Roche S, Bali J P, Galleyrand J C, Magous R
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.
Am J Physiol. 1991 Feb;260(2 Pt 1):G182-8. doi: 10.1152/ajpgi.1991.260.2.G182.
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.
以往的研究表明，胃泌素和胆囊收缩素的羧基末端八肽（CCK-8）可刺激离体兔胃壁细胞的体外酸分泌。这两种肽都与位于这些细胞上的受体位点结合，并以相同的效力和效能诱导磷酸肌醇周转率增加和[14C]氨基吡啶（[14C]AP）摄取。在本研究中，我们使用3-（苯甲酰氨基）-苯并二氮杂卓类似物L365,260和3-（酰基氨基）-苯并二氮杂卓类似物L364,718来研究哪种类型的受体（胃泌素型或CCK-A型）参与兔胃壁细胞H+分泌活性的调节。单独的L365,260和L364,718均未引起[3H]肌醇磷酸酯（[3H]InsP）生成的刺激。每种类似物均抑制125I标记的胃泌素或125I-CCK-8与壁细胞的结合以及胃泌素或CCK-8诱导的[3H]InsP生成和[14C]AP积累。在所有情况下，L365,260的效力比L364,718高约70-100倍（L365,260的IC50约为2-4 nM，L364,718的IC50约为0.2-0.4 microM）。然而，每种拮抗剂在抑制胃泌素或CCK-8的作用方面表现出相同的效力。这些结果表明，胃泌素和CCK-8与壁细胞上相同的“胃泌素型受体”相互作用。此外，L365,260表现为胃泌素对壁细胞作用的竞争性拮抗剂。胃泌素在壁细胞刺激后的最初几秒钟内会诱导肌醇1,4,5-三磷酸[Ins(1,4,5)P3]和肌醇1,3,4,5-四磷酸[Ins(1,3,4,5)P4]水平升高。L365,260（10 nM）完全抑制胃泌素诱导的Ins(1,4,5)P3和Ins(1,3,4,5)P4形成这一事实表明，这些异构体通过胃泌素受体激活参与酸分泌的介导。
