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

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 (I-Na) mediated by Na(v)1.6. 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 I-Na, thought to underlie high-frequency firing in Na(v)1.6-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 Na(v)1.6 at the AIS, we observed an increase in Na(v)1.1, whereas Na(v)1.2 was unchanged. This indicates that beta 1 is required for normal localization of Nav1.6 at the AIS during the postnatal developmental switch to Na(v)1.6-mediated high-frequency firing. In agreement with this, beta 1 is normally expressed with a subunits at the AIS of P14 CGNs. We propose reciprocity of function between beta 1 and Na(v)1.6 such that beta 1-mediated neurite outgrowth requires Na(v)1.6-mediated I-Na, and Na(v)1.6 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.