The Gastrin-ECL Cell Axis. Functional Aspects

Abstract: The ECL cells constitute a prominent endocrine cell population in the acid-producing part of the stomach. They are controlled by circulating gastrin released from G-cells in the antrum. In response to gastrin, they secrete histamine, that in turn stimulates the parietal cell to secrete acid. The first aim of the study was to prepare isolated ECL cells of high purity and to study and identify regulators of secretion from such cells in primary culture. Gastrin and pituitary adenylate cyclase activating peptide (PACAP) effectively evoked ECL-cell secretion. Vasoactive intestinal peptide (VIP) and adrenaline also evoked secretion but with a lower efficacy. Somatostatin, galanin and prostaglandins inhibited stimulated ECL-cell secretion. Elevation of the intracellular calcium concentration ([Ca2+]i) is a key event in the regulation of many cellular processes. Gastrin binds to the CCK2 receptor causing Ca2+ entry through L-type and N-type Ca2+ channels followed by exocytosis. PACAP binds to PAC1 receptors, causing Ca2+ entry through L-type and receptor-operated channels. Somatostatin, misoprostol and galanin bind to receptors that are coupled to inhibitory G-proteins that block conductance through Ca2+ channels. Somatostatin and misoprostol interfere with L-type, N-type and receptor-operated Ca2+ channels, thereby preventing Ca2+ influx following either gastrin or PACAP challenge. For unknown reasons, galanin interfere with L-type Ca2+ channels only. Gastrin is a recognized growth-promoting hormone for the acid-producing part of the stomach and for the ECL cells in particular. The trophic effect of gastrin is probably exerted on stem cells and ECL cells. The ECL cells are known to respond to gastrin not only with the mobilization of secretory products, but also with increased expression of proteins, such as the histamine-forming enzyme histidine decarboxylase (HDC). To elucidate the action of gastrin on the stomach we attempted to identify genes that are regulated by gastrin in oxyntic mucosa and in isolated ECL cells. In order to detect altered gene expression in oxyntic mucosa and in ECL cells in response to sustained hypergastrinemia, differential display reverse transcriptase reactions were conducted. Our results revealed gastrin-evoked upregulation of several genes that may be involved in secretory processes, e.g. mRNA for HDC and synaptotagmin V. The effects of gastrin on the ECL cell can be prevented by a CCK2 receptor antagonist. We conducted a pharmacological analysis of a series of CCK2 receptor antagonists on gastrin-stimulated secretion from ECL cells in primary culture. The most potent of the antagonists were YM022 and YF476. Both agents produced a rightward and parallell shift in the gastrin dose-response curve, suggesting surmountable and competitive antagonism. The effects of CCK2 receptor blockade on oxyntic mucosa and ECL cells were studied in the developing and mature rat. CCK2 receptor blockade in the rat affected the oxyntic mucosa but not extra-gastric sites. In the developing rat, neither the post-natal body weight gain nor the onset of weaning were affected by CCK2 receptor blockade. ECL cells failed to respond to gastrin before weaning, but their activity was clearly gastrin-dependent after weaning.