Rapsyn interaction with calpain stabilizes AChR clusters at the neuromuscular junction
Rapsyn interaction with calpain stabilizes AChR clusters at the neuromuscular junction
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DOI：
10.1016/j.neuron.2007.06.031
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发表时间：
2007-07-19
期刊：
影响因子：
16.2
通讯作者：
Luo, Zhen-Ge
中科院分区：
文献类型：
--
作者：
Chen, Fei;Qian, Lei;Luo, Zhen-Ge
在神经肌肉突触发生过程中，聚集蛋白诱导乙酰胆碱受体（AChR）聚集，而乙酰胆碱（ACh）分散。这种反作用的相互作用导致最终分散的非突触AChR丰富的网站和形成的受体簇在postjunctional膜。然而，其潜在机制尚未完全了解。在这里，我们表明，钙蛋白酶，钙依赖性蛋白酶，被激活的胆碱能刺激和所需的AChR集群诱导分散。有趣的是，AChR相关蛋白rapsyn以聚集蛋白依赖的方式与钙蛋白酶相互作用，这种相互作用抑制了钙蛋白酶的蛋白酶活性。破坏内源性rapsyn/钙蛋白酶相互作用增强了Cch诱导的AChR簇的分散。此外，AChR簇在聚集蛋白突变小鼠的损失部分获救的抑制钙蛋白酶通过过表达钙蛋白酶抑制剂，内源性钙蛋白酶抑制剂，或注射钙蛋白酶肽，细胞渗透性钙蛋白酶抑制剂。这些结果表明，钙蛋白酶参与乙酰胆碱诱导的AChR簇的分散，rapsyn通过抑制钙蛋白酶活性稳定AChR簇。
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, is activated by the cholinergic stimulation and is required for induced dispersion of AChR clusters. Interestingly, the AChR-associated protein rapsyn interacted with calpain in an agrin-dependent manner, and this interaction inhibited the protease activity of calpain. Disrupting the endogenous rapsyn/calpain interaction enhanced CCh-induced dispersion of AChR clusters. 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 participates in ACh-induced dispersion of AChR clusters, and rapsyn stabilizes AChR clusters by suppressing calpain activity.