期刊
BRAIN RESEARCH
卷 1529, 期 -, 页码 165-177出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.brainres.2013.07.005
关键词
Small fiber neuropathy; Dorsal root ganglia; Hyperexcitability; Sodium channel; Na(v)1.7; Hodgkin-Huxley
资金
- Medical Research Service and Rehabilitation Research Service, Department of Veterans Administration Rehabilitation Research and Development Service
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. (C) 2013 Elsevier B.V. All rights reserved.
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