M1胆碱受体激动剂对Gαq、Gαs及β-arrestin信号通路的偏向性激活及其分子机制

项目名称： M1胆碱受体激动剂对Gαq、Gαs及β-arrestin信号通路的偏向性激活及其分子机制

项目编号： No.81503174

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 徐见容

作者单位： 上海交通大学

项目金额： 18.2万元

中文摘要： G蛋白偶联受体（GPCRs）是最重要的一类药物靶点，配体在激动GPCRs时可不同程度地同时激活多条由不同Gα亚型及β-arrestin介导的信号通路，产生信号通路偏好。激动剂只有激活特定信号通路才能治疗疾病，激活其他通路则导致副作用。M1胆碱受体（M1受体）属于GPCRs，与阿尔茨海默病、精神分裂症认知障碍等重大疾病密切相关，然而多种M1受体调控剂的研发均因临床试验中不良反应多发而终止，M1受体激活下游的Gαs及β-arrestin通路是不良反应潜在来源。因此，有必要探究各类激动剂对M1受体的信号通路偏好，解析激动剂与信号通路偏好之间的构效关系，阐明信号通路偏好产生的分子机制。上述研究不仅能加深对M1受体信号转导复杂性的认识，还能完善其调控剂内在活性的评价方法，为发现具有信号通路选择性的调控剂提供理论支持及实验基础。

中文关键词： 毒蕈碱型乙酰胆碱受体；信号通路偏好；内在活性；构效关系；分子机制

英文摘要： G-protein coupled receptors (GPCRs) are the most important targets in drug discovery. Ligands can simultaneously activate several signaling pathways mediated by Gα subtypes and β-arrestin at different degrees to generate signaling bias. The therapeutic effects can be achieved by agonists through activating some specific pathway, while the activation of other pathways may cause side effects. M1 muscarinic acetylcholine receptor (M1 receptor) belongs to GPCRs, and it is closely related to many serious diseases, such as cognitive deficits in Alzheimer’s disease, and schizophrenia. However, the development of several M1 receptor modulators were terminated for the adverse events frequently occurred in clinical trials. The activation of Gαs and β-arrestin signaling pathways mediated by M1 receptor could be the potential source of these adverse events. Therefore, it is desiderate to explorer the signaling bias of various agonists to M1 receptor, to construct the structure-activity relationship between agonists and the signaling bias, and to elucidate the molecular mechanism of signaling bias in M1 receptor. The study can deepen the understanding of the complexity in the signaling transduction of M1 receptor, improve the assay developments of the whole intrinsic efficacy, and provide theoretical support and experimental basis for the discovery of modulators with pathway selectivity.

英文关键词： muscarinic acetylcholine receptor;biased signaling;intrinsic efficacy;structure-activity relationship;molecular mechanism