Hollinger Susanne, Hepler John R
Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Pharmacol Rev. 2002 Sep;54(3):527-59. doi: 10.1124/pr.54.3.527.
Regulators of G protein signaling (RGS) and RGS-like proteins are a family (>30 members) of highly diverse, multifunctional signaling proteins that bind directly to activated G alpha subunits. Family members are defined by a shared RGS domain, which is responsible for G alpha binding and markedly stimulates the GTPase activity of G alpha subunits leading to their deactivation and termination of downstream signals. Although much has been learned in recent years about the biochemistry of RGS/G alpha interactions, considerably less is known about the broader cellular roles and regulation of RGS proteins. Recent findings indicate that cellular mechanisms such as covalent modification, alternative gene splicing, and protein processing can dictate the activity and subcellular localization of RGS proteins. Many family members also directly link G proteins to a growing list of signaling proteins with diverse cellular roles. New findings indicate that RGS proteins act not as dedicated inhibitors but, rather, as tightly regulated modulators and integrators of G protein signaling. In some cases, RGS proteins modulate the lifetime and kinetics of both slow-acting (e.g., Ca(2+) oscillations) and fast-acting (e.g., ion conductances, phototransduction) signaling responses. In other cases, RGS proteins integrate G proteins with signaling pathways linked to such diverse cellular responses as cell growth and differentiation, cell motility, and intracellular trafficking. These and other recent studies with animal model systems indicate that RGS proteins play important roles in both physiology and disease. Recognition of the central functions these proteins play in vital cellular processes has focused our attention on RGS proteins as exciting new candidates for therapeutic intervention and drug development.
G蛋白信号调节因子（RGS）和RGS样蛋白是一个高度多样化的多功能信号蛋白家族（超过30个成员），它们直接与活化的Gα亚基结合。家族成员由一个共享的RGS结构域定义，该结构域负责与Gα结合，并显著刺激Gα亚基的GTP酶活性，导致其失活并终止下游信号。尽管近年来在RGS/Gα相互作用的生物化学方面已经有了很多了解，但对于RGS蛋白更广泛的细胞作用和调节却知之甚少。最近的研究结果表明，诸如共价修饰、可变基因剪接和蛋白质加工等细胞机制可以决定RGS蛋白的活性和亚细胞定位。许多家族成员还直接将G蛋白与越来越多具有不同细胞作用的信号蛋白联系起来。新的研究结果表明，RGS蛋白并非专门的抑制剂，而是G蛋白信号的严格调控的调节剂和整合剂。在某些情况下，RGS蛋白调节缓慢作用（如Ca(2+)振荡）和快速作用（如离子电导、光转导）信号反应的持续时间和动力学。在其他情况下，RGS蛋白将G蛋白与与细胞生长和分化、细胞运动和细胞内运输等多种细胞反应相关的信号通路整合起来。这些以及最近在动物模型系统中的其他研究表明，RGS蛋白在生理和疾病中都发挥着重要作用。认识到这些蛋白在重要细胞过程中发挥的核心功能，使我们将注意力集中在RGS蛋白上，它们是治疗干预和药物开发中令人兴奋的新候选物。
