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Title: Rapsyn抑制神经肌肉接头部位Calpain的活性
Author: 钱磊
Degree Level: 博士
Issued Date: 2007-11-16
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: 钙依赖蛋白酶 ; 受体偶联蛋白 ; 聚集素 ; 细胞周期蛋白依赖性激酶5 ; 乙酰胆碱受体聚集 ; 神经肌肉接头 ; 突触发生
Alternative Title: Rapsyn inhibits calpain activity at the neuromuscular junction
Major: 神经生物学
Abstract: 神经肌肉接头突触形成过程受到两种信号分子的作用:其一是agrin,通过其下游MuSK/rapsyn通路诱导乙酰胆碱受体(AChR)聚集;其二是乙酰胆碱 (ACh),通过激活Cdk5促使已形成的AChR聚集体消散。两种作用相互拮抗的最终结果使突触后膜AChR聚集,突触以外部分AChR聚集体解体。但是,目前对agrin和ACh相互拮抗的分子机制仍不清楚。本研究揭示了calpain与rapsyn的相互作用在神经肌肉接头突触后分化中的作用。我们发现钙依赖蛋白酶calpain能够被胆碱能激动剂激活,并且参与Cdk5介导的乙酰胆碱受体聚集体的消散过程。用calpain的抑制剂或siRNA处理肌细胞,能够稳定AChR聚集。另一方面,与AChR结合在一起的agrin的下游信号分子—偶联蛋白rapsyn也能与calpain结合并抑制其活性,这种相互作用受到agrin的调节。下调rapsyn的表达能提高calpain的活性。通过转基因技术使agrin基因突变小鼠的肌肉组织特异地过量表达calpain的内源性抑制剂calpastatin可以挽救agrin突变小鼠的表型,减少AChR聚集体的消散。这些结果显示calpain参与了ACh诱导的AChR聚集体的消散过程,而agrin通过rapsyn抑制calpain的活性,稳定AChR聚集。
English Abstract: The neuromuscular synaptogenesis is regulated by two interdependent effects evoked by an essential synaptic organizing protein, agrin, and the neuromuscular transmitter, acetylcholine (ACh). Agrin induces acetylcholine receptor (AChR) clusters through MuSK / rapsyn pathway, whereas ACh disperses the clusters in a Cdk5-dependent manner. 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. The present study uncovers a role of calpain interaction with rapsyn in regulating postsynaptic differentiation at the neuromuscular junction. We found that calpain, a calcium-dependent protease, was activated by the cholinergic stimulation and involved in the Cdk5-dependent dispersal of AChR clusters. Inhibition or down-regulation of calpain increased AChR cluster stability in cultured myotubes. Interestingly, the AChR-associated protein rapsyn interacted with calpain in an agrin dependent manner, and this interaction inhibited the protease activity of calpain. Down-regulation of rapsyn increased the activity of calpain. Moreover, the loss of AChR clusters in agrin mutant mice was partially rescued by the inhibition of calpain via over-expressing calpastatin, an endogenous calpain inhibitor. These results demonstrate that calpain participates in ACh-induced dispersion of AChR clusters, and agrin stabilizes AChR clusters by suppressing calpain activity through rapsyn-calpain interaction.
Language: 中文
Content Type: 学位论文
URI: http://ir.sibs.ac.cn/handle/331001/2387
Appears in Collections:神经所(总)_学位论文

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Recommended Citation:
Rapsyn抑制神经肌肉接头部位Calpain的活性.钱磊[d].中国科学院上海生命科学研究院,2007.20-25
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