Heterologous expression and functional analysis of rat Nav1.8 (SNS) voltage-gated sodium channels in the dorsal root ganglion neuroblastoma cell line ND7-23

The voltage-gated sodium channel NaV1.8 (SNS, PN3) is thought to be a molecular correlate of the dorsal root ganglion (DRG) tetrodotoxin resistant (TTX-R) Na+ current. TTX-R/NaV1.8 is an attractive therapeutic drug target for inflammatory and neuropathic pain on the basis of its specific distributio...

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Published in:Neuropharmacology 2004-03, Vol.46 (3), p.425-438
Main Authors: John, Victoria H, Main, Martin J, Powell, Andrew J, Gladwell, Zoe M, Hick, Caroline, Sidhu, Harjeet S, Clare, Jeff J, Tate, Simon, Trezise, Derek J
Format: Article
Language:English
Subjects:
Animals
Cell Line
Cell Line, Tumor
Female
Ganglia, Spinal - drug effects
Ganglia, Spinal - metabolism
Gene Expression Regulation - drug effects
Gene Expression Regulation - physiology
Humans
Male
Membrane Potentials - drug effects
Membrane Potentials - physiology
NAV1.8 Voltage-Gated Sodium Channel
Nerve Tissue Proteins - antagonists & inhibitors
Nerve Tissue Proteins - biosynthesis
Nerve Tissue Proteins - genetics
Nerve Tissue Proteins - physiology
Neuroblastoma - metabolism
Rats
Rats, Sprague-Dawley
Sodium Channel Blockers - chemistry
Sodium Channel Blockers - pharmacology
Sodium Channels - biosynthesis
Sodium Channels - genetics
Sodium Channels - physiology
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Summary:The voltage-gated sodium channel NaV1.8 (SNS, PN3) is thought to be a molecular correlate of the dorsal root ganglion (DRG) tetrodotoxin resistant (TTX-R) Na+ current. TTX-R/NaV1.8 is an attractive therapeutic drug target for inflammatory and neuropathic pain on the basis of its specific distribution in sensory neurones and its modulation by inflammatory mediators. However, detailed analysis of recombinant NaV1.8 has been hampered by difficulties in stably expressing the functional protein in mammalian cells. Here, we show stable expression and functional analysis of rat NaV1.8 (rNaV1.8) in the rat DRG/mouse N18Tg2 neuroblastoma hybridoma cell line ND7-23. Rat NaV1.8 Na+ currents were recorded (789 +/- 89 pA, n=62, over 20-cell passages) that qualitatively resembled DRG TTX-R in terms of gating kinetics and voltage-dependence of activation and inactivation. The local anaesthetic drug tetracaine produced tonic inhibition of rNaV1.8 (mean IC50 value 12.5 microM) and in repeated gating paradigms (2-10 Hz) also showed frequency-dependent block. There was a correlation between the ability of several analogues of the anticonvulsant/analgesic compound lamotrigine to inhibit TTX-R and rNaV1.8 (r=0.72, P
ISSN:0028-3908
DOI:10.1016/j.neuropharm.2003.09.018