Nav1.7 mutant A863P in erythromelalgia:: Effects of altered activation and steady-state inactivation on excitability of nociceptive dorsal root ganglion neurons

被引:123
作者
Harty, T. Patrick
Dib-Hajj, Sulayman D.
Tyrrell, Lynda
Blackman, Rachael
Hisama, Fuki M.
Rose, John B.
Waxman, Stephen G.
机构
[1] Yale Univ, Sch Med, Dept Neurol, New Haven, CT 06510 USA
[2] Yale Univ, Sch Med, Ctr Neurosci & Regenerat Res, New Haven, CT 06510 USA
[3] Vet Affairs Connecticut Healthcare Syst, Rehabil Res Ctr, West Haven, CT 06516 USA
[4] Childrens Hosp, Dept Anesthesiol & Crit Care Med, Philadelphia, PA 19104 USA
关键词
ion channel; neuropathic pain; erythermalgia; sensory neuron; voltage clamp; current clamp;
D O I
10.1523/JNEUROSCI.3424-06.2006
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
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 Nav1.7, which is preferentially expressed in most nociceptive dorsal root ganglia (DRGs) and sympathetic ganglion neurons. Several mutations occur in cytoplasmic linkers of Nav1.7, 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(v)1.7. 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 +6mV 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.
引用
收藏
页码:12566 / 12575
页数:10
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