Digestive Diseases Branch, NIDDK, National Institutes of Health, Bethesda, MD 20892-1804, USA.
Peptides. 2010 Aug;31(8):1569-78. doi: 10.1016/j.peptides.2010.04.023. Epub 2010 May 12.
The orphan receptor, bombesin receptor subtype-3(BRS-3) is a G-protein-coupled receptor classified in the bombesin (Bn) receptor family because of its high homology (47-51%) with other members of this family [gastrin-releasing peptide receptor [GRPR] and neuromedin B receptor [NMBR]]. There is increasing interest in BRS-3, because primarily from receptor knockout studies, it seems important in energy metabolism, glucose control, insulin secretion, motility and tumor growth. Pharmacological tools to study the role of BRS-3 in physiology/pathophysiology are limited because the natural ligand is unknown and BRS-3 has low affinity for all naturally occurring Bn-related peptides. However, a few years ago a synthetic high-affinity agonist [dTyr(6),betaAla(11),Phe(13),Nle(14)]Bn-(6-14) was described but was nonselective for BRS-3 over other Bn receptors. Based on this peptide, in various studies a number of putative selective, high-potency hBRS-3 agonists were described, however the results on their selectivity are conflicting in a number of cases. The purpose of the present study was to thoroughly study the pharmacology of four of the most select/potent putative hBRS-3 agonists (#2-4, 16a). Each was studied in multiple well-characterized Bn receptor-transfected cells and native Bn receptor bearing cells, using binding studies, alterations in cellular signaling (PLC, PKD) and changes in cellular function(growth). Two peptides (#2, #3) had nM affinities/potencies for hBRS-3, peptide #4 had low affinity/potency, and peptide #16a very low (>3000 nM). Peptide#3 had the highest selectivity for hBRS-3 (100-fold), whereas #2, 4 had lower selectivity. Peptide #16a's selectivity could not be determined because of its low affinity/potencies for all hBn receptors. These results show that peptide #3 is the preferred hBRS-3 agonist for studies at present, although its selectivity of only 100-fold may limit its utility in some cases. This study underscores the importance of full pharmacological characterization of newly reported selective agonists.
孤儿受体、蛙皮素受体亚型-3（BRS-3）是一种 G 蛋白偶联受体，因其与该家族的其他成员（胃泌素释放肽受体 [GRPR] 和神经肽 B 受体 [NMBR]）具有 47-51%的同源性，而被归类为蛙皮素（Bn）受体家族。由于主要通过受体敲除研究，BRS-3 似乎在能量代谢、葡萄糖控制、胰岛素分泌、运动和肿瘤生长中很重要，因此人们对 BRS-3 的兴趣日益增加。用于研究 BRS-3 在生理学/病理生理学中作用的药理学工具受到限制，因为天然配体未知，并且 BRS-3 对所有天然存在的 Bn 相关肽的亲和力较低。然而，几年前，人们描述了一种合成的高亲和力激动剂 [dTyr(6),betaAla(11),Phe(13),Nle(14)]Bn-(6-14)，但对其他 Bn 受体而言，它对 BRS-3 的选择性不高。基于该肽，在各种研究中，描述了一些假定的选择性、高效力的 hBRS-3 激动剂，然而，在许多情况下，它们的选择性结果存在冲突。本研究的目的是彻底研究四种最具选择性/效力的假定 hBRS-3 激动剂（#2-4、16a）的药理学。在多个经过良好表征的 Bn 受体转染细胞和携带天然 Bn 受体的细胞中，使用结合研究、细胞信号转导（PLC、PKD）的改变和细胞功能（生长）的改变，对每种激动剂进行了研究。两种肽（#2、#3）对 hBRS-3 的亲和力/效力具有纳摩尔级，肽 #4 的亲和力/效力较低，而肽 #16a 的亲和力/效力非常低（>3000 纳摩尔）。肽 #3 对 hBRS-3 的选择性最高（100 倍），而 #2、#4 的选择性较低。由于肽 #16a 对所有 hBn 受体的亲和力/效力均较低，因此无法确定其选择性。这些结果表明，尽管肽 #3 的选择性仅为 100 倍，但在某些情况下可能会限制其在研究中的应用，因此肽 #3 是目前研究 hBRS-3 的首选激动剂。本研究强调了对新报道的选择性激动剂进行全面药理学表征的重要性。
