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Title: 聚集素通过抑制calpain和caspase-3的活性稳定神经肌肉接头处乙酰胆碱受体的聚集
Author: 陈飞
Degree Level: 博士
Issued Date: 2008-06-16
Degree Grantor: 中国科学院上海生命科学研究院
Place of Degree Grantor: 上海生命科学研究院
Supervisor: 罗振革
Keyword: 神经肌肉接头 ; 聚集素 ; 乙酰胆碱 ; 半胱氨酸天冬氨酸蛋白酶-3 ; 乙酰胆碱受体聚集体 ; 突触受体偶联蛋白 ; 钙依赖蛋白酶
Alternative Title: Agrin stabilizes AChR clusters by suppressing calpain and caspase-3 activity at the neuromuscular junction
Major: 神经生物学
Abstract: 神经肌肉接头突触发生的过程受到两种因子的调节:运动神经元产生的聚集素(agrin),诱导和稳定乙酰胆碱受体(AChR)的聚集,神经递质乙酰胆碱(ACh),促进AChR聚集体的解聚。两者协同作用,使突触部位聚集AChR,非突触部位的AChR聚集体被解聚。但是agrin对抗ACh作用的分子机制目前还不清楚。我们的工作证明了钙依赖蛋白酶(calpain)和半胱氨酸天冬氨酸蛋白酶-3(caspase-3)能被胆碱能激动剂(CCh)激活,而agrin能抑制calpain和caspase-3的活性。抑制calpain和caspase-3的活性可以阻止CCh解聚AChR聚集物。有趣的是,与AChR结合在一起的突触受体偶联蛋白rapsyn能结合calpain且抑制calpain的活性。agrin促进rapsyn和calpain的结合,抑制突触部位calpain的活性。在体外培养肌肉细胞中阻断rapsyn和calpain的结合会加快CCh引起的AChR聚集体的解聚过程。此外,注射calpain的抑制剂calpeptin,或是肌肉特异地过表达calpain的内源性抑制剂calpastatin均能部分挽救agrin突变小鼠的表型。这些结果显示calpain和caspase-3参与了ACh解聚AChR聚集体的过程,agrin通过抑制它们的活性稳定突触部位的AChR聚集体。
English Abstract: Agrin induces, whereas acetylcholine (ACh) disperses, ACh receptor (AChR) clusters during neuromuscular synaptogenesis. Such counteractive interaction leads to eventual dispersal of nonsynaptic AChR-rich sites and formation of receptor clusters at the postjunctional membrane. However, the underlying mechanisms are not well understood. Here we show that calpain, a calcium-dependent protease, and caspase-3, an effector caspase in apoptotic pathway, are activated by the cholinergic stimulation while inhibited by agrin. Inhibition of calpain and caspase-3 prevents CCh-induced dispersion of AChR clusters. Interestingly, the AChR-associated protein rapsyn interacted with and inhibited the protease activity of calpain. Agrin increased interaction of rapsyn with calpain. Disrupting the endogenous rapsyn / calpain interaction enhanced CCh-induced dispersion of AChR clusters in vitro. Moreover, the loss of AChR clusters in agrin mutant mice was partially rescued by the inhibition of calpain via overexpressing calpastatin, an endogenous calpain inhibitor, or injecting calpeptin, a cell-permeable calpain inhibitor. These results demonstrate that calpain and caspase-3 participates in ACh-induced dispersion of AChR clusters, and agrin stabilizes AChR clusters by suppressing their activity.
Language: 中文
Content Type: 学位论文
URI: http://ir.sibs.ac.cn/handle/331001/2356
Appears in Collections:神经所(总)_学位论文

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Recommended Citation:
聚集素通过抑制calpain和caspase-3的活性稳定神经肌肉接头处乙酰胆碱受体的聚集.陈飞[d].中国科学院上海生命科学研究院,2008.20-25
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