RGS4 REGULATION OF RECEPTOR AND G PROTEIN SIGNALING

描述（改编自研究者摘要）：许多激素和 神经递质依赖于Gq类异源三聚体G蛋白 （Gq α、G11 α、G14 α和G16 α）和肌醇脂质信号传导 在靶组织中发挥作用的途径。 RGS蛋白（调节剂 G蛋白信号传导）是一个新发现的家族（17种亚型）， 完全阻断G蛋白功能的蛋白质， 在调节激素受体和G蛋白信号传导中的作用。 之甚少 已知RGS蛋白质的广泛细胞作用以及它们如何在细胞中发挥作用。 功能是规范的。 PI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RGS 4， 并消除受体和G蛋白指导的肌醇脂质 细胞膜中的信号。 初步研究还表明，RGS 4， 固有亲水性蛋白质，位于质膜上， 哺乳动物细胞 这些观察结果提出了机械问题， RGS 4与Gqalpha信号通路的相互作用。 PI已经生成了 研究RGS蛋白质和G 这些蛋白质将使他能够定义细胞和生化机制， 潜在的RGS 4/Gqalpha相互作用。 通过结合生物化学，细胞， 和分子方法，这些研究的主要目标是：1。 确定RGS 4是否可以调节G11 α、G14 α和G15 α的功能。 G16 alpha和Gqalpha。 2. 定义RGS 4的分子基础 膜协会和确定潜在的生化因素及其 在RGS 4功能和肌醇脂质信号传导中的作用。 3. 确定是否 Gq α相关信号通路的激活调节细胞水平 内源性RGS 4和其他RGS蛋白抑制Gq α信号传导。 这些实验将确定决定RGS和G 蛋白质相互作用，并提供新的见解，调节受体 信号 RGS蛋白是近年来发现的重要的G 蛋白质信号传导，它们的作用可能是人们知之甚少的人类 疾病状态和/或有助于对临床耐受性的发生 刺激G蛋白信号通路的药物。 从以下来源获得的信息： 这些研究将帮助我们更好地了解RGS蛋白作为潜在的 治疗目标

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.