INTRACELLULAR REACTIONS IN GASTRIC MUCOSA

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The long-term goal of this project is to identify and characterize the intracellular reactions which underlie the secretion of hydrochloric acid by the gastric parietal cell. Gastric acid secretion plays an important role in the digestive process, and it is a major contributing factor in peptic ulcer disease and reflux esophagitis. Information on how gastric acid secretion is regulated, thus, would contribute both to gastrointestinal physiology and to the clinical management of gastrointestinal diseases. The specific aims of this proposal will seek to study the mechanisms which lead to activation of the gastric H-K ATPase, known to be responsible for proton transport by this tissue. One set of studies is designed to formulate a quantitative kinetic model for activation and inactivation of the proton pump in the intact parietal cell. These studies will employ the recently developed methods for measuring H-K ATPase activity in situ to estimate the number of active proton pumps in relation to acid secretory rate. Measurements of the number of active proton pumps under steady-state conditions and during the onset or recovery of secretion will be used to construct a quantitative model for active pump turnover. The results will be used to test the hypothesis that acid secretion is regulated by the distribution of H-K ATPase between active and inactive forms. A second set of studies will employ gastric membrane vesicles to characterize two transport processes, a Cl- conductance and a cation exchanger, which recently have been identified as existing in the same membrane as the H-K ATPase. These studies will provide information on the nature of these processes and their possible role in regulating the activity of the H-K ATPase. Additionally, since several projects employ omeprazole, a new antiulcer agent, information will be obtained on the mechanisms of action of this compound which could be important for understanding the clinical actions of this new therapeutic agent.