The Parietal Cell as a Therapeutic Target

Abstract

Inhibition of acid secretion or an improvement in mucosal resistance is central to treatment of upper gastrointestinal tract ulcers. Initiation of secretion is largely brought about by activation of the H₂-histamine receptor, though other receptors are also involved to a lesser extent. Activation of the parietal cell by histamine is dependent on adenylate cyclase, and is a result of direct stimulation of the enzyme by histamine. Cyclic AMP can mimic the effect of H₂-receptor activation. Mechanisms of cholinergic and gastrinergic stimulation involve different receptors and second messengers. These three systems can be used to construct a model of the parietal cell and its activation. On activation, changes in metabolism, structure and H' pump function occur in the parietal cell, and these suggest the possibility of several sites of action for the phosphokinases activated by the second messengers cyclic AMP and Ca²⁺. Detailed studies have been carried out on the H+K+ATPase of hog gastric mucosa and a reaction sequence has been proposed, which can be correlated to the transport functions of the enzyme. The molecular weight of the enzyme is 94,000 and a part of its amino acid sequence has been determined. As knowledge about the enzyme becomes more precise, it should be possible to design a specific inhibitor. Such a terminal step inhibitor should be able to completely inhibit acid secretion in therapeutic doses.