Functional reciprocity between Na+ channel Nav1.6 and beta1 subunits in the coordinated regulation of excitability and neurite outgrowth.
Voltage-gated Na(+) channel (VGSC) beta1 subunits regulate cell-cell adhesion and channel activity in vitro. We previously showed that beta1 promotes neurite outgrowth in cerebellar granule neurons (CGNs) via homophilic cell adhesion, fyn kinase, and contactin. Here we demonstrate that beta1-mediated neurite outgrowth requires Na(+) current (I(Na)) mediated by Na(v)1.6. In addition, beta1 is required for high-frequency action potential firing. Transient I(Na) is unchanged in Scn1b (beta1) 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 Na(v)1.6 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 beta1 is required for normal localization of Na(v)1.6 at the AIS during the postnatal developmental switch to Na(v)1.6-mediated high-frequency firing. In agreement with this, beta1 is normally expressed with alpha subunits at the AIS of P14 CGNs. We propose reciprocity of function between beta1 and Na(v)1.6 such that beta1-mediated neurite outgrowth requires Na(v)1.6-mediated I(Na), and Na(v)1.6 localization and consequent high-frequency firing require beta1. We conclude that VGSC subunits function in macromolecular signaling complexes regulating both neuronal excitability and migration during cerebellar development.
Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI 48109-5632, USA.
William J
WJ
Brackenbury
Jeffrey D
JD
Calhoun
Chunling
C
Chen
Haruko
H
Miyazaki
Nobuyuki
N
Nukina
Fumitaka
F
Oyama
Barbara
B
Ranscht
Lori L
LL
Isom
D000200:Action Potentials / Q000502:physiology; D000818:Animals; D001369:Axons / Q000378:metabolism; D002531:Cerebellum / Q000166:cytology / Q000254:growth & development / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008959:Models, Neurological; D046912:Multiprotein Complexes; D062557:NAV1.6 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000378:metabolism*; D016501:Neurites / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction; D015222:Sodium Channels / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013779:Tetrodotoxin / Q000633:toxicity; D062547:Voltage-Gated Sodium Channel beta-1 Subunit
D046912:Multiprotein Complexes; D062557:NAV1.6 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C524974:Scn1b protein, mouse; C491046:Scn8a protein, mouse; D015222:Sodium Channels; D062547:Voltage-Gated Sodium Channel beta-1 Subunit; D013779:Tetrodotoxin