The visual/β-arrestins, a small family of proteins originally described for their role in the desensitization and intracellular trafficking of G protein-coupled receptors (GPCRs), have emerged as key regulators of multiple signaling pathways. Evolutionarily related to a larger group of regulatory scaffolds that share a common arrestin fold, the visual/β-arrestins acquired the capacity to detect and bind activated GPCRs on the plasma membrane, which enables them to control GPCR desensitization, internalization, and intracellular trafficking. By acting as scaffolds that bind key pathway intermediates, visual/β-arrestins both influence the tonic level of pathway activity in cells and, in some cases, serve as ligand-regulated scaffolds for GPCR-mediated signaling. Growing evidence supports the physiologic and pathophysiologic roles of arrestins and underscores their potential as therapeutic targets. Circumventing arrestin-dependent GPCR desensitization may alleviate the problem of tachyphylaxis to drugs that target GPCRs, and find application in the management of chronic pain, asthma, and psychiatric illness. As signaling scaffolds, arrestins are also central regulators of pathways controlling cell growth, migration, and survival, suggesting that manipulating their scaffolding functions may be beneficial in inflammatory diseases, fibrosis, and cancer. In this review we examine the structure-function relationships that enable arrestins to perform their diverse roles, addressing arrestin structure at the molecular level, the relationship between arrestin conformation and function, and sites of interaction between arrestins, GPCRs, and nonreceptor-binding partners. We conclude with a discussion of arrestins as therapeutic targets and the settings in which manipulating arrestin function might be of clinical benefit.

中文翻译：

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Arrestin支架在G蛋白偶联受体信号传导中的不同作用。

视觉/β-arrestins是一小类蛋白质，最初因其在G蛋白偶联受体（GPCR）的脱敏和细胞内运输中的作用而描述，已成为多种信号通路的关键调节剂。从视觉上讲，视觉/β-arrestin与共享共同的抑制蛋白折叠的更大的调节支架相关，因此具有检测并结合质膜上活化的GPCR的能力，从而使它们能够控制GPCR脱敏，内在化和细胞内运输。通过充当结合关键途径中间体的支架，视觉/β-arrestin既影响细胞中途径活性的强直水平，在某些情况下，还充当GPCR介导的信号传导的配体调节支架。越来越多的证据支持抑制蛋白的生理和病理生理作用，并强调它们作为治疗靶标的潜力。规避抑制素依赖的GPCR脱敏可以减轻对靶向GPCR的药物的速激肽反应问题，并在慢性疼痛，哮喘和精神疾病的治疗中得到应用。作为信号转导支架，抑制蛋白也是控制细胞生长，迁移和存活的途径的中心调节剂，表明操纵其支架功能可能对炎性疾病，纤维化和癌症有益。在这篇综述中，我们研究了结构-功能关系，使抑制蛋白能够发挥其不同的作用，在分子水平上研究抑制蛋白的结构，抑制蛋白构象与功能之间的关系，以及抑制蛋白，GPCR和非受体结合伴侣之间相互作用的位点。最后，我们讨论了将抑制蛋白作为治疗靶点以及调控抑制蛋白功能可能具有临床意义的设置。