title: Partial agonism by gastrin for a cholecystokinin receptor mediating pepsinogen secretion.
abstract: Isolated gastric glands from rabbit were used to characterize the functional cholecystokinin (CCK)-like peptide receptors that mediate pepsinogen secretion. Pepsinogen secretion was stimulated by both CCK octapeptide sulfate (CCK-8) and A-71378, a selective CCK-A-type receptor agonist, with similar mean effective doses (1.0 and 0.8 nM, respectively). Compared with CCK-8, gastrin-17 (G-17-I) showed reduced potency and only partial efficacy for stimulation of pepsinogen secretion while inhibiting the maximal CCK-8-stimulated response. The nonpeptide inhibitors, asperlicin and L-364,718, inhibited pepsinogen secretion with identical pA2 values for antagonism of both CCK and gastrin, indicating that both peptides interact with the same functional receptor. Specific binding of [3H]CCK-8 to isolated chief cell membranes was displaced fully by both CCK and gastrin, indicating full receptor occupancy by both peptides. A novel synthetic peptide analogue, pseudogastrin [(Glu)5-Ala-Tyr-Nle-Gly-Trp-Nle-Asp-Phe-NH2], was used to investigate the structural basis for the lower potency and efficacy of G-17-I. The potency of CCK and gastrin analogues for pepsinogen secretion was found to be dependent on both sulfation of a tyrosine residue and the position of the tyrosine residue relative to the COOH-terminal phenylalanine amide. The efficacy appears to be determined partially by the extended NH2-terminal sequence of G-17-I. The results of the present study are interpreted to show that pepsinogen secretion is mediated by a CCK-A-type receptor and gastrin acts at the same receptor as a partial agonist.
authors.affiliation: Department of Physiology, Emory University School of Medicine, Atlanta, Georgia 30322.
authors.forename: L H
authors.initials: LH
authors.lastname: Tang
authors.forename: M D
authors.initials: MD
authors.lastname: Miller
authors.forename: J R
authors.initials: JR
authors.lastname: Goldenring
authors.forename: I M
authors.initials: IM
authors.lastname: Modlin
authors.forename: S J
authors.initials: SJ
authors.lastname: Hersey
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001570:Benzodiazepinones / Q000494:pharmacology; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002766:Cholecystokinin / Q000037:antagonists & inhibitors; D020109:Devazepide; D005753:Gastric Mucosa / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D005755:Gastrins / Q000494:pharmacology*; D006728:Hormones / Q000494:pharmacology; D066298:In Vitro Techniques; D007700:Kinetics; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000494:pharmacology; D010435:Pepsinogens / Q000378:metabolism*; D011817:Rabbits; D011949:Receptors, Cholecystokinin / Q000187:drug effects / Q000502:physiology*; D017386:Sequence Homology, Amino Acid; D012844:Sincalide / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D001570:Benzodiazepinones; D005755:Gastrins; D006728:Hormones; D009842:Oligopeptides; D010435:Pepsinogens; D011949:Receptors, Cholecystokinin; C063897:A 71378; C013550:gastrin 17; D002766:Cholecystokinin; D020109:Devazepide; D012844:Sincalide; C046367:asperlicin