Balanced Rac1 activity controls formation and maintenance of neuromuscular acetylcholine receptor clusters
Balanced Rac1 activity controls formation and maintenance of neuromuscular acetylcholine receptor clusters
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平衡的 Rac1 活性控制神经肌肉乙酰胆碱受体簇的形成和维持。
DOI：
10.1242/jcs.215251
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发表时间：
2018-08-01
影响因子：
4
通讯作者：
Shi, Lei
中科院分区：
文献类型：
--
作者：
Bai, Yanyang;Guo, Daji;Shi, Lei
Rac1是一种重要的Rho GT3，调节肌动蛋白细胞骨架，长期以来一直被认为参与突触后神经肌肉接头处的乙酰胆碱受体（AChR）聚集。然而，Rac1是如何调节的，以及它如何影响AChR簇仍然没有被探索。这项研究表明，打破Rac1调节的平衡，通过增加或降低其活性，导致AChR簇的形成和维持受损。通过操纵Rac1活性在不同阶段的AChR集群在培养的肌管，我们表明，Rac1激活所需的AChR集群的初始形成，但其持续激活导致AChR不稳定，和不受控制的超激活Rac1甚至导致过度的肌管融合。Rac1诱导的AChR扩散和肌管融合均依赖于其下游效应子Pak1。两个Rac1 GAP和六个Rac1 GEFs进行了筛选，发现是重要的正常乙酰胆碱受体聚类。这项研究表明，虽然一般Rac1活性保持在低水平，在终末分化的肌管和AChR集群的维护，严格调节Rac1活性控制正常的AChR集群。
Rac1, an important Rho GTPase that regulates the actin cytoskeleton, has long been suggested to participate in acetylcholine receptor (AChR) clustering at the postsynaptic neuromuscular junction. However, how Rac1 is regulated and how it influences AChR clusters have remained unexplored. This study shows that breaking the balance of Rac1 regulation, by either increasing or decreasing its activity, led to impaired formation and maintenance of AChR clusters. By manipulating Rac1 activity at different stages of AChR clustering in cultured myotubes, we show that Rac1 activation was required for the initial formation of AChR clusters, but its persistent activation led to AChR destabilization, and uncontrolled hyperactivation of Rac1 even caused excessive myotube fusion. Both AChR dispersal and myotube fusion induced by Rac1 were dependent on its downstream effector Pak1. Two Rac1 GAPs and six Rac1 GEFs were screened and found to be important for normal AChR clustering. This study reveals that, although general Rac1 activity remains at low levels during terminal differentiation of myotubes and AChR cluster maintenance, tightly regulated Rac1 activity controls normal AChR clustering.