Functional reciprocity between [Na.sup.+] channel [Na.sub.v]1.6 and [beta]1 subunits in the coordinated regulation of excitability and neurite outgrowth

Voltage-gated [Na.sup.+] 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.sup.+] current ([I.sub.Na]) mediated by [Na.sub.v]1.6. In addition, [beta]1 is required for high-frequency action potential firing. Transient [I.sub.Na] is unchanged in Scn1b ([beta]1) null CGNs; however, the resurgent [I.sub.Na], thought to underlie high-frequency firing in [Na.sub.v]1.6-expressing cerebellar neurons, is reduced. The proportion of axon initial segments (AIS) expressing [Na.sub.v]1.6 is reduced in Scn1b null cerebellar neurons. In place of [Na.sub.v]1.6 at the AIS, we observed an increase in [Na.sub.v]1.1, whereas [Na.sub.v]1.2 was unchanged. This indicates that [beta]1 is required for normal Iocalization of [Na.sub.v]1.6 at the AIS during the postnatal developmental switch to [Na.sub.v]1.6-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 [Na.sub.v]1.6 such that [beta]1-mediated neurite outgrowth requires [Na.sub.v]1.6-mediated [I.sub.Na], and [Na.sub.v]1.6 Iocalization 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. cell adhesion | cerebellum | resurgent current | axon initial segment | action potential doi/10.1073/pnas.0909434107