Functional reciprocity between Na+ channel Nav1.6 and β1 subunits in the coordinated regulation of excitability and neurite outgrowth

William J. Brackenbury, Jeffrey D. Calhoun, Chunling Chen, Haruko Miyazaki, Nobuyuki Nukina, Fumitaka Oyama, Barbara Ranscht, Lori L. Isom

Research output: Contribution to journalArticlepeer-review

94 Citations (Scopus)

Abstract

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 (I Na) 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 Na v1.6 is reduced in Scn1b null cerebellar neurons. In place of Na v1.6 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-frequencyfiring. 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 Na v1.6 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.

Original languageEnglish
Pages (from-to)2283-2288
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number5
DOIs
Publication statusPublished - Feb 2 2010
Externally publishedYes

Keywords

  • Action potential
  • Axon initial segment
  • Cell adhesion
  • Cerebellum
  • Resurgent current

ASJC Scopus subject areas

  • General

Fingerprint

Dive into the research topics of 'Functional reciprocity between Na<sup>+</sup> channel Na<sub>v</sub>1.6 and β1 subunits in the coordinated regulation of excitability and neurite outgrowth'. Together they form a unique fingerprint.

Cite this