Parietal cell

Abstract: Studies both in vivo and in vitro have shown that substituted benzimidazoles inhibit the stimulation of acid secretion produced by dibutyryl cyclic AMP and histamine. Furthermore, the results differ from those produced by H2 antagonists and anticholinergic agents in that the inhibition is not competitive, and the site of action is intracellular and peripheral to that of dibutyryl cyclic AMP. To investigate the biochemical mechanism of action of substituted benzimidazoles, one such compound, H 149/94 (2-([2-(3-methyl)pyridyl-methyl]-sulphinyl)-5-methoxycarbonyl-6-methylbenzimidazol), has been tested either directly on an (H+ + K+)ATPase isolated from pig and human gastric mucosa or on the function of this enzyme in gastric glands isolated from rabbit and human gastric mucosa. (H+ + K+)ATPase, which has only been found at the secretory surface of the parietal cell, catalyses a one-to-one exchange of protons and potassium ions. It is possibly the proton pump within the gastric mucosa, and may thus be the terminal or one of the terminal steps of the acid secretory process. We show here that H 149/94 inhibits (H+ + K+)ATPase, which may explain its inhibitory action on acid secretion in vitro and in vivo. Because of the unique distribution and properties of the (H+ + K+)ATPase, the inhibitory action of H 149/94 on this enzyme may be a highly selective clinical means of suppressing the acid secretory process.

Abstract: Gastrin is an important stimulant of acid secretion by gastric parietal cells and is structurally related to the peptide hormone cholecystokinin (CCK) The pharmacologic properties of the parietal cell gastrin receptor are very similar to the predominant CCK receptor in the brain, CCK-B Neither the gastrin nor the CCK-B receptor have been cloned thus far, making it difficult to resolve whether these two receptors are distinct We have isolated a clone encoding the canine gastrin receptor by screening a parietal cell cDNA expression library using a radioligand-binding strategy Nucleotide sequence analysis revealed an open reading frame encoding a 453-amino acid protein with seven putative hydrophobic transmembrane domains and significant homology with members of the beta-adrenergic family of G protein-coupled receptors The expressed recombinant receptor shows the same binding specificity for gastrin/CCK agonists and antagonists as the canine parietal cell receptor Gastrin-stimulated phosphatidylinositol hydrolysis and intracellular Ca2+ mobilization in COS-7 cells expressing the cloned receptor suggest second-messenger signaling through phospholipase C Affinity labeling of the expressed receptor in COS-7 cells revealed a protein identical in size to the native parietal cell receptor Gastrin receptor transcripts were identified by high-stringency RNA blot analysis in both parietal cells and cerebral cortex, suggesting that the gastrin and CCK-B receptors are either highly homologous or identical