MECHANISM AND REGULATION OF RECEPTOR-G PROTEIN SIGNALING

描述（由申请人提供）：本项目的长期目标是确定G蛋白偶联受体（GPCR）控制信号转导的机制。本申请的焦点是一类发育调节的视觉和神经系统特异性G23二聚体，其由G25组成，G25是最分歧和最不了解的G2家族成员，结合到G蛋白调节剂的RGS 7（R7）家族的任何成员的G3样结构域。R7-G25异二聚体结合R7 BP，一种新的棕榈酰化SNARE样蛋白。本申请的中心假设是R7 BP上的棕榈酸循环控制R7-G25-R7 BP复合物作为神经元结构和功能的调节剂的定位和功能。本项目将通过跨学科的细胞、分子和电生理学实验来验证这一假设，具体目的如下：1）确定R7 BP棕榈酸循环和运输的调控机制; 2）确定R7 BP如何调控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;和3）鉴定R7-G25-R7 BP复合物调节神经元发育、可塑性和形态发生的信号传导机制。 公共卫生相关性：目前用于治疗帕金森病、癫痫、成瘾、疼痛和抑郁症等慢性中枢神经系统疾病的药物的功效往往受到副作用或耐受性发展的限制。了解调节药物作用的机制可能会导致识别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物作用的新机制来推进这一目标，该蛋白质复合物调节可卡因和吗啡的作用，并且可能通过神经系统中的调节性G蛋白偶联受体起作用的其他药物。

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.