TY - JOUR
T1 - Differential effect of D623N variant and wild-type Na(v)1.7 sodium channels on resting potential and interspike membrane potential of dorsal root ganglion neurons
AU - Ahn, Hye-Sook
AU - Vasylyev, Dmytro V.
AU - Estacion, Mark
AU - Macala, Lawrence J.
AU - Shah, Palak
AU - Faber, Catharina G.
AU - Merkies, Ingemar S. J.
AU - Dib-Hajj, Sulayman D.
AU - Waxman, Stephen G.
PY - 2013/9/5
Y1 - 2013/9/5
N2 - Sodium channel Na(v)1.7 is preferentially expressed in dorsal root ganglion (DRG) and sympathetic ganglion neurons. Gain-of-function Na(v)1.7 mutations/variants have been identified in the painful disorders inherited erythromelalgia and small-fiber neuropathy (SFN). DRG neurons transfected with these channel variants display depolarized resting potential, reduced current-threshold, increased firing-frequency and spontaneous firing. Whether the depolarizing shift in resting potential and enhanced spontaneous firing are due to persistent activity of variant channels, or to compensatory changes in other conductance(s) in response to expression of the variant channel, as shown in model systems, has not been studied. We examined the effect of wild-type Na(v)1.7 and a Na(v)1.7 mutant channel, D623N, associated with SFN, on resting potential and membrane potential during interspike intervals in DRG neurons. Resting potential in DRG neurons expressing D623N was depolarized compared to neurons expressing WT-Na(v)1.7. Exposure to TTX hyperpolarized resting potential by 7 mV, increased current-threshold, decreased firing-frequency, and reduced NMDG-induced-hyperpolarization in DRG neurons expressing D623N. To assess the contribution of depolarized resting potential to DRG neuron excitability, we mimicked the mutant channel's depolarizing effect by current injection to produce equivalent depolarization; the depolarization decreased current threshold and increased firing-frequency. Voltage-clamp using ramp or repetitive action potentials as commands showed that D623N channels enhance the TTX-sensitive inward current, persistent at subthreshold membrane voltages, as predicted by a Hodgkin-Huxley model. Our results demonstrate that a variant of Na(v)1.7 associated with painful neuropathy depolarizes resting membrane potential and produces an enhanced inward current during interspike intervals, thereby contributing to DRG neuron hyperexcitability.
AB - Sodium channel Na(v)1.7 is preferentially expressed in dorsal root ganglion (DRG) and sympathetic ganglion neurons. Gain-of-function Na(v)1.7 mutations/variants have been identified in the painful disorders inherited erythromelalgia and small-fiber neuropathy (SFN). DRG neurons transfected with these channel variants display depolarized resting potential, reduced current-threshold, increased firing-frequency and spontaneous firing. Whether the depolarizing shift in resting potential and enhanced spontaneous firing are due to persistent activity of variant channels, or to compensatory changes in other conductance(s) in response to expression of the variant channel, as shown in model systems, has not been studied. We examined the effect of wild-type Na(v)1.7 and a Na(v)1.7 mutant channel, D623N, associated with SFN, on resting potential and membrane potential during interspike intervals in DRG neurons. Resting potential in DRG neurons expressing D623N was depolarized compared to neurons expressing WT-Na(v)1.7. Exposure to TTX hyperpolarized resting potential by 7 mV, increased current-threshold, decreased firing-frequency, and reduced NMDG-induced-hyperpolarization in DRG neurons expressing D623N. To assess the contribution of depolarized resting potential to DRG neuron excitability, we mimicked the mutant channel's depolarizing effect by current injection to produce equivalent depolarization; the depolarization decreased current threshold and increased firing-frequency. Voltage-clamp using ramp or repetitive action potentials as commands showed that D623N channels enhance the TTX-sensitive inward current, persistent at subthreshold membrane voltages, as predicted by a Hodgkin-Huxley model. Our results demonstrate that a variant of Na(v)1.7 associated with painful neuropathy depolarizes resting membrane potential and produces an enhanced inward current during interspike intervals, thereby contributing to DRG neuron hyperexcitability.
KW - Small fiber neuropathy
KW - Dorsal root ganglia
KW - Hyperexcitability
KW - Sodium channel
KW - Na(v)1.7
KW - Hodgkin-Huxley
U2 - 10.1016/j.brainres.2013.07.005
DO - 10.1016/j.brainres.2013.07.005
M3 - Article
SN - 0006-8993
VL - 1529
SP - 165
EP - 177
JO - Brain Research
JF - Brain Research
ER -