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）：最初被认为是通过G蛋白的G蛋白偶联受体（GPCR）信号的负调节剂。最近的发现表明，抑制素受体复合物通过不同的G蛋白非依赖性途径（包括调节细胞死亡，生存和通过MAP激酶增殖的途径）引发信号传导。突变或环境侮辱引起的GPCR信号的错误调节是许多人类疾病的基础。不幸的是，由于缺乏非视觉亚型的选择性，通过抑制蛋白（天然GPCR调节剂）通过抑制蛋白进行治疗性靶向受体信号传导，这两者都与数十个GPCR相互作用。在这里，我们提出构建并在功能上表征非视野逮捕蛋白，其特异性显着增强了单个GPCR。受体特异性突变体及其增强的磷酸化非依赖性变体，将测试其通过G蛋白，抑制蛋白和受体运输的特殊GPCR亚型选择性调节信号的能力。优先与特定受体相互作用的突变体将测试其选择性破坏受体的能力耦合到同名G蛋白。对D1和D2多巴胺受体偏爱的突变体将用于确定哪种受体亚型在运动障碍的发展中起关键作用，这是当前抗帕金森氏症治疗的最常见毁灭性副作用。 GPCR信号的受体特异性调节在与先天性或细胞信号中获得的多种疾病中具有治疗潜力。