[Leu15]-Gastrin I (human)

Ageing cells, especially post-mitotic cells, are known to accumulate pigments, i.e. highly electron-dense material, referred to as ceroid or lipofuscin. This material is formed as a consequence of autophagocytosis and peroxidation of the products undergoing degradation. The present study describes the development of lipofuscin in the ECL cells of the rat stomach. These cells produce and secrete histamine in response to gastrin. They are rich in secretory vesicles, which fuse to form vacuoles in hypergastrinaemic rats. Hypergastrinaemia was induced by continuous infusion of human Leu15-gastrin-17 for 6 days or by daily treatment with omeprazole for 10 weeks. Either treatment caused both vacuoles and lipofuscin bodies to appear in large numbers; the vacuoles disappeared promptly after interruption of the hypergastrinaemia, whereas the lipofuscin bodies remained. Antrectomy-evoked hypogastrinaemia was associated with a reduced number and volume density of lipofuscin bodies. Treatment with alpha-fluoromethylhistidine, an irreversible inhibitor of the histamine-forming enzyme, resulted in depletion of ECL-cell histamine and was found to prevent the omeprazole-evoked formation of vacuoles and lipofuscin. The numbers of both vacuoles and lipofuscin bodies were well-correlated with the serum gastrin concentration, suggesting that gastrin stimulates the development not only of vacuoles but also of lipofuscin, perhaps through enhanced autophagocytosis and/or oxidative stress. Thus, lipofuscin bodies may develop from vacuoles, and both vacuoles and lipofuscin bodies may reflect the efforts of overstimulated ECL cells to cope with the excessive formation of secretory products.

The effect of gastrin on secretin binding sites in the stomach was studied using the plasma membranes from rat gastric mucosa and vascularly perfused rat stomach. Tetragastrin transiently increased secretin binding to the mucosal plasma membranes. In the perfused stomach secretin binding was also modulated by the inclusion of tetragastrin or human [Leu15] gastrin I in the perfusate. However, histamine did not show such a modulatory effect. Tetragastrin had an insignificant effect on secretin binding sites in rat pancreas. These results suggest that the direct modulation of secretin binding by gastrin to its receptors may be involved in the inhibitory action of secretin on acid secretion induced by gastrin.

Background & aims:Gastrin and cholecystokinin (CCK) are gut-brain peptides, with multiple functions in the gastrointestinal tract mediated through CCK-B-gastrin and CCK-A receptors. The receptor localization is, however, not well established in humans. The aim of this study was to investigate the distribution and pharmacological characteristics of CCK-A and CCK-B receptors in the human upper gastrointestinal tract and compare them with those in the rat and dog.Methods:CCK receptors were localized by in vitro receptor autoradiography with 125I-[Leu15]gastrin-I and 125I-[D-Tyr-Gly, Nle(28,31)]-CCK 26-33 in stomach and gallbladder.Results:High concentrations of CCK-B-gastrin receptors were detected in the midglandular region of the human fundic mucosa. CCK-A receptors were found in the basal region of the antral and fundic mucosa. CCK-A receptors were also located in the muscularis propria of antrum, fundus, and gallbladder, whereas CCK-B-gastrin receptors were only detected in gastric fundic circular muscle. Two nonpeptide CCK receptor antagonists distinguish both receptor subtypes. Comparisons among humans, dogs, and rats suggest that localization and density of CCK receptor subtypes in the upper gastrointestinal tract are species-dependent.Conclusions:Localization of CCK receptor subtypes in human upper gastrointestinal tract provides a biochemical and morphological basis for the separate regulatory roles of gastrin and CCK.