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 ␤2 subunits, encoded by Scn2b, selectively regulate TTX-S ␣ 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 ␤1 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 .VGSCs 3 comprise one pore-forming ␣ subunit and two ␤ subunits (␤1-␤4, encoded by Scn1b-Scn4b) that do not form the pore but play critical roles in channel subcellular localization, regulation of I Na , VGSC gene transcription, and cell adhesive interactions leading to cytoskeletal modulation, changes in cell morphology, and cellular migration (1-3).All four mammalian VGSC ␤ subunit gene products are expressed in DRG neurons (4); however, little is known about their roles in nociception. The role of Scn1b in DRG neurons in vivo has not been investigated. Scn1b mRNA is expressed in DRG neurons (4), and the Scn1b splice variant ␤1B is expressed in adult rat DRG neurons as assessed by immunohistochemistry (5). Scn1b mRNA expression changes in the dorsal horn of the spinal cord in a model of neuropathic pain in rats (6), suggesting that ␤1/␤1B are important in nociception. Despite this, the effects of ␤1 on the functioning of heterologously overexpressed sensory neuronal VGSCs are controversial.

MicroRNA cluster miR-17-92 regulates multiple functionally related voltage-gated potassium channels in chronic neuropathic pain

“…Notably, DPP10 expression was detected only in small DRG neurons that expressed K V 4.3, exactly consistent with a previous report38. In contrast, Na V β1 distribution, which was mainly detected in medium/large DRG neurons in this study, is poorly understood, although Na V β1 null mutant mice exhibited hyperexcitability of small DRG neurons27. Given that miR-17-92 cluster members targeted 3′-UTR sequences to repress gene expression, miR-17-92 may directly decrease multiple potassium channel expression in a cell-autonomous fashion.…”

Sodium Channel β Subunits: Emerging Targets in Channelopathies

“…Scn1b null DRG neurons are hyperexcitable, consistent with observations in central neurons, exhibiting a complex phenotype that includes decreased persistent I Na , a hyperpolarizing shift in inactivation and slowed recovery from inactivation, and decreased surface expression of Na v 1.9 (120). Taken together, these observations suggest that global loss of Scn1b leads to allodynia.…”

Altered Cardiac Electrophysiology and SUDEP in a Model of Dravet Syndrome

“…Changes in the expression of a single ion channel gene often result in changes in the expression levels of other ion channel genes [29,69,70]. Scn1a null mice have increased Na v 1.3 expression in the hippocampus [34].…”