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Regulation of GPCR signaling with receptor-specific arrestins

使用受体特异性抑制蛋白调节 GPCR 信号传导

基本信息

批准号：
9189631
负责人：
VSEVOLOD V. GUREVICH
金额：
$ 37.17万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-01-01 至 2017-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9189631
关键词：
Adverse effects Affect Affinity Agonist Allosteric Site Animals Antiparkinson Agents Arrestins Asthma Attenuated Binding Binding Sites Cell Death Cells Clinical Complex Coupling Data Development Disease Dopamine Dopamine D1 Receptor Dopamine D2 Receptor Dopamine Receptor Down-Regulation Drug usage Dyskinetic syndrome Engineering Family G Protein-Coupled Receptor Signaling G-Protein-Coupled Receptors G-substrate GTP-Binding Proteins Genes Heart Diseases Individual Induced Mutation Inherited L-DOPA induced dyskinesia Levodopa Ligand Binding MAPK10 gene MAPK3 gene Mammals Mediating Mitogen-Activated Protein Kinases Modeling Mus Mutation Parkinson Disease Pathway interactions Pharmaceutical Preparations Phosphorylation Photoreceptors Play Property Receptor Activation Receptor Signaling Regulation Replacement Therapy Research Retina Rhodopsin Role Signal Pathway Signal Transduction Signaling Protein Sorting - Cell Movement Specificity Structure Surface Testing Therapeutic Translating Transmembrane Domain Variant Visual arrestin 1 arrestin 2 arrestin3 base design extracellular human disease in vivo mutant nervous system disorder non-visual arrestins preference prevent protein protein interaction public health relevance receptor receptor binding receptor coupling receptor expression receptor internalization receptor-mediated signaling response targeted treatment therapeutic target trafficking virtual

项目摘要

DESCRIPTION (provided by applicant): Arrestins were originally discovered as negative regulators of G protein-coupled receptor (GPCR) signaling via G proteins. Recent discoveries show that the arrestin-receptor complex initiates signaling through distinct G protein-independent pathways, including those that regulate cell death, survival, and proliferation via MAP kinases. Faulty regulation of GPCR signaling induced by mutations or environmental insults underlies many human diseases. Unfortunately, therapeutic targeting receptor signaling via arrestins, which are natural GPCR regulators, is hampered by lack of selectivity of the non- visual subtypes, both of which interact with dozens of GPCRs. Here we propose to construct and functionally characterize non-visual arrestins with dramatically enhanced specificity for individual GPCRs. Receptor-specific mutants, as well as their enhanced phosphorylation-independent variants, will be tested for their ability to selectively regulate signaling by particuar GPCR subtypes via G proteins, arrestins, and receptor trafficking. Mutants that preferentially interact with particular receptors will be tested for their ability to selectively disrupt receptor coupling to cognate G proteins. Mutants with high preference for D1 and D2 dopamine receptors will be used to determine which receptor subtype plays key role in the development of dyskinesia, the most common devastating side effect of current anti- parkinsonian therapy. Receptor-specific regulation of GPCR signaling has therapeutic potential in multiple disorders associated with congenital or acquired imbalances in cell signaling.

描述（由申请人提供）：Arrestins最初是作为G蛋白偶联受体（GPCR）信号传导的负调节因子被发现的。最近的发现表明，阻滞蛋白受体复合物通过不同的G蛋白非依赖性途径启动信号传导，包括那些通过MAP激酶调节细胞死亡、存活和增殖的途径。突变或环境损伤诱导的GPCR信号的错误调控是许多人类疾病的基础。不幸的是，通过抑制因子（一种天然的GPCR调节因子）靶向受体信号的治疗受到非视觉亚型缺乏选择性的阻碍，这两种亚型都与数十种GPCR相互作用。在这里，我们提出构建和功能表征非视觉抑制与显著提高特异性的单个gpcr。受体特异性突变体，以及它们增强的磷酸化非依赖性突变体，将测试它们通过G蛋白、抑制因子和受体运输选择性调节特定GPCR亚型信号的能力。优先与特定受体相互作用的突变体将被测试其选择性破坏受体的能力