Mutation I136V alters electrophysiological properties of the NaV1.7 channel in a family with onset of erythromelalgia in the second decade
Mutation I136V alters electrophysiological properties of the NaV1.7 channel in a family with onset of erythromelalgia in the second decade
复制标题
DOI：
10.1186/1744-8069-4-1
复制
发表时间：
2008-01-02
期刊：
影响因子：
3.3
通讯作者：
Waxman, Stephen G.
中科院分区：
文献类型：
--
作者：
Cheng, Xiaoyang;Dib-Hajj, Sulayman D.;Waxman, Stephen G.
背景资料：原发性红斑性肢痛症是一种常染色体显性疼痛疾病，其特征是四肢的烧灼痛和皮肤发红，在迄今为止对其突变进行生理学研究的家族中，症状在第一个十年期间发作。电压门控Na+通道Na（V）1.7的几种突变与原发性红斑性肢痛症有关。最近，在一个台湾家族中报道了一种新的替代Na（V）1.7/I136 V，其中疼痛出现在较晚的年龄（9-22岁，7名家族成员中有5名在17岁或更晚发病），进展相对缓慢（8-10年），累及手部。先证者在11岁时首先在他的脚上出现症状，然后在19岁时发展到他的手。新突变位于结构域1（DI）的跨膜区段1（SI）中，这与迄今为止报道的所有NaV1.7突变形成对比，所述NaV1.7突变已定位于DI、II和III中的电压传感器S4、连接区段S4和S5的接头或孔衬区段S5和S6中。在这项研究中，我们的特点是门控和动力学特性的I136 V突变通道在HEK 293细胞使用全细胞膜片钳。I136 V使激活的电压依赖性偏移-5.7mV，这是比其他已表征的红斑性肢痛症突变更小的激活偏移。I136 V也降低了失活速率，并产生更大的斜坡电流。结论：NaV1.7中I136 V的取代改变了通道的门控和动力学性质。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的兴奋性增加，这是红斑性肢痛症疼痛的基础。与其他报告的遗传性红斑性肢痛症病例相比，NaV1.7激活的电压依赖性变化较小，可能导致与该突变相关的症状发作年龄较晚和进展较慢。
Background: 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 Na(V)1.7 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(SI) of domain 1(DI) in contrast to all NaV1.7 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.Results: 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 -5.7mV, 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.Conclusion: The I136V substitution in NaV1.7 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 NaV1.7, 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.