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.
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