Cold-aggravated pain in humans caused by a hyperactive NaV1.9 channel mutant.
Cold-aggravated pain in humans caused by a hyperactive NaV1.9 channel mutant.
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DOI：
10.1038/ncomms10049
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发表时间：
2015-12-08
影响因子：
16.6
通讯作者：
Kurth I
中科院分区：
文献类型：
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作者：
Leipold E;Hanson-Kahn A;Frick M;Gong P;Bernstein JA;Voigt M;Katona I;Oliver Goral R;Altmüller J;Nürnberg P;Weis J;Hübner CA;Heinemann SH;Kurth I
人类 SCN11A 编码的电压门控 Na+ 通道 NaV1.9 的功能获得突变会导致严重的疼痛疾病，从神经性疼痛到先天性疼痛不敏感。然而，NaV1.9 疾病的整个谱系尚未确定。应用全外显子组测序，我们在 NaV1.9 中发现了一个错义变化 (p.V1184A)，它会导致人类寒冷加剧的外周疼痛。电生理学分析表明，p.V1184A 将通道开放的电压依赖性转变为超极化电位，从而赋予 NaV1.9 功能增益特征。突变的通道降低了小鼠初级感觉神经元的静息膜电位，并导致伤害感受器的耐冷过度兴奋，这表明疼痛表型的温度依赖性存在机制基础。在直接比较与冷加重疼痛或疼痛不敏感相关的突变的基础上，我们提出了一个模型，其中突变的生理后果，即疼痛增强与消失，很大程度上取决于 NaV1.9 过度活跃的类型。 钠通道 Nav1.9 的突变已在一个家庭中被发现，并被证明与寒冷加剧的疼痛有关。在这里，作者描述了这种突变的电生理后果，并提出了一种个体经历疼痛的机制。
Gain-of-function mutations in the human SCN11A-encoded voltage-gated Na+ channel NaV1.9 cause severe pain disorders ranging from neuropathic pain to congenital pain insensitivity. However, the entire spectrum of the NaV1.9 diseases has yet to be defined. Applying whole-exome sequencing we here identify a missense change (p.V1184A) in NaV1.9, which leads to cold-aggravated peripheral pain in humans. Electrophysiological analysis reveals that p.V1184A shifts the voltage dependence of channel opening to hyperpolarized potentials thereby conferring gain-of-function characteristics to NaV1.9. Mutated channels diminish the resting membrane potential of mouse primary sensory neurons and cause cold-resistant hyperexcitability of nociceptors, suggesting a mechanistic basis for the temperature dependence of the pain phenotype. On the basis of direct comparison of the mutations linked to either cold-aggravated pain or pain insensitivity, we propose a model in which the physiological consequence of a mutation, that is, augmented versus absent pain, is critically dependent on the type of NaV1.9 hyperactivity. A mutation in the sodium channel Nav1.9 has been identified in a family and shown to associate with cold-aggravated pain. Here, the authors characterize the electrophysiological consequences of this mutation and propose a mechanism for the pain that the individuals experience.