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标题：Functional reciprocity between Na+ channel Nav1.6 and β1 subunits in the coordinated regulation of excitability and neurite outgrowth
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作者：William J. Brackenbury ; Jeffrey D. Calhoun ; Chunling Chen 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2010
卷号：107
期号：5
页码：2283-2288
DOI：10.1073/pnas.0909434107
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Voltage-gated Na+ channel (VGSC) {beta}1 subunits regulate cell-cell adhesion and channel activity in vitro. We previously showed that {beta}1 promotes neurite outgrowth in cerebellar granule neurons (CGNs) via homophilic cell adhesion, fyn kinase, and contactin. Here we demonstrate that {beta}1-mediated neurite outgrowth requires Na+ current (INa) mediated by Nav1.6. In addition, {beta}1 is required for high-frequency action potential firing. Transient INa is unchanged in Scn1b ({beta}1) 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 {beta}1 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, {beta}1 is normally expressed with {alpha} subunits at the AIS of P14 CGNs. We propose reciprocity of function between {beta}1 and Nav1.6 such that {beta}1-mediated neurite outgrowth requires Nav1.6-mediated INa, and Nav1.6 localization and consequent high-frequency firing require {beta}1. We conclude that VGSC subunits function in macromolecular signaling complexes regulating both neuronal excitability and migration during cerebellar development.
关键词：cell adhesion ; cerebellum ; resurgent current ; axon initial segment ; action potential