Abstract
The role of the peptide hormone gastrin in stimulating gastric acid secretion is well established. Mature amidated gastrin is processed from larger peptide precursor forms. Increasingly these processing intermediates, such as glycine-extended gastrin (G-Gly) and progastrin, have been shown to have biological activities of their own, often separate and complementary to gastrin. Although G-Gly is synthesized and secreted by gastric antral G-cells, the physiological functions of this putative mediator are unclear. Gastrin and cholecystokinin (CCK) stimulate the secretion of somatostatin from gastric D-cells as part of the feedback control of gastric acid. In this study the effect of G-Gly and gastrin on the release of somatostatin from rabbit fundic D-cells was examined. D-cells were obtained by collagenase-EDTA digestion and elutriation and cultured for 48 hours. With a 2 hour exposure to the peptides, gastrin but not G-Gly stimulated somatostatin release. Treatment of D-cells for 24 hours with gastrin or G-Gly individually, significantly enhanced subsequent basal as well as CCK- and GLP-1-stimulated somatostatin release. Twenty four hours exposure to gastrin combined with G-Gly synergistically enhanced basal and agonist-stimulated somatostatin release and cellular somatostatin content. Gastrin and G-Gly may be important in the longer term regulation of D-cell function.
Highlights
Gastrin is initially synthesized as a larger precursor protein and subsequently processed, via a multi-step pathway, to the classical active carboxyl-terminal amidated peptide[1]
The majority of studies have examined the pathophysiological roles of gastrin precursors in gastrointestinal cancers and considerable data have implicated these peptides as stimulants of proliferation and/or inhibitors of apoptosis in a variety of tissues and cell lines, including Barrett’s oeosphagus and oesophageal adenocarcinoma[2,3], stomach[4,5], pancreas[6,7] and normal and malignant colonic epithelium[8,9,10,11,12].Growth promoting effects of G-Gly on lung cancer have been reported[13]
Gastrin alone did stimulate somatostatin release but was less effective than CCK and neither gastrin nor the gastrin plus G-Gly combination had any effect on CCK-stimulated gastrin release
Summary
Gastrin is initially synthesized as a larger precursor protein and subsequently processed, via a multi-step pathway, to the classical active carboxyl-terminal amidated peptide[1]. The precise cell signaling pathways activated by gastrinprocessing intermediates have not been definitively described, it seems in most cases that mechanisms distinct from the classical gastrin (CCK2) receptor are involved[3,6,10] It is not yet clear whether these gastrin-processing intermediates have distinct physiological, as opposed to pathophysiological roles. Glycine-extended gastrin is produced and stored in significant amounts in the gastric antrum, has gastrointestinal trophic effects and interacts with amidated gastrin to modulate gene expression and gastric acid secretion[14,15,16] Gastrin stimulates both acid secretion and somatostatin release as a feedback inhibitory mechanism[17]. The current study was designed to assess the effects of G-Gly on somatostatin release from D-cells and compare these effects with those of amidated gastrin
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