RGS4 REGULATION OF RECEPTOR AND G PROTEIN SIGNALING

描述(改编自《调查者摘要》)：多种激素和 神经递质依赖于GQ类异源三聚体G蛋白 (Gqpha、G11pha、G14pha和G16pha)和肌醇脂信号转导 在靶组织中发挥作用的途径。RGS蛋白(调节剂 是新发现的G蛋白信号转导家族(17个亚型)。 完全阻断G蛋白功能并发挥中心作用的蛋白质 调节激素受体和G蛋白信号转导。很少有 已知RGS蛋白的广泛细胞作用以及它们如何 职能受到规范。私家侦探最近的研究提供了第一个证据 在大脑中发现的一种RGS蛋白质，RGS4，直接抑制功能 并取消受体和G蛋白介导的肌醇脂质 细胞膜上的信号。初步研究还显示，RGS4、An 固有的亲水性蛋白，定位在质膜上 哺乳动物细胞。这些观察表明，机械的问题是关于 RGS4与GqAlpha信号通路的相互作用。PI已生成 研究RGS蛋白和G的广泛实验工具 使他能够定义细胞和生化机制的蛋白质 潜在的RGS4/GqAlpha相互作用。通过将生化、细胞、 和分子方法，这些研究的主要目标将是：1. 确定RGS4是否可以调节G11α、G14α和G14α的功能 G16Alpha和GqAlpha。2.确定RGS4的分子基础 膜结合和识别潜在的生化因子及其相互作用 在RGS4功能和肌醇脂质信号中的作用。3.确定是否 激活GqAlpha连接的信号通路调节细胞水平 内源性RGS4和其他RGS蛋白抑制GqAlpha信号转导。 这些实验将定义决定RGS和G的分子机制 蛋白质相互作用，并为受体的调节提供了新的视角 发信号。RGS蛋白是新发现的重要G调节蛋白 蛋白质信号，以及它们的行为可能是对人类知之甚少的基础 疾病状态和/或导致临床耐受性的开始 刺激G蛋白信号通路的药物。从以下方面获得的信息 这些研究将帮助我们更好地理解Rgs蛋白作为潜在的 治疗靶点。

DESCRIPTION (Adapted from Investigator's Abstract): Many hormones and neurotransmitters rely on the Gq class of heterotrimeric G proteins (Gqalpha, G11alpha, G14alpha, and G16alpha) and the inositol lipid signaling pathway to exert their actions at target tissues. RGS proteins (Regulators of G protein Signaling) are a newly discovered family (17 isoforms) of proteins that completely block G protein functions and serve a central role in regulating hormone receptor and G protein signaling. Very little is known about the broad cellular actions of RGS proteins and how their functions are regulated. The PI's recent studies provide the first evidence that one RGS protein found in brain, RGS4, directly inhibits the functions of Gqalpha and abolishes receptor and G protein directed inositol lipid signaling in cell membranes. Preliminary studies also reveal that RGS4, an intrinsically hydrophilic protein, is localized at the plasma membrane in mammalian cells. These observations suggest mechanistic questions regarding RGS4 interactions with the Gqalpha signaling pathway. The PI has generated a broad spectrum of experimental tools for studying RGS proteins and G proteins that will allow him to define cellular and biochemical mechanisms underlying RGS4/Gqalpha interactions. By combining biochemical, cellular, and molecular approaches, the major goals of these studies will be to: 1. Determine whether RGS4 can regulate the functions of G11alpha, G14alpha and G16alpha as well as Gqalpha. 2. Define the molecular basis for RGS4 membrane association and identify underlying biochemical factors and their roles in RGS4 function and inositol lipid signaling. 3. Determine whether activation of Gqalpha-linked signaling pathways regulates the cellular level of endogenous RGS4 and other RGS proteins to inhibit Gqalpha signaling. These experiments will define molecular mechanisms that dictate RGS and G protein interactions, and offer new insight into regulation of receptor signaling. RGS proteins are newly appreciated and important regulators of G protein signaling, and their actions may underlie poorly understood human disease states and/or contribute to the onset of tolerance to clinical agents that stimulate G protein signaling pathways. Information gained from these studies will help us better understand RGS proteins as potential therapeutic targets.