Na+ channel Scn1b gene regulates dorsal root ganglion nociceptor excitability in vivo

TY - JOUR

T1 - Na+ channel Scn1b gene regulates dorsal root ganglion nociceptor excitability in vivo

AU - Lopez-Santiago, Luis F

AU - Brackenbury, William J

AU - Chen, Chunling

AU - Isom, Lori L

PY - 2011/7/1

Y1 - 2011/7/1

N2 - Nociceptive dorsal root ganglion (DRG) neurons express tetrodotoxin-sensitive (TTX-S) and -resistant (TTX-R) Na+ current (INa) mediated by voltage-gated Na+ channels (VGSCs). In nociceptive DRG neurons VGSC ß2 subunits, encoded by Scn2b, selectively regulate TTX-S a 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 ß1 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 INa inactivation, reduced persistent TTX-R INa, a prolonged rate of recovery of TTX-R INa from inactivation, and reduced cell surface expression of Nav1.9 compared to their wildtype (WT) littermates. Investigation of action potential (AP) firing shows that Scn1b null DRG neurons are hyperexcitable compared to WT. Consistent with this, transient outward K+ current (Ito) is significantly reduced in null DRG neurons. We conclude that Scn1b regulates the electrical excitability of nociceptive DRG neurons in vivo by modulating both INa and IK.

AB - Nociceptive dorsal root ganglion (DRG) neurons express tetrodotoxin-sensitive (TTX-S) and -resistant (TTX-R) Na+ current (INa) mediated by voltage-gated Na+ channels (VGSCs). In nociceptive DRG neurons VGSC ß2 subunits, encoded by Scn2b, selectively regulate TTX-S a 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 ß1 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 INa inactivation, reduced persistent TTX-R INa, a prolonged rate of recovery of TTX-R INa from inactivation, and reduced cell surface expression of Nav1.9 compared to their wildtype (WT) littermates. Investigation of action potential (AP) firing shows that Scn1b null DRG neurons are hyperexcitable compared to WT. Consistent with this, transient outward K+ current (Ito) is significantly reduced in null DRG neurons. We conclude that Scn1b regulates the electrical excitability of nociceptive DRG neurons in vivo by modulating both INa and IK.

KW - GATED SODIUM-CHANNEL

KW - SENSORY NEURONS

KW - BETA-SUBUNITS

KW - FUNCTIONAL EXPRESSION

KW - RAT

KW - CURRENTS

KW - NA(V)1.8

KW - CELLS

KW - PAIN

KW - AUTOTOMY

UR - http://www.scopus.com/inward/record.url?scp=79959541432&partnerID=8YFLogxK

U2 - 10.1074/jbc.M111.242370

DO - 10.1074/jbc.M111.242370

M3 - Article

C2 - 21555511

SN - 0021-9258

VL - 286

SP - 22913

EP - 22923

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

IS - 26

ER -