Role of RGS Proteins in Opioid Addiction

RGS 蛋白在阿片类药物成瘾中的作用

基本信息

批准号：
9306687
负责人：
Brian S Muntean
金额：
$ 5.71万
依托单位：
SCRIPPS FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9306687
关键词：
Absence of pain sensation Adaptor Signaling Protein Address Adenylate Cyclase Affect Alpha Cell Automobile Driving Behavioral Binding Biological Assay Brain Catalytic Domain Cell membrane Cells Chemicals Chronic Complex Corpus striatum structure Couples Cyclic AMP Cyclic AMP Receptors Data Dependence Development Dimerization Dopamine Drug Addiction Evaluation Exhibits Fluorescence Resonance Energy Transfer G-Protein-Coupled Receptors G-substrate GTP-Binding Protein Regulators GTP-Binding Proteins GTPase-Activating Proteins Gap Junctions Gatekeeping Generations Genetic Goals Image Individual Kinetics Knock-out Knowledge Link Macromolecular Complexes Mediating Membrane Molecular Monitor Morphine Mus Neurons Opiate Addiction Opioid Opioid Receptor Optics Pharmacology Phenotype Physiological Play Positioning Attribute Preparation Process Protein Complex Subunit Protein Family Proteins Public Health RGS Proteins Reaction Receptor Activation Receptor Signaling Recruitment Activity Regulation Reporter Rewards Role Second Messenger Systems Shapes Signal Pathway Signal Transduction Signaling Protein Site Slice System Testing Time Withdrawal Withdrawal Symptom Work addiction base behavioral response dimer drug of abuse effective therapy experimental study flexibility insight mouse model mu opioid receptors novel opiate tolerance opioid withdrawal postsynaptic presynaptic protein complex public health relevance receptor response therapeutic target

项目摘要

DESCRIPTION (provided by applicant): The development of opioid tolerance and dependence continues to be a widespread public health concern. Opioids generate addictive effects by activating G protein coupled receptors in the striatum, which leads to adaptive changes in signaling pathways. Our long-term goal is to understand the molecular regulation of striatal G protein activity due to its importance for managing drug addiction. Recent work has revealed that G protein signaling is deactivated within the cell by a family of proteins termed Regulators of G protein Signaling (RGS). This provides the cell an intrinsic mechanism to modulate signaling during receptor stimulation by drugs of abuse, however little is known about the roles of RGS in addiction. This proposal is focused on the molecular regulation of signaling reactions by essential striatal RGS proteins during the development of opioid tolerance and dependence. Recent work has shown that RGS7 and RGS9-2 bind the same adapter proteins to form macromolecular complexes in the striatum. The abundance of these RGS subunits is sensitive to morphine exposure and mouse models have revealed the differential involvement of the RGS complex subunits in shaping behavioral responses to opioids. Collectively with our preliminary data, we hypothesize the RGS complex plays an essential role in regulating MOR signaling that gates sensitivity to the central downstream effector adenylate cyclase and the generation of the second messenger cAMP. This hypothesis will be tested in two complementary aims: 1) To understand adaptations in adenylate cyclase-cAMP axis in response to opioid receptor activation and the role of RGS complex in this process, 2) To characterize the mechanistic role of individual subunits in the RGS complex in controlling opioid signaling. Our approach will utilize optical assessment of live brain slice preparations from a multitude of genetic mouse models in addition to advanced cell-based assays. The conclusion of these studies will greatly expand our knowledge of opioid signaling plasticity, roles of RGS proteins in addiction, and evaluation of a novel mouse model.

描述（通过应用程序证明）：阿片类药物的耐受性和依赖性的发展继续是纹状体中的兴奋性G g蛋白耦合受体，这会导致信号传导的自适应变化。蛋白质的活性由于其在G蛋白质信号中的重要性。加法。最近的工作表明，RGS9-2结合了相同的适配器蛋白，在这些RGS亚基中形成了大分子的大分子。在剃须行为呼吸中。，2）表征单个亚基在RGS压缩中的机械作用，将利用来自多种基于CED细胞的遗传慕斯的光学评估。我们对阿片类药物信号传导塑性的了解，RGS蛋白的作用以及新型模式的评估。