Department of Pharmacology, School of Medicine, Bushehr University of Medical Sciences, Iran; Education Development Center, Bushehr University of Medical Sciences, Iran.
Department of Toxicology-Pharmacology, School of Pharmacy, Tehran University of Medical Sciences, Iran.
Pharmacol Ther. 2019 Aug;200:148-178. doi: 10.1016/j.pharmthera.2019.05.006. Epub 2019 May 8.
G protein coupled receptors (GPCRs) convey signals across membranes via interaction with G proteins. Originally, an individual GPCR was thought to signal through one G protein family, comprising cognate G proteins that mediate canonical receptor signaling. However, several deviations from canonical signaling pathways for GPCRs have been described. It is now clear that GPCRs can engage with multiple G proteins and the line between cognate and non-cognate signaling is increasingly blurred. Furthermore, GPCRs couple to non-G protein transducers, including β-arrestins or other scaffold proteins, to initiate additional signaling cascades. Receptor/transducer selectivity is dictated by agonist-induced receptor conformations as well as by collateral factors. In particular, ligands stabilize distinct receptor conformations to preferentially activate certain pathways, designated 'biased signaling'. In this regard, receptor sequence alignment and mutagenesis have helped to identify key receptor domains for receptor/transducer specificity. Furthermore, molecular structures of GPCRs bound to different ligands or transducers have provided detailed insights into mechanisms of coupling selectivity. However, receptor dimerization, compartmentalization, and trafficking, receptor-transducer-effector stoichiometry, and ligand residence and exposure times can each affect GPCR coupling. Extrinsic factors including cell type or assay conditions can also influence receptor signaling. Understanding these factors may lead to the development of improved biased ligands with the potential to enhance therapeutic benefit, while minimizing adverse effects. In this review, evidence for ligand-specific GPCR signaling toward different transducers or pathways is elaborated. Furthermore, molecular determinants of biased signaling toward these pathways and relevant examples of the potential clinical benefits and pitfalls of biased ligands are discussed.
G 蛋白偶联受体 (GPCRs) 通过与 G 蛋白的相互作用在膜间传递信号。最初，人们认为单个 GPCR 通过一个 G 蛋白家族发出信号，该家族由介导经典受体信号的同源 G 蛋白组成。然而，已经描述了几种与 GPCR 经典信号通路不同的信号通路。现在很清楚，GPCR 可以与多种 G 蛋白结合，同源和非同源信号之间的界限越来越模糊。此外，GPCR 与非 G 蛋白转导器（包括β-arrestin 或其他支架蛋白）结合，以启动其他信号级联反应。受体/转导器的选择性由激动剂诱导的受体构象以及旁系因素决定。特别是，配体稳定不同的受体构象，以优先激活某些途径，称为“偏向信号”。在这方面，受体序列比对和突变有助于识别受体/转导器特异性的关键受体结构域。此外，与不同配体或转导器结合的 GPCR 分子结构提供了关于偶联选择性机制的详细见解。然而，受体二聚化、区室化和运输、受体-转导器-效应物的比例以及配体停留和暴露时间都可能影响 GPCR 的偶联。外在因素，包括细胞类型或测定条件，也会影响受体信号。了解这些因素可能会导致开发出具有潜在治疗益处的改进的偏向配体，同时最小化不良反应。在这篇综述中，详细阐述了不同配体对不同转导器或途径的 GPCR 信号的证据。此外，还讨论了偏向这些途径的信号的分子决定因素以及偏向配体的潜在临床益处和陷阱的相关示例。
