Gimpl Gerald, Reitz Julian, Brauer Sabine, Trossen Conny
Johannes-Gutenberg University Mainz, Institute of Biochemistry, Becherweg, Mainz, Germany.
Prog Brain Res. 2008;170:193-204. doi: 10.1016/S0079-6123(08)00417-2.
The G protein coupled oxytocin receptor (OTR) reveals some specific molecular and physiological characteristics. Ligand-receptor interaction has been analysed by photoaffinity labelling, site-directed mutagenesis, the construction of receptor chimeras and molecular modelling. Major results of these studies will be summarized. The N-terminus of the OTR is mainly involved in agonist binding. Notably, antagonists that are derived from the ground structure of oxytocin, bind the receptor at distinct sites partly non-overlapping with the agonist binding site. OTRs are able to couple to different G proteins, with a subsequent stimulation of phospholipase C-beta isoforms. In dependence on G protein coupling, OTRs can transduce growth-inhibitory or proliferatory signals. Some evidence is provided that OTRs are also present in form of dimeric or oligomeric complexes at the cell surface. The affinity of the receptor for ligands is strongly dependent on the presence of divalent cations (Mg(2+)) and cholesterol that both act like positive allosteric modulators. While the high-affinity state of the receptor for agonists requires divalent cations and cholesterol, the high-affinity state for antagonists is only dependent on a sufficient amount of cholesterol. Cholesterol affects ligand-binding affinity, receptor signalling and stability. Since the purification of the OTR has never been achieved, alternative methods to study the receptor in its native environment are necessary. Promising strategies for the site-specific labelling of the OTR will be presented. The employment of diverse reporter molecules introduced at different positions within the OTR might allow us in the near future to measure conformational changes of the receptor in its native lipid environment.
G蛋白偶联催产素受体（OTR）具有一些特定的分子和生理特征。已通过光亲和标记、定点诱变、受体嵌合体构建和分子建模分析了配体与受体的相互作用。将总结这些研究的主要结果。OTR的N端主要参与激动剂结合。值得注意的是，源自催产素基本结构的拮抗剂在与激动剂结合位点部分不重叠的不同位点结合受体。OTR能够与不同的G蛋白偶联，随后刺激磷脂酶C-β亚型。根据G蛋白偶联情况，OTR可以转导生长抑制或增殖信号。有证据表明，OTR在细胞表面也以二聚体或寡聚体复合物的形式存在。受体对配体的亲和力强烈依赖于二价阳离子（Mg(2+)）和胆固醇的存在，二者均起正变构调节剂的作用。虽然受体对激动剂的高亲和力状态需要二价阳离子和胆固醇，但对拮抗剂的高亲和力状态仅取决于足够量的胆固醇。胆固醇影响配体结合亲和力、受体信号传导和稳定性。由于从未实现过OTR的纯化，因此需要采用替代方法在其天然环境中研究该受体。将介绍用于OTR位点特异性标记的有前景的策略。在OTR内不同位置引入多种报告分子，可能在不久的将来使我们能够测量受体在其天然脂质环境中的构象变化。
