Department of Neurology, University of Iowa, Iowa City, IA 52242, USA; Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA.
Trends Biochem Sci. 2020 Dec;45(12):1049-1064. doi: 10.1016/j.tibs.2020.07.008. Epub 2020 Aug 26.
Groundbreaking structural and spectroscopic studies of class A G protein-coupled receptors (GPCRs), such as rhodopsin and the β adrenergic receptor, have provided a picture of how structural rearrangements between transmembrane helices control ligand binding, receptor activation, and effector coupling. However, the activation mechanism of other GPCR classes remains more elusive, in large part due to complexity in their domain assembly and quaternary structure. In this review, we focus on the class C GPCRs, which include metabotropic glutamate receptors (mGluRs) and gamma-aminobutyric acid B (GABA) receptors (GABARs) most prominently. We discuss the unique biophysical questions raised by the presence of large extracellular ligand-binding domains (LBDs) and constitutive homo/heterodimerization. Furthermore, we discuss how recent studies have begun to unravel how these fundamental class C GPCR features impact the processes of ligand binding, receptor activation, signal transduction, regulation by accessory proteins, and crosstalk with other GPCRs.
突破性的结构和光谱研究 A 类 G 蛋白偶联受体 (GPCRs)，如视紫红质和β肾上腺素能受体，提供了一幅结构重排如何控制配体结合、受体激活和效应器偶联的画面。然而，其他 GPCR 类别的激活机制仍然更加难以捉摸，这在很大程度上是由于它们的结构域组装和四级结构的复杂性。在这篇综述中，我们重点介绍 C 类 GPCR，其中包括代谢型谷氨酸受体 (mGluRs) 和γ-氨基丁酸 B (GABARs)。我们讨论了大的细胞外配体结合域 (LBD) 和组成型同/异二聚体存在带来的独特的物理问题。此外，我们还讨论了最近的研究如何开始揭示这些基本的 C 类 GPCR 特征如何影响配体结合、受体激活、信号转导、辅助蛋白的调节以及与其他 GPCR 的串扰过程。
