Reiter Eric, Ayoub Mohammed Akli, Pellissier Lucie P, Landomiel Flavie, Musnier Astrid, Tréfier Aurélie, Gandia Jorge, De Pascali Francesco, Tahir Shifa, Yvinec Romain, Bruneau Gilles, Poupon Anne, Crépieux Pascale
PRC, INRA, CNRS, IFCE, Université de Tours, 37380, Nouzilly, France.
PRC, INRA, CNRS, IFCE, Université de Tours, 37380, Nouzilly, France; LE STUDIUM(®) Loire Valley Institute for Advanced Studies, 45000, Orléans, France; Biology Department, College of Science, United Arab Emirates University, Al Ain, United Arab Emirates.
Mol Cell Endocrinol. 2017 Jul 5;449:28-41. doi: 10.1016/j.mce.2017.01.052. Epub 2017 Feb 4.
G protein-coupled receptors (GPCRs) play crucial roles in the ability of target organs to respond to hormonal cues. GPCRs' activation mechanisms have long been considered as a two-state process connecting the agonist-bound receptor to heterotrimeric G proteins. This view is now challenged as mounting evidence point to GPCRs being connected to large arrays of transduction mechanisms involving heterotrimeric G proteins as well as other players. Amongst the G protein-independent transduction mechanisms, those elicited by β-arrestins upon their recruitment to the active receptors are by far the best characterized and apply to most GPCRs. These concepts, in conjunction with remarkable advances made in the field of GPCR structural biology and biophysics, have supported the notion of ligand-selective signalling also known as pharmacological bias. Interestingly, recent reports have opened intriguing prospects to the way β-arrestins control GPCR-mediated signalling in space and time within the cells. In the present paper, we review the existing evidence linking endocrine-related GPCRs to β-arrestin recruitement, signalling, pathophysiological implications and selective activation by biased ligands and/or receptor modifications. Emerging concepts surrounding β-arrestin-mediated transduction are discussed in the light of the peculiarities of endocrine systems.
G蛋白偶联受体（GPCRs）在靶器官对激素信号作出反应的能力中发挥着关键作用。长期以来，GPCRs的激活机制一直被认为是一个将激动剂结合的受体与异源三聚体G蛋白连接起来的双态过程。现在这一观点受到了挑战，因为越来越多的证据表明GPCRs与涉及异源三聚体G蛋白以及其他参与者的大量转导机制相关联。在不依赖G蛋白的转导机制中，β-抑制蛋白在被招募到活性受体时引发的机制是目前研究得最为透彻的，并且适用于大多数GPCRs。这些概念，再加上GPCR结构生物学和生物物理学领域取得的显著进展，支持了配体选择性信号传导这一概念，也称为药理学偏向性。有趣的是，最近的报告为β-抑制蛋白在细胞内时空上控制GPCR介导的信号传导的方式开启了引人入胜的前景。在本文中，我们综述了将内分泌相关GPCRs与β-抑制蛋白招募、信号传导、病理生理意义以及偏向性配体和/或受体修饰的选择性激活联系起来的现有证据。鉴于内分泌系统的特殊性，我们讨论了围绕β-抑制蛋白介导的转导的新兴概念。
