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The Journal of Neuroscience, November 29, 2006, 26(48):12566-12575; doi:10.1523/JNEUROSCI.3424-06.2006

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Cellular/Molecular
Na_v1.7 Mutant A863P in Erythromelalgia: Effects of Altered Activation and Steady-State Inactivation on Excitability of Nociceptive Dorsal Root Ganglion Neurons

T. Patrick Harty,^1,2,3 Sulayman D. Dib-Hajj,^1,2,3 Lynda Tyrrell,^1,2,3 Rachael Blackman,^1,2,3 Fuki M. Hisama,¹ John B. Rose,⁴ and Stephen G. Waxman^1,2,3

¹Department of Neurology and ²Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, Connecticut 06510, ³Rehabilitation Research Center, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut 06516, and ⁴Department of Anesthesiology and Critical Care Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104

Correspondence should be addressed to Dr. Stephen G. Waxman, Department of Neurology, LCI 707, Yale Medical School, P.O. Box 208018, New Haven, CT 06520. Email: Stephen.Waxman{at}yale.edu

Inherited erythromelalgia/erythermalgia (IEM) is a neuropathy characterized by pain and redness of the extremities that is triggered by warmth. IEM has been associated with missense mutations of the voltage-gated sodium channel Na_v1.7, which is preferentially expressed in most nociceptive dorsal root ganglia (DRGs) and sympathetic ganglion neurons. Several mutations occur in cytoplasmic linkers of Na_v1.7, with only two mutations in segment 4 (S4) and S6 of domain I. We report here a simplex case with an alanine 863 substitution by proline (A863P) in S5 of domain II of Na_v1.7. The functional effect of A863P was investigated by voltage-clamp analysis in human embryonic kidney 293 cells and by current-clamp analysis to determine the effects of A863P on firing properties of small DRG neurons. Activation of mutant channels was shifted by –8 mV, whereas steady-state fast inactivation was shifted by +10 mV, compared with wild-type (WT) channels. There was a marked decrease in the rate of deactivation of mutant channels, and currents elicited by slow ramp depolarizations were 12 times larger than for WT. These results suggested that A863P could render DRG neurons hyperexcitable. We tested this hypothesis by studying properties of rat DRG neurons transfected with either A863P or WT channels. A863P depolarized resting potential of DRG neurons by +6 mV compared with WT channels, reduced the threshold for triggering single action potentials to 63% of that for WT channels, and increased firing frequency of neurons when stimulated with suprathreshold stimuli. Thus, A863P mutant channels produce hyperexcitability in DRG neurons, which contributes to the pathophysiology of IEM.

Key words: ion channel; neuropathic pain; erythermalgia; sensory neuron; voltage clamp; current clamp

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Received June 13, 2006; revised Oct. 25, 2006; accepted Oct. 25, 2006.

Correspondence should be addressed to Dr. Stephen G. Waxman, Department of Neurology, LCI 707, Yale Medical School, P.O. Box 208018, New Haven, CT 06520. Email: Stephen.Waxman{at}yale.edu

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