SCN10A Mutation in a Patient with Erythromelalgia Enhances C-Fiber Activity Dependent Slowing.
SCN10A Mutation in a Patient with Erythromelalgia Enhances C-Fiber Activity Dependent Slowing.
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DOI：
10.1371/journal.pone.0161789
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Namer B
中科院分区：
文献类型：
--
作者：
Kist AM;Sagafos D;Rush AM;Neacsu C;Eberhardt E;Schmidt R;Lunden LK;Ørstavik K;Kaluza L;Meents J;Zhang Z;Carr TH;Salter H;Malinowsky D;Wollberg P;Krupp J;Kleggetveit IP;Schmelz M;Jørum E;Lampert A;Namer B
河豚毒素(TTX)敏感的电压门控钠通道(NAV)Nav1.7的功能获得突变被认为是遗传性红斑性肢痛症慢性疼痛的关键机制。TTX耐药通道的突变，如Nav1.8或Nav1.9，最近被认为与遗传性慢性疼痛综合征有关。在这里，我们用显微神经学和膜片钳技术研究了Nav1.8基因p.M650K突变对一名53岁红斑性肢痛症患者的影响。患者周围神经纤维的记录显示，与没有NAV突变的红斑性肢痛症患者对照组相比，CMI的活动依赖性减慢(ADS)增加，自发放电减少。为了评估p.M650K突变对神经元放电和通道门控的影响，我们对转基因的感觉神经元(DRGs)和神经母细胞瘤细胞进行了电流和电压钳记录。P.M650K突变使Nav1.8的稳态快速失活转移到更超极化的电位，并没有显著改变任何其他测试的门控行为。与WT相比，M650K转基因DRGs的AP半宽度明显增宽，刺激动作电位放电频率明显降低。我们讨论了增强的稳态快速失活、更宽的动作电位宽度和潜在的生理后果之间的潜在联系。
Gain-of-function mutations in the tetrodotoxin (TTX) sensitive voltage-gated sodium channel (Nav) Nav1.7 have been identified as a key mechanism underlying chronic pain in inherited erythromelalgia. Mutations in TTX resistant channels, such as Nav1.8 or Nav1.9, were recently connected with inherited chronic pain syndromes. Here, we investigated the effects of the p.M650K mutation in Nav1.8 in a 53 year old patient with erythromelalgia by microneurography and patch-clamp techniques. Recordings of the patient’s peripheral nerve fibers showed increased activity dependent slowing (ADS) in CMi and less spontaneous firing compared to a control group of erythromelalgia patients without Nav mutations. To evaluate the impact of the p.M650K mutation on neuronal firing and channel gating, we performed current and voltage-clamp recordings on transfected sensory neurons (DRGs) and neuroblastoma cells. The p.M650K mutation shifted steady-state fast inactivation of Nav1.8 to more hyperpolarized potentials and did not significantly alter any other tested gating behaviors. The AP half-width was significantly broader and the stimulated action potential firing rate was reduced for M650K transfected DRGs compared to WT. We discuss the potential link between enhanced steady state fast inactivation, broader action potential width and the potential physiological consequences.
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