Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland (J.W., A.-B.O., O.R.-G.); and Department of Pharmacology, Vanderbilt University, Nashville, Tennessee (E.V.G., V.V.G.)
Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland (J.W., A.-B.O., O.R.-G.); and Department of Pharmacology, Vanderbilt University, Nashville, Tennessee (E.V.G., V.V.G.).
Pharmacol Rev. 2023 Sep;75(5):854-884. doi: 10.1124/pharmrev.121.000302. Epub 2023 Apr 7.
The two -arrestins, -arrestin-1 and -2 (systematic names: arrestin-2 and -3, respectively), are multifunctional intracellular proteins that regulate the activity of a very large number of cellular signaling pathways and physiologic functions. The two proteins were discovered for their ability to disrupt signaling via G protein-coupled receptors (GPCRs) via binding to the activated receptors. However, it is now well recognized that both -arrestins can also act as direct modulators of numerous cellular processes via either GPCR-dependent or -independent mechanisms. Recent structural, biophysical, and biochemical studies have provided novel insights into how -arrestins bind to activated GPCRs and downstream effector proteins. Studies with -arrestin mutant mice have identified numerous physiologic and pathophysiological processes regulated by -arrestin-1 and/or -2. Following a short summary of recent structural studies, this review primarily focuses on -arrestin-regulated physiologic functions, with particular focus on the central nervous system and the roles of -arrestins in carcinogenesis and key metabolic processes including the maintenance of glucose and energy homeostasis. This review also highlights potential therapeutic implications of these studies and discusses strategies that could prove useful for targeting specific -arrestin-regulated signaling pathways for therapeutic purposes. SIGNIFICANCE STATEMENT: The two β-arrestins, structurally closely related intracellular proteins that are evolutionarily highly conserved, have emerged as multifunctional proteins able to regulate a vast array of cellular and physiological functions. The outcome of studies with β-arrestin mutant mice and cultured cells, complemented by novel insights into β-arrestin structure and function, should pave the way for the development of novel classes of therapeutically useful drugs capable of regulating specific β-arrestin functions.
两种 arrestin，arrestin-1 和 arrestin-2（系统命名分别为 arrestin-2 和 arrestin-3），是多功能的细胞内蛋白，可调节大量细胞信号通路和生理功能。这两种蛋白因其能够通过与激活的受体结合来破坏 G 蛋白偶联受体 (GPCR) 的信号传递而被发现。然而，现在人们已经充分认识到，两种 arrestin 还可以通过 GPCR 依赖或非依赖机制，作为许多细胞过程的直接调节剂。最近的结构、生物物理和生化研究为 arrestin 如何与激活的 GPCR 和下游效应蛋白结合提供了新的见解。用 arrestin 突变小鼠进行的研究确定了由 arrestin-1 和/或 arrestin-2 调节的许多生理和病理生理过程。在简要总结最近的结构研究之后，本文主要关注 arrestin 调节的生理功能，特别关注中枢神经系统以及 arrestin 在致癌作用和关键代谢过程（包括葡萄糖和能量稳态的维持）中的作用。本文还强调了这些研究的潜在治疗意义，并讨论了针对特定 arrestin 调节的信号通路进行治疗的有前途的策略。
两种β-arrestin，结构上密切相关的细胞内蛋白，在进化上高度保守，已成为多功能蛋白，能够调节大量细胞和生理功能。β-arrestin 突变小鼠和培养细胞研究的结果，加上对β-arrestin 结构和功能的新见解，应该为开发新型治疗有用药物铺平道路，这些药物能够调节特定的β-arrestin 功能。
