Human voltage-gated sodium channel mutations that cause inherited neuronal and muscle channelopathies increase resurgent sodium currents
Human voltage-gated sodium channel mutations that cause inherited neuronal and muscle channelopathies increase resurgent sodium currents
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DOI：
10.1172/jci40801
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发表时间：
2010-01-01
影响因子：
15.9
通讯作者：
Cummins, Theodore R.
中科院分区：
文献类型：
--
作者：
Jarecki, Brian W.;Piekarz, Andrew D.;Cummins, Theodore R.
电压门控钠通道（VGSC；或 Nav）的遗传性突变会导致许多兴奋性障碍，包括癫痫、慢性疼痛、肌强直和心律失常。了解致病突变的功能后果可能会为了解 VGSC 在正常和异常兴奋性中发挥的作用提供宝贵的见解。在这里，我们试图检验这样的假设：致病突变会导致复活电流增加，这是一种不寻常的钠电流，以前并未与兴奋性障碍有关。我们证明，人外周神经元钠通道 Nav1.7 中的阵发性极度疼痛障碍 (PEPD) 突变、人骨骼肌钠通道 Nav1.4 中的先天性副肌强直 (PMC) 突变以及人心脏钠通道 Nav1.5 中的长 QT3/SIDS 突变均显着增加了优化的成年大鼠来源的背根神经节神经元表达系统中的复苏钠电流的幅度。计算机模拟表明，与 Nav1.7 突变相关的复活电流可以诱导伤害性神经元高频动作电位放电，而与 Nav1.5 突变相关的复活电流可以扩大心肌细胞的动作电位。这些作用与相应通道病相关的病理生理学一致。我们的结果表明，复苏电流与多种通道病相关，并且可能是神经元和肌肉兴奋性紊乱的重要原因。
Inherited mutations in voltage-gated sodium channels (VGSCs; or Nav) cause many disorders of excitability, including epilepsy, chronic pain, myotonia, and cardiac arrhythmias. Understanding the functional consequences of the disease-causing mutations is likely to provide invaluable insight into the roles that VGSCs play in normal and abnormal excitability. Here, we sought to test the hypothesis that disease-causing mutations lead to increased resurgent currents, unusual sodium currents that have not previously been implicated in disorders of excitability. We demonstrated that a paroxysmal extreme pain disorder (PEPD) mutation in the human peripheral neuronal sodium channel Nav1.7, a paramyotonia congenita (PMC) mutation in the human skeletal muscle sodium channel Nav1.4, and a long-QT3/SIDS mutation in the human cardiac sodium channel Nav1.5 all substantially increased the amplitude of resurgent sodium currents in an optimized adult rat-derived dorsal root ganglion neuronal expression system. Computer simulations indicated that resurgent currents associated with the Nav1.7 mutation could induce high-frequency action potential firing in nociceptive neurons and that resurgent currents associated with the Nav1.5 mutation could broaden the action potential in cardiac myocytes. These effects are consistent with the pathophysiology associated with the respective channelopathies. Our results indicate that resurgent currents are associated with multiple channelopathies and are likely to be important contributors to neuronal and muscle disorders of excitability.