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控制G蛋白偶联受体(GPCRs)信号转导的机制。本申请的重点是一类发育调节的、视觉和神经系统特异的G23二聚体，由G25组成，G25是最分散和最不被理解的G2家族成员，与G蛋白调节蛋白RGS7(R7)家族中任何成员的G3样结构域结合。R7-G25异源二聚体结合一种新的棕榈酰化SNARE样蛋白R7BP。这一应用的中心假设是，R7BP上的棕榈酸酯循环控制着R7-G25-R7BP复合体的定位和功能，作为神经元结构和功能的调节器。本项目将利用跨学科的细胞、分子和电生理分析来验证这一假说，以解决以下具体目标：1)确定调控R7BP棕榈酸循环和原代神经元运输的机制；2)确定R7BP如何调控R7-G25复合体调节突触传递的能力以及棕榈酰化在这些过程中的作用；以及3)确定R7-G25-R7BP复合体调控神经元发育、可塑性和形态发生的信号机制。 公共卫生相关性：目前用于治疗帕金森氏症、癫痫、成瘾、疼痛和抑郁等中枢神经系统慢性疾病的药物的疗效往往受到副作用或耐受性发展的限制。了解调控药物作用的机制可能会导致确定增强药物疗效或特异性的新方法。该项目通过阐明控制蛋白质复合体的作用的新机制来推进这一目标，这些复合体调节可卡因和吗啡的作用，可能还有其他通过神经系统中调节G蛋白偶联受体发挥作用的药物。

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.