High constitutive signaling of the ghrelin receptor - Identification of a potent inverse agonist
High constitutive signaling of the ghrelin receptor - Identification of a potent inverse agonist
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DOI：
10.1210/me.2003-0069
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发表时间：
2003-11-01
影响因子：
--
通讯作者：
Schwartz, TW
中科院分区：
文献类型：
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作者：
Holst, B;Cygankiewicz, A;Schwartz, TW
生长素释放肽是一种释放生长激素的肽，作为促进食欲的激素刺激食物摄入也发挥着重要作用。通过测量磷酸肌醇周转率或使用报告基因测定 cAMP 响应元件控制的转录活性，生长素释放肽受体在转染的 COS-7 或人胚胎肾 293 细胞中显示出强烈的、不依赖于配体的信号传导。生长素释放肽和许多已知的非肽 GH 促分泌素充当激动剂，进一步刺激肌醇磷酸盐周转。相比之下，低效生长素释放肽拮抗剂 [D-Arg(1)、D-Phe(5)、D-Trp(7,9)、Leu(11)]- P 物质令人惊讶地发现是一种高效 (EC50 = 5.2 nM) 完全反向激动剂，因为它将生长素释放肽受体的组成型信号传导降低至未转染细胞中观察到的水平。同源胃动素受体充当阴性对照，因为它没有表现出任何组成活性的迹象；然而，在激动剂刺激后，胃动素受体的信号与未刺激的生长素释放肽受体一样强烈。结论是，生长素释放肽受体具有高度的组成活性，并且这种活性对于其作为生长激素分泌和食欲控制的调节剂的作用具有重要的生理意义。有人建议，生长素释放肽受体的反向激动剂对于治疗肥胖症可能特别有意义。
Ghrelin is a GH-releasing peptide that also has an important role as an orexigenic hormone-stimulating food intake. By measuring inositol phosphate turnover or by using a reporter assay for transcriptional activity controlled by cAMP-responsive elements, the ghrelin receptor showed strong, ligand-independent signaling in transfected COS-7 or human embryonic kidney 293 cells. Ghrelin and a number of the known nonpeptide GH secretagogues acted as agonists stimulating inositol phosphate turnover further. In contrast, the low potency ghrelin antagonist, [D-Arg(1), D-Phe(5), D-Trp(7,9), Leu(11)]- substance P was surprisingly found to be a high potency (EC50 = 5.2 nM) full inverse agonist as it decreased the constitutive signaling of the ghrelin receptor down to that observed in untransfected cells. The homologous motilin receptor functioned as a negative control as it did not display any sign of constitutive activity; however, upon agonist stimulation the motilin receptor signaled as strongly as the unstimulated ghrelin receptor. It is concluded that the ghrelin receptor is highly constitutively active and that this activity could be of physiological importance in its role as a regulator of both GH secretion and appetite control. It is suggested that inverse agonists for the ghrelin receptor could be particularly interesting for the treatment of obesity.