The two β-arrestins, β-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 β-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 β-arrestins bind to activated GPCRs and downstream effector proteins. Studies with β-arrestin mutant mice have identified numerous physiologic and pathophysiological processes regulated by β-arrestin-1 and/or -2. Following a short summary of recent structural studies, this review primarily focuses on β-arrestin-regulated physiologic functions, with particular focus on the central nervous system and the roles of β-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 β-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.

中文翻译：

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β-抑制蛋白：结构、功能、生理学和药理学观点。

两种 β-arrestin，β-arrestin-1 和 -2（系统名称分别为：arrestin-2 和 -3）是多功能细胞内蛋白，可调节大量细胞信号传导途径和生理功能的活性。这两种蛋白质被发现能够通过与激活的受体结合来破坏 G 蛋白偶联受体 (GPCR) 的信号传导。然而，现在人们普遍认识到，两种 β-抑制蛋白还可以通过 GPCR 依赖或独立机制充当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 β-arrestins 如何与激活的 GPCR 和下游效应蛋白结合提供了新的见解。对 β-arrestin 突变小鼠的研究已经确定了许多由 β-arrestin-1 和/或 -2 调节的生理和病理生理过程。在对最近的结构研究进行简短总结之后，本综述主要关注 β-arrestin 调节的生理功能，特别关注中枢神经系统以及 β-arrestin 在致癌和关键代谢过程（包括维持葡萄糖和能量）中的作用体内平衡。本综述还强调了这些研究的潜在治疗意义，并讨论了可能被证明可用于针对特定 β-抑制蛋白调节信号通路以达到治疗目的的策略。意义陈述：这两种β-抑制蛋白是结构上密切相关的细胞内蛋白，在进化上高度保守，已成为能够调节大量细胞和生理功能的多功能蛋白。对 β-arrestin 突变小鼠和培养细胞的研究结果，加上对 β-arrestin 结构和功能的新见解，应该为开发能够调节特定 β-arrestin 功能的新型治疗有用药物铺平道路。