| 蒋敏洁,张永芳,王冬雪,王 昊,徐见容,赵兰雪.Aβ寡聚体调控M1胆碱受体下游信号转导通路的机制研究[J].,2022,(17):3201-3207 |
| Aβ寡聚体调控M1胆碱受体下游信号转导通路的机制研究 |
| The Mechanism of Aβ Oligomers Regulating the Downstream Signaling Transduction of M1 Muscarinic Acetylcholine Receptor |
| 投稿时间：2022-02-22 修订日期：2022-03-16 |
| DOI：10.13241/j.cnki.pmb.2022.17.001 |
| 中文关键词: Aβ寡聚体 M1毒蕈碱型乙酰胆碱受体 信号转导通路 阿尔茨海默病 G蛋白偶联受体 |
| 英文关键词: Aβ oligomer M1 muscarinic acetylcholine receptor Signaling pathway Alzheimer's disease G-protein-coupled receptor |
| 基金项目:上海市卫计委临床研究专项（20194Y0056）；国家自然科学基金面上项目（82173798） |
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| 中文摘要: |
| 摘要 目的：阿尔茨海默病（Alzheimer's disease, AD）病理状态下M1胆碱受体功能受损，无法对配体做出正确响应。本研究模拟AD早期Aβ寡聚体富集的病理状态，考察对M1胆碱受体下游信号通路关键分子活性的影响，以期为AD病理状态下M1胆碱受体信号偶联障碍机制提供新的见解。方法：制备Aβ寡聚体（Aβ oligomers, AβOs），1 μM AβOs预处理CHO-M1细胞30 min、24 h和48 h，加入胆碱受体激动剂乙酰胆碱或者卡巴胆碱激活M1胆碱受体，利用Ca2+检测实验、IP-One-Gq KIT检测实验及Western blot实验检测受体激动后下游关键信号分子Ca2+、IP1的释放量以及ERK磷酸化的动态变化。结果：AβOs预处理导致激活细胞内M1胆碱受体其下游Ca2+和IP1的释放量减少、ERK被更快激活。结论：AβOs预处理导致激活M1胆碱受体下游关键信号分子释放水平、磷酸化水平异常，揭示在阿尔茨海默病早期M1胆碱受体便出现功能障碍，无法正确激活信号转导通路。 |
| 英文摘要: |
| ABSTRACT Objective: M1 muscarinic receptors are functional impairment in Alzheimer's disease (AD) and fail to respond to ligands properly. This study simulated the pathological state of Aβ oligomers enrichment in early AD, and investigated the effects on the activities of key molecules in the downstream signaling pathway of M1 muscarinic receptors, in order to provide new insights into the mechanism of M1 muscarinic receptors coupling disorder in AD. Methods: Aβ oligomers were successfully prepared in vitro. CHO-M1 cells were pretreated with 1 μM Aβ oligomers for 30 min, 24 h, and 48 h, and then ACh or CCh agonists were adopted to activate the M1 muscarinic receptors. Calcium mobilization assay, IP-One-Gq KIT and Western blot were utilized to detect the downstream key signaling molecules Ca2+, IP1 and the dynamic changes of ERK phosphorylation after receptors activation. Results: Aβ oligomers preconditioning resulted in reduced Ca2+ and IP1 release and earlier activation of ERK in the downstream of the activated M1 muscarinic receptors. Conclusion: Aβ oligomers pretreatment lead to abnormal release and phosphorylation levels of key signaling molecules downstream of activated M1 muscarinic receptors, revealing that M1 muscarinic receptors are dysfunctional in the early stages of AD and cannot correctly activate signaling transduction pathways. |
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