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E3 Ligases and Deubiquitinases in GPCR downregulation

GPCR 下调中的 E3 连接酶和去泛素酶

基本信息

批准号：
7269341
负责人：
SUDHA K SHENOY
金额：
$ 25.89万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-08-01 至 2010-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7269341
关键词：
Adaptor Signaling Protein Address Adrenergic Agents Adrenergic Receptor Agonist Arrestin Arrestins Asthma Binding Biology Cardiovascular system Cell Surface Receptors Cell surface Cells Characteristics Chronic Cleaved cell Cysteine Protease Degradation Pathway Deubiquitinating Enzyme Deubiquitination Development Down-Regulation Duct (organ) structure Enzymes Family Fluorescence Resonance Energy Transfer G Protein-Coupled Receptor Signaling G-Protein-Coupled Receptors Goals Heart failure Isoproterenol Kidney Knowledge Lead Libraries Life Life Cycle Stages Location Lung diseases Lysine Lysosomes Mediating Modification Molecular Object Attachment Post-Translational Protein Processing Process Protein Overexpression Proteins Pulmonary Hypertension Rate Recycling Regulation Research Personnel Role Signal Transduction Site Small Interfering RNA Sorting - Cell Movement Specificity Substrate Specificity Time Ubiquitin Ubiquitination V2 Receptors Vasopressin Receptor Vasopressins adapter protein adrenergic antidiuretic attenuation base beta-2 Adrenergic Receptors beta-arrestin cell type design member mutant novel novel therapeutics prevent programs receptor receptor downregulation receptor internalization research study response trafficking ubiquitin-protein ligase ubiquitin-specific protease

项目摘要

DESCRIPTION (provided by applicant): The beta 1 and beta 2 adrenergic receptors are members of the super-family of G protein-coupled receptors (GPCRs). This receptor super-family comprises some of the most important pharmacological targets for the treatment of cardiovascular (e.g. heart failure, hypertension) and pulmonary diseases (e.g. asthma). A major cause for the observed attenuation of adrenergic response in heart failure and asthma is receptor downregulation, which results from chronic agonist exposure. Recently, ubiquitination of cell-surface receptors has been implicated as an important mechanism for post-endocytic sorting to lysosomes. Ubiquitination is a post-translational modification of proteins orchestrated by a well-defined process involving a cascade of three enzymatic activities. Of these the final step, catalyzed by the enzyme, E3 ubiquitin ligase, determines the specificity of substrate ubiquitination. We have demonstrated that two representative GPCRs, the beta2 adrenergic receptor and the V2 vasopressin receptor and their adaptor protein beta-arrestin become ubiquitinated upon agonist stimulation. Ubiquitination of beta-arrestin is crucial for receptor internalization, whereas ubiquitination of the receptor is essential for the proper sorting and downregulation of the internalized and activated receptors. We hypothesize that ubiquitination and deubiquitination coordinate the trafficking and signaling of GPCRs and involve a specific set of endocytic adapter proteins including beta-arrestins. The specific aims are: 1) to define the molecular mechanisms of receptor ubiquitination leading to receptor downregulation, and 2) to determine the roles of deubiquitinating enzyme(s) in receptor trafficking. Unraveling the molecular mechanisms governing the regulation of GPCRs, especially beta ARs, by ubiquitination could have a great impact on the development of novel therapeutic strategies for cardiovascular and pulmonary diseases.

描述（由申请人提供）：β 1和β 2肾上腺素能受体是G蛋白偶联受体（GPCR）超家族的成员。该受体超家族包括用于治疗心血管疾病（例如心力衰竭、高血压）和肺部疾病（例如哮喘）的一些最重要的药理学靶标。在心力衰竭和哮喘中观察到的肾上腺素能反应减弱的主要原因是受体下调，这是由慢性激动剂暴露引起的。最近，细胞表面受体的泛素化被认为是溶酶体内吞后分选的重要机制。泛素化是蛋白质的翻译后修饰，其由涉及三种酶活性级联的明确定义的过程协调。其中，由酶E3泛素连接酶催化的最后一步决定底物泛素化的特异性。我们已经证明，两个代表性的GPCR，β 2肾上腺素能受体和V2加压素受体和它们的衔接蛋白β-arrestin激动剂刺激后变得泛素化。β-抑制蛋白的泛素化对于受体内化是至关重要的，而受体的泛素化对于内化和活化的受体的正确分选和下调是必不可少的。我们假设泛素化和去泛素化协调GPCR的运输和信号传导，并涉及一组特定的内吞衔接蛋白，包括β-arrestins。具体目标是：1）确定受体泛素化导致受体下调的分子机制，和2）确定去泛素化酶在受体运输中的作用。揭示通过泛素化调控GPCR，特别是β AR的分子机制可能对心血管和肺部疾病的新治疗策略的发展产生重大影响。