Regulation of Striatal Signaling by RGS Proteins

RGS 蛋白对纹状体信号传导的调节

• 批准号: 8923232
• 负责人: Kirill A. Martemyanov
• 金额: $ 47.28万
• 依托单位: SCRIPPS FLORIDA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8923232
• 关键词: Address; Adenylate Cyclase; Amphetamines; Animal Model; Behavioral; Behavioral Genetics; Binding; Binding Proteins; Biochemical; Biological Assay; Brain; Brain Diseases; Cell Nucleus; Cells; Cocaine; Complex; Corpus striatum structure; Coupled; Cyclic AMP; Data; Development; Dopamine; Dopamine Receptor; Drug Addiction; Drug Exposure; Drug effect disorder; Employee Strikes; Environment; Event; G Protein-Coupled Receptor Signaling; G-Protein Signaling Pathway; G-Protein-Coupled Receptors; G-substrate; GTP-Binding Protein Regulators; GTP-Binding Proteins; Goals; Health; Imaging Techniques; Kinetics; Knock-out; Knockout Mice; Lead; Macromolecular Complexes; Mediating; Molecular; Morphine; Mus; Neurotransmitters; Opioid; Opioid Receptor; Pathway interactions; Pharmaceutical Preparations; Phosphorylation; Physiological; Play; Positioning Attribute; Process; Protein Biochemistry; Protein Isoforms; Protein Subunits; Proteins; Proteomics; RGS Proteins; Reagent; Receptor Signaling; Regulation; Research; Role; Signal Transduction; Signal Transduction Pathway; Societies; Substance Addiction; System; Testing; Therapeutic; Up-Regulation; addiction; base; behavioral response; calmodulin-dependent protein kinase II; design; drug of abuse; effective therapy; innovation; mouse model; nervous system disorder; neuronal excitability; neurotransmission; novel strategies; psychostimulant; receptor; research study; reward processing; signal processing; small molecule; therapeutic target

DESCRIPTION (provided by applicant): G protein signal transduction pathways in the striatum play a pivotal role in the development of drug addiction. Many drugs of abuse including opioids and psychostimulants produce their effects by activating G proteins in the striatum, a major reward-processing nucleus in the brain. Our long term goal is to elucidate molecular and cellular mechanisms that regulate signaling in the striatal G protein pathways as a necessary prerequisite to understanding events that lead to substance dependence and designing strategies for the therapeutic correction. Increasing evidence suggests that Regulators of G protein Signaling (RGS) proteins play a crucial role in controlling G protein signaling pathways implicated in addiction. RGS proteins serve to curb G protein signaling and thus are optimally positioned to naturally counteract excessive activation of the G protein coupled receptors by drugs of abuse. Small molecule therapeutics targeting RGS proteins are emerging as promising therapeutic strategies. However, the mechanisms of RGS action in regulation of striatal G protein pathways are poorly understood. This proposal is focused on delineating the mechanisms by which key striatal RGS proteins: RGS9-2 and RGS7 regulate cellular signaling. Our recent findings indicate that the function of the two RGS proteins is closely intertwined. They exist as macromolecular complexes with several binding partners and undergo striking remodeling upon drug exposure as well as changes in neuronal excitability suggesting that plasticity in the RGS system contributes to molecular adaptations leading to addiction. Based on accumulated preliminary data we hypothesize that striatal RGS9-2 and RGS7 in cooperation with their binding partners differentially regulate G protein signaling from opioid and dopamine receptors to the central downstream effector adenylyl cyclase and that the plasticity in this system is a critical determinant of the addictive drug actions. This hypothesis will be tested by pursuing three complementary Specific Aims that seek to (1) to determine mechanisms of cAMP regulation by striatal RGS complexes, (2) understand receptor and G protein selectivity of their action and (3) test the role CaMKII? in regulating plasticity of striatal RGS complexes. The strategy proposed to address these Aims will entail a synergistic combination of genetic, behavioral, biochemical, and physiological approaches, exploiting the existence of a powerful array of reagents and animal models.

描述（由申请人提供）：纹状体中的G蛋白信号转导途径在药物成瘾的发展中起关键作用。包括阿片类药物和精神刺激剂在内的许多滥用药物通过激活纹状体中的G蛋白来产生其作用，纹状体是大脑中主要的奖励处理核。我们的长期目标是阐明调节纹状体G蛋白途径中信号传导的分子和细胞机制，这是理解导致治疗校正的物质依赖和设计策略的事件的必要先决条件。 越来越多的证据表明，G蛋白信号传导（RGS）蛋白的调节剂在控制与成瘾有关的G蛋白信号传导途径中起着至关重要的作用。 RGS蛋白可用于遏制G蛋白信号传导，因此可以最佳地定位于通过滥用药物自然抵消G蛋白偶联受体的过度激活。针对RGS蛋白的小分子疗法正在成为有希望的治疗策略。但是，RGS作用在调节纹状体G蛋白途径中的机制知之甚少。 该建议的重点是描述关键纹状体RGS蛋白：RGS9-2和RGS7调节细胞信号的机制。我们最近的发现表明，两种RGS蛋白的功能紧密相互交织。它们以具有几个结合伴侣的大分子复合物的形式存在，并在药物暴露时进行了惊人的重塑以及神经元兴奋性的变化，这表明RGS系统中的可塑性有助于分子适应，从而导致成瘾。 基于累积的初步数据，我们假设纹状体RGS9-2和RGS7与它们的结合伴侣合作，差异地调节了G蛋白信号从阿片类药物和多巴胺受体到中央下游效应子腺苷酸环化酶的蛋白质信号传导，并且该系统中的可变性是对成瘾性药物的关键确定性。该假设将通过追求三个互补的特定目的来检验，这些特定目的（1）通过纹状体RGS复合物来确定cAMP调节的机制，（2）了解其作用的受体和G蛋白选择性以及（3）测试CAMKII的作用？在调节纹状体RGS复合物的可塑性中。提出的解决这些目标的策略将需要遗传，行为，生化和生理方法的协同组合，从而利用强大的试剂和动物模型的存在。