title: Na+ channel Scn1b gene regulates dorsal root ganglion nociceptor excitability in vivo.
abstract: Nociceptive dorsal root ganglion (DRG) neurons express tetrodotoxin-sensitive (TTX-S) and -resistant (TTX-R) Na(+) current (I(Na)) mediated by voltage-gated Na(+) channels (VGSCs). In nociceptive DRG neurons, VGSC β2 subunits, encoded by Scn2b, selectively regulate TTX-S α subunit mRNA and protein expression, ultimately resulting in changes in pain sensitivity. We hypothesized that VGSCs in nociceptive DRG neurons may also be regulated by β1 subunits, encoded by Scn1b. Scn1b null mice are models of Dravet Syndrome, a severe pediatric encephalopathy. Many physiological effects of Scn1b deletion on CNS neurons have been described. In contrast, little is known about the role of Scn1b in peripheral neurons in vivo. Here we demonstrate that Scn1b null DRG neurons exhibit a depolarizing shift in the voltage dependence of TTX-S I(Na) inactivation, reduced persistent TTX-R I(Na), a prolonged rate of recovery of TTX-R I(Na) from inactivation, and reduced cell surface expression of Na(v)1.9 compared with their WT littermates. Investigation of action potential firing shows that Scn1b null DRG neurons are hyperexcitable compared with WT. Consistent with this, transient outward K(+) current (I(to)) is significantly reduced in null DRG neurons. We conclude that Scn1b regulates the electrical excitability of nociceptive DRG neurons in vivo by modulating both I(Na) and I(K).
authors.affiliation: Department of Pharmacology, University of Michigan, Ann Arbor, Michigan 48109-0632, USA.
authors.forename: Luis F
authors.initials: LF
authors.lastname: Lopez-Santiago
authors.forename: William J
authors.initials: WJ
authors.lastname: Brackenbury
authors.forename: Chunling
authors.initials: C
authors.lastname: Chen
authors.forename: Lori L
authors.initials: LL
authors.lastname: Isom
mesh_terms: D000818:Animals; D020739:Brain Diseases, Metabolic, Inborn / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005727:Ganglia, Spinal / Q000378:metabolism*; D015640:Ion Channel Gating / Q000502:physiology*; D008564:Membrane Potentials / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009619:Nociceptors / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism*; D009435:Synaptic Transmission / Q000502:physiology*; D013577:Syndrome; D062547:Voltage-Gated Sodium Channel beta-1 Subunit; D062548:Voltage-Gated Sodium Channel beta-2 Subunit
chemical_list: D012333:RNA, Messenger; C540272:SCN2B protein, mouse; C524974:Scn1b protein, mouse; D015222:Sodium Channels; D062547:Voltage-Gated Sodium Channel beta-1 Subunit; D062548:Voltage-Gated Sodium Channel beta-2 Subunit