MECHANISM AND REGULATION OF RECEPTOR-G PROTEIN SIGNALING

描述（由申请人提供）：该项目的长期目标是确定G蛋白偶联受体（gpcr）信号转导的调控机制。本应用的重点是一类发育调控的、视觉和神经系统特异性的G23二聚体，由G25组成，G25是G2家族成员中分化最广、了解最少的，与G蛋白调节剂RGS7 （R7）家族的任何成员的g3样结构域结合。R7-G25异源二聚体结合R7BP，一种新的棕榈酰化snare样蛋白。该应用的中心假设是棕榈酸盐在R7BP上的循环控制R7-G25-R7BP复合物的定位和功能，作为神经元结构和功能的调节剂。该项目将通过采用跨学科的细胞、分子和电生理分析来验证这一假设，以解决以下具体目标：1)确定调节R7BP棕榈酸盐循环和初级神经元运输的机制；2)确定R7BP如何调节R7- G25复合物调节突触传递的能力以及棕榈酰化在这些过程中的作用；3)确定R7-G25-R7BP复合物调控神经元发育、可塑性和形态发生的信号机制。

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.