Cardiovascular Research Center, Rhode Island Hospital and Alpert Medical School of Brown University, 1 Hoppin St, Providence, RI 02903, USA.
Circ Res. 2011 Jul 22;109(3):320-33. doi: 10.1161/CIRCRESAHA.110.231423.
Signal transduction through G-protein-coupled receptors (GPCRs) is central for the regulation of virtually all cellular functions and has been widely implicated in human disease. Regulators of G-protein signaling (RGS proteins) belong to a diverse protein family that was originally discovered for their ability to accelerate signal termination in response to GPCR stimulation, thereby reducing the amplitude and duration of GPCR effects. All RGS proteins share a common RGS domain that interacts with G protein α subunits and mediates their biological regulation of GPCR signaling. However, RGS proteins differ widely in size and the organization of their sequences flanking the RGS domain, which contain several additional functional domains that facilitate protein-protein (or protein-lipid) interactions. RGS proteins are subject to posttranslational modifications, and, in addition, their expression, activity, and subcellular localization can be dynamically regulated. Thus, there exists a wide array of mechanisms that facilitate their proper function as modulators and integrators of G-protein signaling. Several RGS proteins have been implicated in the cardiac remodeling response and heart rate regulation, and changes in RGS protein expression and/or function are believed to participate in the pathophysiology of cardiac hypertrophy, failure and arrhythmias as well as hypertension. This review is based on recent advances in our understanding of the expression pattern, regulation, and functional role of canonical RGS proteins, with a special focus on the healthy heart and the diseased heart. In addition, we discuss their potential and promise as therapeutic targets as well as strategies to modulate their expression and function.
G 蛋白偶联受体（GPCRs）的信号转导对于几乎所有细胞功能的调节都至关重要，并且广泛涉及人类疾病。G 蛋白信号转导调节剂（RGS 蛋白）属于一个多样化的蛋白质家族，最初因其能够响应 GPCR 刺激加速信号终止的能力而被发现，从而降低 GPCR 效应的幅度和持续时间。所有 RGS 蛋白都共享一个常见的 RGS 结构域，该结构域与 G 蛋白 α 亚基相互作用，并介导其对 GPCR 信号的生物学调节。然而，RGS 蛋白在大小和 RGS 结构域侧翼序列的组织上差异很大，这些序列包含几个额外的功能结构域，这些结构域有助于蛋白质-蛋白质（或蛋白质-脂质）相互作用。RGS 蛋白会发生翻译后修饰，此外，其表达、活性和亚细胞定位可以动态调节。因此，存在多种机制可以促进它们作为 G 蛋白信号调节剂和整合器的正常功能。一些 RGS 蛋白已被牵涉到心脏重构反应和心率调节中，并且 RGS 蛋白表达和/或功能的变化被认为参与了心脏肥大、衰竭和心律失常以及高血压的病理生理学。本综述基于我们对经典 RGS 蛋白表达模式、调节和功能作用的最新理解进展，特别关注健康心脏和患病心脏。此外，我们还讨论了它们作为治疗靶点的潜力和前景，以及调节它们的表达和功能的策略。
