Regulation of GPCR signaling with receptor-specific arrestins

描述（由申请人提供）：抑制蛋白最初被发现为通过G蛋白的G蛋白偶联受体（GPCR）信号传导的负调节剂。最近的发现表明，arrestin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，包括通过MAP激酶调节细胞死亡、存活和增殖的途径。由突变或环境损伤诱导的GPCR信号转导的基因调控是许多人类疾病的基础。不幸的是，通过抑制蛋白（其是天然GPCR调节剂）靶向受体信号传导的治疗受到缺乏非视觉亚型的选择性的阻碍，这两种亚型都与数十种GPCR相互作用。在这里，我们建议构建和功能特性的非视觉arrestins显着增强的特异性，个别GPCR。将测试受体特异性突变体及其增强的磷酸化非依赖性变体通过特定GPCR亚型经由G蛋白、抑制蛋白和受体运输选择性调节信号传导的能力。将测试优先与特定受体相互作用的突变体选择性破坏受体的能力。 与同源G蛋白偶联。对D1和D2多巴胺受体具有高度偏好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，运动障碍是目前抗帕金森病治疗最常见的破坏性副作用。GPCR信号的受体特异性调节在与先天性或获得性细胞信号失衡相关的多种疾病中具有治疗潜力。

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.