Cheng Xiaoyang, Dib-Hajj Sulayman D, Tyrrell Lynda, Waxman Stephen G
Department of Neurology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
Mol Pain. 2008 Jan 2;4:1. doi: 10.1186/1744-8069-4-1.
Primary erythromelalgia is an autosomal dominant pain disorder characterized by burning pain and skin redness in the extremities, with onset of symptoms during the first decade in the families whose mutations have been physiologically studied to date. Several mutations of voltage-gated Na+ channel NaV1.7 have been linked with primary erythromelalgia. Recently, a new substitution Na(v)1.7/I136V has been reported in a Taiwanese family, in which pain appeared at later ages (9-22 years, with onset at 17 years of age or later in 5 of 7 family members), with relatively slow progression (8-10 years) to involvement of the hands. The proband reported onset of symptoms first in his feet at the age of 11, which then progressed to his hands at the age of 19. The new mutation is located in transmembrane segment 1 (S1) of domain I (DI) in contrast to all Na(v)1.7 mutations reported to date, which have been localized in the voltage sensor S4, the linker joining segments S4 and S5 or pore-lining segments S5 and S6 in DI, II and III.
In this study, we characterized the gating and kinetic properties of I136V mutant channels in HEK293 cells using whole-cell patch clamp. I136V shifts the voltage-dependence of activation by -5.7 mV, a smaller shift in activation than the other erythromelalgia mutations that have been characterized. I136V also decreases the deactivation rate, and generates larger ramp currents.
The I136V substitution in Na(v)1.7 alters channel gating and kinetic properties. Each of these changes may contribute to increased excitability of nociceptive dorsal root ganglion neurons, which underlies pain in erythromelalgia. The smaller shift in voltage-dependence of activation of Na(v)1.7, compared to the other reported cases of inherited erythromelalgia, may contribute to the later age of onset and slower progression of the symptoms reported in association with this mutation.
原发性红斑性肢痛症是一种常染色体显性疼痛障碍，其特征为四肢出现灼痛和皮肤发红，在迄今已对其突变进行生理学研究的家族中，症状在第一个十年内出现。电压门控钠离子通道NaV1.7的几种突变已与原发性红斑性肢痛症相关联。最近，在一个台湾家族中报道了一种新的替代突变Na(v)1.7/I136V，在该家族中疼痛出现在较晚年龄（9 - 22岁，7名家族成员中有5名在17岁或之后发病），进展相对缓慢（8 - 10年），且累及手部。先证者报告其症状于11岁时首先出现在足部，然后在19岁时进展至手部。与迄今报道的所有Na(v)1.7突变不同，新突变位于结构域I（DI）的跨膜片段1（S1）中，迄今报道的所有Na(v)1.7突变均位于电压感受器S4、连接S4和S5片段的连接区或DI、II和III中的孔衬片段S5和S6中。
在本研究中，我们使用全细胞膜片钳技术对HEK293细胞中I136V突变通道的门控和动力学特性进行了表征。I136V使激活的电压依赖性负移5.7 mV，与其他已表征的红斑性肢痛症突变相比，激活的负移较小。I136V还降低了失活速率，并产生更大的斜坡电流。
Na(v)1.7中的I136V替代改变了通道的门控和动力学特性。这些变化中的每一个都可能导致伤害性背根神经节神经元兴奋性增加，这是红斑性肢痛症疼痛的基础。与其他报道的遗传性红斑性肢痛症病例相比，Na(v)1.7激活的电压依赖性较小的负移可能导致与该突变相关的症状发病较晚且进展较慢。
