Characterization of a gastrin-type receptor on rabbit gastric parietal cells using L365,260 and L364,718.
Previous studies have demonstrated that gastrin and the COOH-terminal octapeptide of cholecystokinin (CCK-8) stimulated in vitro acid secretion from isolated rabbit gastric parietal cells. Both peptides bind to receptor sites located on these cells and induce an increase in phosphoinositide turnover and an uptake of [14C]aminopyrine ([14C]AP) with the same efficacy and potency. In the present study, we used the 3-(benzoylamino)-benzodiazepine analogue L365,260 and the 3-(acylamino)-benzodiazepine analogue L364,718 to investigate what type of receptor (gastrin type or CCK-A type) is involved in the regulation of the H+ secretory activity of the rabbit parietal cell. Neither L365,260 nor L364,718 alone caused stimulation of [3H]inositol phosphates ([3H]InsP) production. Each analogue inhibited 125I-labeled gastrin or 125I-CCK-8 binding to parietal cells and gastrin- or CCK-8-induced [3H]InsP production and [14C]AP accumulation. In all cases, L365,260 was approximately 70-100 times more potent than L364,718 (IC50 approximately 2-4 nM for L365,260 and approximately 0.2-0.4 microM for L364,718). Nevertheless, each antagonist displayed the same potency to inhibit the effects of gastrin or CCK-8. These results demonstrate that gastrin and CCK-8 interact with the same "gastrin-type" receptor on parietal cells. Moreover, L365,260 behaves as a competitive antagonist of the action of gastrin on parietal cells. Gastrin induces a rise in the levels of inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] and inositol 1,3,4,5-tetrakisphosphate [Ins(1,3,4,5)P4] within the first seconds after parietal cell stimulation. The fact that L365,260 (10 nM) totally suppressed the gastrin-induced formation of Ins(1,4,5)P3 and Ins(1,3,4,5)P4 suggests the involvement of these isomers in the mediation of acid secretion through gastrin receptor activation.
Roche
S
S
Laboratoire de Biochimie des Membranes, Centre National de la Recherche Scientifique UPR-8402, Institut National de la Santé et de la Recherche Médicale U249 Faculté de Pharmacie, Montpellier, France.
Bali
J P
JP
Galleyrand
J C
JC
Magous
R
R
D000632:Aminopyrine / Q000378:metabolism; D000818:Animals; D001570:Benzodiazepinones / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D002766:Cholecystokinin / Q000037:antagonists & inhibitors*; D002851:Chromatography, High Pressure Liquid; D020109:Devazepide; D005755:Gastrins / Q000378:metabolism / Q000494:pharmacology*; D066298:In Vitro Techniques; D007295:Inositol Phosphates / Q000302:isolation & purification / Q000378:metabolism*; D007700:Kinetics; D010295:Parietal Cells, Gastric / Q000378:metabolism*; D010671:Phenylurea Compounds; D011817:Rabbits; D011949:Receptors, Cholecystokinin / Q000187:drug effects / Q000378:metabolism*; D012844:Sincalide / Q000494:pharmacology*
D001570:Benzodiazepinones; D005755:Gastrins; D007295:Inositol Phosphates; D010671:Phenylurea Compounds; D011949:Receptors, Cholecystokinin; D000632:Aminopyrine; C058121:L 365260; D002766:Cholecystokinin; D020109:Devazepide; D012844:Sincalide