Neurotransmitter acetylcholine negatively regulates neuromuscular synapse formation by a Cdk5-dependent mechanism
Neurotransmitter acetylcholine negatively regulates neuromuscular synapse formation by a Cdk5-dependent mechanism
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DOI：
10.1016/j.neuron.2005.04.002
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发表时间：
2005-05-19
期刊：
影响因子：
16.2
通讯作者：
Lee, KF
中科院分区：
文献类型：
--
作者：
Lin, WC;Dominguez, B;Lee, KF
突触的形成需要突触前和突触后细胞之间的相互作用，以建立突触前神经末梢与富含神经递质受体的突触后装置的连接。在发育中的脊椎动物神经肌肉接头中，新生突触后装置的乙酰胆碱受体（AChR）簇不与突触前神经末梢并列。两个相反的活动随后促进突触的形成：正信号稳定受神经支配的AChR簇，而负信号分散那些不受神经支配的。虽然神经源性蛋白聚集蛋白已被认为是一个积极的信号，负信号仍然难以捉摸。在这里，我们表明，细胞周期蛋白依赖性激酶5（Cdk5）被激活的乙酰胆碱激动剂，并需要乙酰胆碱激动剂诱导的分散的乙酰胆碱受体簇，还没有稳定的聚集蛋白。遗传消除Cdk5或阻断ACh的产生可防止AChR簇在聚集蛋白突变体中的分散。因此，我们建议ACh负调控神经肌肉突触的形成通过Cdk5依赖的机制。
Synapse formation requires interactions between pre- and postsynaptic cells to establish the connection of a presynaptic nerve terminal with the neurotransmitter receptor-rich postsynaptic apparatus. At developing vertebrate neuromuscular junctions, acetylcholine receptor (AChR) clusters of nascent postsynaptic apparatus are not apposed by presynaptic nerve terminals. Two opposing activities subsequently promote the formation of synapses: positive signals stabilize the innervated AChR clusters, whereas negative signals disperse those that are not innervated. Although the nerve-derived protein agrin has been suggested to be a positive signal, the negative signals remain elusive. Here, we show that cyclin-dependent kinase 5 (Cdk5) is activated by ACh agonists and is required for the ACh agonist-induced dispersion of the AChR clusters that have not been stabilized by agrin. Genetic elimination of Cdk5 or blocking ACh production prevents the dispersion of AChR clusters in agrin mutants. Therefore, we propose that ACh negatively regulates neuromuscular synapse formation through a Cdk5-dependent mechanism.