1960s, which was subsequently extended to the H, K-ATPase system
Studies with phospholipase[14] and mild ethanol treatment[15,16] revealed that the HAF dimer is rather loosely associated with the membrane-bound H, K-ATPase system, and the phospholipid is in some way involved in this process. Such a loose association of the HAF with the secretory membrane of the parietal cell became clear when we studied the effects of HAF on the isolated apical (APM) and tubulovesicular (TV) membranes from rabbit gastric glands and observed characteristic differential effects[17]

Summary

Introduction

At the peak of acid secretion gastric juice has a pH close to 0.1 compared to blood (pH, 7.4). The pure TV membranes exhibited a very low or negligible basal activity, but the very high K-stimulated ATPase activity only required a small amount of stimulation (only about 60%) by the HAF17 These studies revealed that the HAF is loosely bound to the APM and plays an essential role in gastric acid secretion supporting our earlier conclusion. It is obvious that an appropriate level of Ca (below 1 μM) facilitates a direct contact of the HAF with the catalytic surface of the enzyme while a higher concentration of Ca interferes presumably by building a critical barrier on the enzyme/HAF interface, preventing a direct interaction with the HAF Under this condition, the apical membrane-located H, K-ATPase system would be acting as a provisional device for pumping out calcium prior to the onset of acid secretion[17,18]. Such intimate interplay between Ca and HAF would help the parietal cells to conserve energy by preventing

Conclusion

Davenport HW

Findings

Ray TK