Deletion mutation of sodium channel NaV1.7 in inherited erythromelalgia: enhanced slow inactivation modulates dorsal root ganglion neuron hyperexcitability
Deletion mutation of sodium channel NaV1.7 in inherited erythromelalgia: enhanced slow inactivation modulates dorsal root ganglion neuron hyperexcitability
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DOI：
10.1093/brain/awr143
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发表时间：
2011-07-01
期刊：
影响因子：
14.5
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.
电压门控钠通道Na（V）1.7的功能获得性错义突变与遗传性红斑性肢痛症的疼痛性疾病有关。这些突变使慢斜坡刺激诱发的电流（斜坡电流）过度激活、缓慢失活和增强。最近提出了遗传性红斑性肢痛症的发病年龄与突变型Na（V）1.7通道激活的超极化转变程度之间的相关性;引起大激活转变的突变与遗传性红斑性肢痛症的早期发病年龄有关，而引起小激活转变的突变与生命的第二个十年内的发病年龄有关。在这里，我们报告了一个家族遗传性红斑性肢痛症与一个单一的残基-亮氨酸955（Del-L955）在DII/S6的框内缺失。先证者直到15岁才出现症状，而她的患病母亲在青春期只出现轻度症状，在38岁时症状消失。Del-L955显示对Na（V）1.7电流密度和快速失活没有影响，但引起激活的约-24 mV偏移，以及持续电流和斜坡电流的幅度增加。该突变还在缓慢失活中产生约-40 mV的偏移，这降低了通道的可用性。Del-L955突变对背根神经节神经元过度兴奋的影响与另一种不增强缓慢失活的遗传性红斑性肢痛症突变（L 858 F）产生的影响的比较表明，延迟的发病年龄和较轻的症状与通道激活的大偏移相关，增强的持续性和增强的斜坡电流可能与Del-L955缓慢失活的约-40 mV偏移有关，这是迄今为止在突变Na（V）1.7通道中证明的最大偏移。我们的研究结果表明，尽管激活转变在遗传性红斑性肢痛症的发展中起着关键作用，但缓慢失活可能通过改变通道的可用性来调节临床表型。
Gain-of-function missense mutations of voltage-gated sodium channel Na(V)1.7 have been linked to the painful disorder inherited erythromelalgia. These mutations hyperpolarize activation, slow deactivation and enhance currents evoked by slow ramp stimuli (ramp currents). A correlation has recently been suggested between the age of onset of inherited erythromelalgia and the extent of hyperpolarizing shifts in mutant Na(V)1.7 channel activation; mutations causing large activation shifts have been linked to early age of onset inherited erythromelalgia, while mutations causing small activation shifts have been linked to age of onset within the second decade of life. Here, we report a family with inherited erythromelalgia with an in-frame deletion of a single residue-leucine 955 (Del-L955) in DII/S6. The proband did not show symptoms until the age of 15 years, and her affected mother only experienced mild symptoms during adolescence, which disappeared at the age of 38 years. Del-L955 shows no effect on Na(V)1.7 current density and fast inactivation, but causes an approximately -24 mV shift in activation, together with increases in amplitude of persistent currents and ramp currents. The mutation also produces an approximately -40 mV shift in slow inactivation, which reduces channel availability. Comparison of the effects of the Del-L955 mutation on dorsal root ganglion neuron hyperexcitability with those produced by another inherited erythromelalgia mutation (L858F) that does not enhance slow inactivation suggests that a delayed age of onset and milder symptoms in association with a large shift of channel activation, enhanced persistent and enhanced ramp currents may be related to the approximately -40 mV shift in slow inactivation for Del-L955, the largest shift thus far demonstrated in mutant Na(V)1.7 channels. Our results suggest that despite the pivotal role of activation shift in inherited erythromelalgia development, slow inactivation may regulate clinical phenotype by altering channel availability.