MECHANISM AND REGULATION OF RECEPTOR-G PROTEIN SIGNALING

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DESCRIPTION (provided by applicant): The long-term goal of this project is to define mechanisms that govern signal transduction by G protein-coupled receptors (GPCRs). The focus of the present application is a class of developmentally-regulated, visual and nervous system-specific G23 dimers consisting of G25, the most diverged and least understood G2 family member, bound to the G3-like domain of any member of the RGS7 (R7) family of G protein regulators. R7-G25 heterodimers bind R7BP, a novel palmitoylated SNARE-like protein. The central hypothesis of this application is that palmitate cycling on R7BP controls the localization and function of R7-G25-R7BP complexes as regulators of neuronal structure and function. This project will test this hypothesis by employing interdisciplinary cell, molecular and electrophysiological assays that address the following Specific Aims: 1) identify mechanisms that regulate R7BP palmitate cycling and trafficking in primary neurons; 2) determine how R7BP regulates the ability of R7- G25 complexes to modulate synaptic transmission and the role of palmitoylation in these processes; and 3) identify signaling mechanisms whereby R7-G25-R7BP complexes regulate neuronal development, plasticity and morphogenesis. PUBLIC HEALTH RELEVANCE: The efficacy of drugs currently used to treat chronic disorders of the central nervous system, such as Parkinson's disease, epilepsy, addiction, pain and depression, often is limited by side effects or the development of tolerance. Understanding the mechanisms that regulate drug action could lead to the identification of novel means of augmenting drug efficacy or specificity. This project advances this goal by elucidating new mechanisms controlling the action of protein complexes that regulate the action of cocaine and morphine, and probably other drugs that act via modulatory G protein- coupled receptors in the nervous system.