Biochemical mechanisms of acid secretion by gastric parietal cells

Academic Article


  • Knowledge of the biochemical basis of gastric acid secretion has progressed dramatically in the last 25-30 years. Today, only the overall physiological consequences can be described by the carbonic anhydrase reaction; the biochemical details are much more complicated and remain incompletely resolved. The controversy between a redox, directly substrate linked, mechanism and an ATPase mechanism seems largely resolved. The marked redox changes in gastric mitochondria have been ascribed to anoxia of in vitro mucosae since isolated cells and gastric glands do not demonstrate these transitions. These findings are also in accord with stable content of NAD/NADH and NADP/NADPH in resting and secreting in vivo canine gastric mucosa. The subsequent finding that acid secretion by permeabilized gastric glands is ATP dependent even when substrate and mitochondrial metabolism is blocked by cyanide is convincing support for a proton-ATPase mechanism. Techniques for isolation and purification of mucosal membranes have yielded considerable progress in defining the enzymatic mechanism of acid secretion. Electron microscopy has demonstrated the unique system of intra-cellular membranes of the parietal cell. Several investigators have isolated these membranes by centrifugation and free-flow electrophoresis of mucosal cell membranes. In the purest preparations the membranes appear to contain only a few peptides, most of which seem to be components of the gastric ATPase. SDS polyacrylamide electrophoresis of these purified membranes has demonstrated a 100K dalton peptide that is phosphorylated in the presence of ATP. Radiation target analysis suggests that the native ATPase exists as a trimer of the 100K dalton peptide. A variety of techniques have demonstrated that spherical membrane fragments from gastric fundus can accumulate acid and that this sequestration is dependent on both potassium and ATP. These same fragments contain an ATPase that is stimulated by potassium but not sodium and is not inhibited by ouabain. This distinguishes it from the sodium-potassium ATPase. In the membrane vesicles the mechanism appears to be a neutral exchange of potassium and protons; a 1,000-10,000-fold proton gradient can be generated. Several issues remain unresolved: the mechanism of activation of the K+-H+ exchange; the mechanism of potassium entry into the canalicular lumen; the chloride permeation mechanism; and the conditions for formation of physiological (million-fold) concentration gradients of acid. This enzyme appears to be the site of action of the new inhibitory drugs, the substituted benzimidazoles, which block acid secretion in vivo, in in vitro mucosae, and in isolated membranes by inhibiting the H+/K+-ATPase. Further knowledge of the biochemical events from the receptor to the canalicular membrane will enable development of more specific approaches to the control of acid secretion and to the control of associated disease. © Lippincott-Raven Publishers.
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  • Spenney JG
  • Start Page

  • 7
  • End Page

  • 15
  • Volume

  • 5