Partial agonism by gastrin for a cholecystokinin receptor mediating pepsinogen secretion.
Partial agonism by gastrin for a cholecystokinin receptor mediating pepsinogen secretion.
复制标题
胃泌素对介导胃蛋白酶原分泌的胆囊收缩素受体的部分激动。
DOI：
10.1152/ajpgi.1993.265.5.g865
复制
发表时间：
1993
期刊：
影响因子：
--
通讯作者：
Hersey,SJ
中科院分区：
文献类型：
--
作者：
Tang,LH;Miller,MD;Goldenring,JR;Modlin,IM;Hersey,SJ
分离的兔胃腺被用来鉴定介导胃蛋白酶原分泌的功能性CCK样多肽受体。CCK-8和选择性CCK-A型受体激动剂A-71378以相似的平均有效剂量(分别为1.0nM和0.8nM)刺激胃蛋白酶原的分泌。与CCK-8相比，胃泌素-17(G-17-I)刺激胃蛋白酶原分泌的效力降低，仅有部分作用，但抑制CCK-8刺激的最大反应。非肽类抑制剂天冬氨酸和L-364,718对胃泌素和胃泌素的拮抗作用具有相同的PA2值，表明两种多肽与同一功能受体相互作用。CCK和胃泌素完全取代了[~3H]CCK-8与分离的主细胞膜的特异性结合，表明这两种多肽都能完全占据受体。用一种新的合成肽类似物[(Glu)5-Ala-Tyr-NLe-Gly-Trp-NLe-Asp-Phe-NH2]研究了G-17-I效价和药效降低的结构基础。研究发现，CCK和胃泌素类似物对胃蛋白酶原分泌的效力既取决于酪氨酸残基的硫酸化，也取决于酪氨酸残基相对于COOH末端苯丙氨酸酰胺的位置。疗效似乎部分由G-17-I延长的NH2末端序列决定。本研究的结果被解释为胃蛋白酶原的分泌是由CCK-A型受体介导的，胃泌素作为部分激动剂作用于同一受体。
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.