A sodium channel gene SCN9A polymorphism that increases nociceptor excitability.
Sodium channel Na(V)1.7, encoded by the SCN9A gene, is preferentially expressed in nociceptive primary sensory neurons, where it amplifies small depolarizations. In studies on a family with inherited erythromelalgia associated with Na(V)1.7 gain-of-function mutation A863P, we identified a nonsynonymous single-nucleotide polymorphism within SCN9A in the affected proband and several unaffected family members; this polymorphism (c. 3448C&T, Single Nucleotide Polymorphisms database rs6746030, which produces the amino acid substitution R1150W in human Na(V)1.7 [hNa(V)1.7]) is present in 1.1 to 12.7% of control chromosomes, depending on ethnicity. In this study, we examined the effect of the R1150W substitution on function of the hNa(V)1.7 channel, and on the firing of dorsal root ganglion (DRG) neurons in which this channel is normally expressed. We show that this polymorphism depolarizes activation (7.9-11mV in different assays). Current-clamp analysis shows that the 1150W allele depolarizes (6mV) resting membrane potential and increases ( approximately 2-fold) the firing frequency in response to depolarization in DRG neurons in which it is present. Our results suggest that polymorphisms in the Na(V)1.7 channel may influence susceptibility to pain.
Estacion
Mark
M
Department of Neurology, Yale University School of Medicine, New Haven CT.
Harty
T Patrick
TP
Choi
Jin-Sung
JS
Tyrrell
Lynda
L
Dib-Hajj
Sulayman D
SD
Waxman
Stephen G
SG
D000818:Animals; D001120:Arginine / Q000235:genetics; D055592:Biophysical Phenomena / Q000235:genetics; D002461:Cell Line, Transformed; D004558:Electric Stimulation; D005727:Ganglia, Spinal / Q000166:cytology; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D008564:Membrane Potentials / Q000235:genetics; D051379:Mice; D062556:NAV1.7 Voltage-Gated Sodium Channel; D009619:Nociceptors / Q000502:physiology*; D018408:Patch-Clamp Techniques; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011984:Sensory Receptor Cells / Q000502:physiology; D012684:Sensory Thresholds / Q000502:physiology*; D015222:Sodium Channels / Q000235:genetics*; D014162:Transfection / Q000379:methods; D014364:Tryptophan / Q000235:genetics
D062556:NAV1.7 Voltage-Gated Sodium Channel; C486866:SCN9A protein, human; D015222:Sodium Channels; D049452:Green Fluorescent Proteins; D014364:Tryptophan; D001120:Arginine