title: Somatostatin, misoprostol and galanin inhibit gastrin- and PACAP-stimulated secretion of histamine and pancreastatin from ECL cells by blocking specific Ca2+ channels.
abstract: The oxyntic mucosa is rich in ECL cells. They secrete histamine and chromogranin A-derived peptides, such as pancreastatin, in response to gastrin and pituitary adenylate cyclase-activating peptide (PACAP). Secretion is initiated by Ca2+ entry. While gastrin stimulates secretion by opening L-type and N-type Ca2+ channels, PACAP stimulates secretion by activating L-type and receptor-operated Ca2+ channels. Somatostatin, galanin and prostaglandin E2 (PGE2) inhibit gastrin- and PACAP-stimulated secretion from the ECL cells. In the present study, somatostatin and the PGE2 congener misoprostol inhibited gastrin- and PACAP-stimulated secretion 100%, while galanin inhibited at most 60-65%. Bay K 8644, a specific activator of L-type Ca2+ channels, stimulated ECL-cell secretion, an effect that was inhibited equally effectively by somatostatin, misoprostol and galanin (75-80% inhibition). Pretreatment with pertussis toxin, that inactivates inhibitory G-proteins, prevented all three agents from inhibiting stimulated secretion (regardless of the stimulus). Pretreatment with nifedipine (10 microM), an L-type Ca2+ channel blocker, reduced PACAP-evoked pancreastatin secretion by 50-60%, gastrin-evoked secretion by approximately 80% and abolished the response to Bay K 8644. The nifedipine-resistant response to PACAP was abolished by somatostatin and misoprostol but not by galanin. Gastrin and PACAP raised the intracellular Ca2+ concentration in a biphasic manner, believed to reflect mobilization of internal Ca2+ followed by Ca2+ entry. Somatostatin and misoprostol blocked Ca2+ entry (and histamine and pancreastatin secretion) but not mobilization of internal Ca2+. The present observations on isolated ECL cells suggest that Ca2+ entry rather than mobilization of internal Ca2+ triggers exocytosis, that gastrin and PACAP activate different (but over-lapping) Ca2+ channels, that somatostatin, misoprostol and galanin interact with inhibitory G-proteins to block Ca2+ entry via L-type Ca2+ channels, and that somatostatin and misoprostol (but not galanin) in addition block N-type and/or receptor-operated Ca2+ channels.
authors.affiliation: Institute of Physiological Sciences, Department of Pharmacology, University of Lund, Sölvegatan 19, BMC F13, S-227 34 Lund, Sweden. maria.bjorkqvist@medkem.lu.se
authors.forename: Maria
authors.initials: M
authors.lastname: Björkqvist
authors.forename: Maria
authors.initials: M
authors.lastname: Bernsand
authors.forename: Lena
authors.initials: L
authors.lastname: Eliasson
authors.forename: Rolf
authors.initials: R
authors.lastname: Håkanson
authors.forename: Erik
authors.initials: E
authors.lastname: Lindström
mesh_terms: D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000818:Animals; D000897:Anti-Ulcer Agents / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism*; D002478:Cells, Cultured; D053379:Chromogranin A; D004305:Dose-Response Relationship, Drug; D019861:Enterochromaffin-like Cells / Q000378:metabolism*; D005089:Exocytosis; D019004:Galanin / Q000378:metabolism / Q000494:pharmacology*; D005755:Gastrins / Q000378:metabolism*; D006632:Histamine / Q000378:metabolism*; D006728:Hormones / Q000494:pharmacology; D008297:Male; D018715:Microscopy, Video; D016595:Misoprostol / Q000378:metabolism / Q000494:pharmacology*; D008954:Models, Biological; D009543:Nifedipine / Q000494:pharmacology; D010187:Pancreatic Hormones / Q000378:metabolism*; D010456:Peptides, Cyclic / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013004:Somatostatin / Q000378:metabolism / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D000897:Anti-Ulcer Agents; D015220:Calcium Channels; D053379:Chromogranin A; D005755:Gastrins; D006728:Hormones; C121568:PRL 2903; D010187:Pancreatic Hormones; D010456:Peptides, Cyclic; D016595:Misoprostol; C050836:pancreastatin; D013004:Somatostatin; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D006632:Histamine; D019004:Galanin; D009543:Nifedipine; D002118:Calcium