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首页> 美国卫生研究院文献>Proceedings of the National Academy of Sciences of the United States of America >Functional reciprocity between Na+ channel Nav1.6 and β1 subunits in the coordinated regulation of excitability and neurite outgrowth
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Functional reciprocity between Na+ channel Nav1.6 and β1 subunits in the coordinated regulation of excitability and neurite outgrowth

机译：Na +通道Nav1.6和β1亚基在兴奋性和神经突生长协同调控中的功能互易性

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Voltage-gated Na+ channel (VGSC) β1 subunits regulate cell–cell adhesion and channel activity in vitro. We previously showed that β1 promotes neurite outgrowth in cerebellar granule neurons (CGNs) via homophilic cell adhesion, fyn kinase, and contactin. Here we demonstrate that β1-mediated neurite outgrowth requires Na+ current (INa) mediated by Nav1.6. In addition, β1 is required for high-frequency action potential firing. Transient INa is unchanged in Scn1b (β1) null CGNs; however, the resurgent INa, thought to underlie high-frequency firing in Nav1.6-expressing cerebellar neurons, is reduced. The proportion of axon initial segments (AIS) expressing Nav1.6 is reduced in Scn1b null cerebellar neurons. In place of Nav1.6 at the AIS, we observed an increase in Nav1.1, whereas Nav1.2 was unchanged. This indicates that β1 is required for normal localization of Nav1.6 at the AIS during the postnatal developmental switch to Nav1.6-mediated high-frequency firing. In agreement with this, β1 is normally expressed with α subunits at the AIS of P14 CGNs. We propose reciprocity of function between β1 and Nav1.6 such that β1-mediated neurite outgrowth requires Nav1.6-mediated INa, and Nav1.6 localization and consequent high-frequency firing require β1. We conclude that VGSC subunits function in macromolecular signaling complexes regulating both neuronal excitability and migration during cerebellar development.
机译：电压门控的Na + 通道（VGSC）β1亚基在体外调节细胞间粘附和通道活性。先前我们发现，β1通过同源细胞粘附，fyn激酶和contactin促进小脑颗粒神经元（CGNs）中的神经突生长。在这里，我们证明β1介导的神经突生长需要Nav1.6介导的Na + 电流（INa）。另外，高频动作电位点火需要β1。在Scn1b（β1）空CGN中，瞬态INa不变；然而，被认为是表达Nav1.6的小脑神经元高频放电的基础的新生INa减少了。在Scn1b小脑神经元中，表达Nav1.6的轴突初始节段（AIS）的比例降低。代替AIS的Nav1.6，我们观察到Nav1.1有所增加，而Nav1.2则保持不变。这表明在出生后发育转换为Nav1.6介导的高频发射期间，β1是Nav1.6在AIS正常定位所必需的。与此相符的是，β1通常在P14 CGN的AIS中以α亚基表达。我们建议在β1和Nav1.6之间进行功能互易，以使β1介导的神经突向外生长需要Nav1.6介导的INa，而Nav1.6定位和随后的高频发射则需要β1。我们得出的结论是，VGSC亚基在小分子发育过程中调节神经元兴奋性和迁移的大分子信号复合物中起作用。

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