MECHANISM AND REGULATION OF RECEPTOR-G PROTEIN SIGNALING

受体-G 蛋白信号传导的机制和调控

基本信息

批准号：
8911322
负责人：
Kendall J Blumer
金额：
$ 56.03万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1990
资助国家：
美国
起止时间：
1990-07-01 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8911322
关键词：
Absence of pain sensation Address Adenylate Cyclase Adjuvant Adverse effects Agonist Amphetamines Animals Arrestins Binding Binding Proteins Biological Cell Nucleus Cell membrane Cells Chronic Clinical Cocaine Complex Cyclic AMP Data Disease Dopamine Agonists Dose-Limiting Drug Targeting Drug Tolerance Drug effect disorder Drug usage Enzymes Excision Exhibits Family G Protein-Coupled Receptor Signaling G-Protein-Coupled Receptors GTP-Binding Proteins Goals Health Heroin Individual Knockout Mice Knowledge Malaria Malignant Neoplasms Mediating Modeling Molecular Morphine Motor Motor Activity Mus Nerve Degeneration Nervous system structure Neurobiology Neurologic Neurons Neurotransmitters Opioid Organ Palmitates Parkinson Disease Phenotype Phosphorylation Protein Binding Protein Isoforms Proteins RGS Proteins Regulation Research Personnel Role SNAP receptor Selective Serotonin Reuptake Inhibitor Signal Pathway Signal Transduction System Therapeutic Therapeutic Agents Therapeutic Uses Tissues addiction cell type chronic pain drug discovery drug of abuse genetic analysis human Huntingtin protein improved inhibitor/antagonist nervous system disorder novel novel therapeutics overexpression palmitoylation protein function receptor segregation signal processing small molecule trafficking v-src Oncogenes

项目摘要

DESCRIPTION (provided by applicant): G protein-coupled receptors (GPCRs) and their signaling pathways are the targets of many current therapeutics as well as drugs of abuse. Most currently used therapeutics were developed decades ago when few components of GPCR signaling systems were known. However, new therapeutics, such as agonists biased to evoke GPCR-arrestin signaling, are being developed as a consequence of identifying novel components and regulators of GPCR signaling networks. Such novel targets potentially enable long-standing problems associated with current therapeutics, such as drug tolerance, side effects or addiction, to be reduced or eliminated. This project addresses these long-term goals by identifying novel mechanisms that control GPCR signaling in the nervous system. It focuses on the R7 RGS family of G protein regulators, which have been shown genetically to be critical intracellular regulators of GPCR signaling throughout the nervous system, and which regulate the biological effects of opioids and amphetamines, and side effects of L-DOPA. The Aims will determine how R7 RGS proteins under the control of a palmitoylated allosteric regulator called R7BP (R7 RGS-binding protein) regulate the activity of adenylyl cyclases and cAMP signaling in neuronal cells. They will identify novel enzymes that regulate palmitate turnover on R7BP and establish the functions of these enzymes as regulators of GPCR signaling in neuronal cells. Lastly, they will determine whether global or local cycles of palmitate turnover regulate the intracellular trafficking and function of R7BP-bound R7 RGS complexes. New knowledge gained by this project will provide deeper understanding of neurobiological signaling processes controlled by R7 RGS proteins, new models for elucidating the functions of palmitate turnover in diverse aspects of cell signaling and disease, and new drug targets that potentially enhance the action or reduce the side effects of GPCR-targeted neurotherapeutics.

描述（由申请人提供）：G蛋白偶联受体（GPCR）及其信号通路是许多当前治疗剂和滥用药物的靶标。当前使用的治疗剂是几十年前开发的，当时很少有GPCR信号系统的组件。然而，由于鉴定新的组件和GPCR信号网络的调节剂，正在开发新的治疗剂，例如偏向GPCR-arrestin信号传导的激动剂。这种新颖的目标有可能导致与当前治疗剂有关的长期存在的问题，例如药物耐受性，副作用或成瘾，以减少或消除。该项目通过确定控制神经系统中GPCR信号的新机制来解决这些长期目标。它着重于G蛋白调节剂的R7 RGS家族，在整个神经系统中，遗传上已显示为GPCR信号的关键细胞内调节剂，并调节阿片类药物和苯丙胺的生物学作用，以及L-DOPA的侧面作用。目的将决定R7 RGS蛋白如何控制棕榈酰化的变构调节剂R7BP（R7 RGS结合蛋白）调节腺苷酸环酶和神经元细胞中cAMP信号的活性。他们将鉴定出调节R7BP棕榈酸酯周转率的新型酶，并确定这些酶作为神经元细胞中GPCR信号的调节剂的功能。最后，他们将确定棕榈酸酯离职率的全球或局部周期是否调节了R7BP结合的R7 RGS复合物的细胞内贩运和功能。该项目获得的新知识将提供对由R7 RGS蛋白控制的神经生物学信号传导过程的更深入的了解，这是用于阐明细胞信号传导和疾病各个方面的棕榈酸酯更换功能的新模型，以及新的药物靶标，这些靶标有可能增强或降低涉及GPCR神经疗法的副作用的作用。