The Salk Institute, La Jolla, California, USA.
Nat Neurosci. 2011 Mar;14(3):324-30. doi: 10.1038/nn.2747.
Positive and negative regulation of neurotransmitter receptor aggregation on the postsynaptic membrane is a critical event during synapse formation. Acetylcholine (ACh) and agrin are two opposing signals that regulate ACh receptor (AChR) clustering during neuromuscular junction (NMJ) development. ACh induces dispersion of AChR clusters that are not stabilized by agrin via a cyclin-dependent kinase 5 (Cdk5)-mediated mechanism, but regulation of Cdk5 activation is poorly understood. We found that the intermediate filament protein nestin physically interacts with Cdk5 and is required for ACh-induced association of p35, the co-activator of Cdk5, with the muscle membrane. Blockade of nestin-dependent signaling inhibited ACh-induced Cdk5 activation and the dispersion of AChR clusters in cultured myotubes. Similar to the effects of Cdk5 gene inactivation, knockdown of nestin in agrin-deficient mouse embryos substantially restored AChR clusters. These results suggest that nestin is required for ACh-induced, Cdk5-dependent dispersion of AChR clusters during NMJ development.
神经递质受体在突触后膜上的聚集的正、负调控是突触形成过程中的一个关键事件。乙酰胆碱（ACh）和神经胶质细胞来源的神经营养因子（agrin）是两种相反的信号，它们在神经肌肉接头（NMJ）发育过程中调节 ACh 受体（AChR）的聚集。乙酰胆碱通过细胞周期蛋白依赖性激酶 5（Cdk5）介导的机制诱导不稳定的 AChR 簇的分散，但 Cdk5 激活的调节机制尚不清楚。我们发现中间丝蛋白巢蛋白与 Cdk5 物理相互作用，并且是 ACh 诱导的 p35（Cdk5 的共激活因子）与肌膜结合所必需的。阻断巢蛋白依赖性信号通路抑制了 ACh 诱导的 Cdk5 激活和 AChR 簇的分散。类似 Cdk5 基因失活的作用，在 agrin 缺陷型小鼠胚胎中敲低巢蛋白也大大恢复了 AChR 簇。这些结果表明，在 NMJ 发育过程中，巢蛋白对于 ACh 诱导的、Cdk5 依赖性的 AChR 簇的分散是必需的。
