Huang Chiung-Wei, Lai Hsing-Jung, Huang Po-Yuan, Lee Ming-Jen, Kuo Chung-Chin
Department of Physiology, National Taiwan University College of Medicine, Taipei, Taiwan.
Department of Neurology, National Taiwan University Hospital Jinshan Branch, New Taipei City, Taiwan.
PLoS Biol. 2016 Sep 21;14(9):e1002561. doi: 10.1371/journal.pbio.1002561. eCollection 2016 Sep.
The Nav1.7 channel critically contributes to the excitability of sensory neurons, and gain-of-function mutations of this channel have been shown to cause inherited erythromelalgia (IEM) with neuropathic pain. In this study, we report a case of a severe phenotype of IEM caused by p.V1316A mutation in the Nav1.7 channel. Mechanistically, we first demonstrate that the Navβ4 peptide acts as a gating modifier rather than an open channel blocker competing with the inactivating peptide to give rise to resurgent currents in the Nav1.7 channel. Moreover, there are two distinct open and two corresponding fast inactivated states in the genesis of resurgent Na+ currents. One is responsible for the resurgent route and practically existent only in the presence of Navβ4 peptide, whereas the other is responsible for the "silent" route of recovery from inactivation. In this regard, the p.V1316A mutation makes hyperpolarization shift in the activation curve, and depolarization shift in the inactivation curve, vividly uncoupling inactivation from activation. In terms of molecular gating operation, the most important changes caused by the p.V1316A mutation are both acceleration of the transition from the inactivated states to the activated states and deceleration of the reverse transition, resulting in much larger sustained as well as resurgent Na+ currents. In summary, the genesis of the resurgent currents in the Nav1.7 channel is ascribable to the transient existence of a distinct and novel open state promoted by the Navβ4 peptide. In addition, S4-5 linker in domain III where V1316 is located seems to play a critical role in activation-inactivation coupling, chiefly via direct modulation of the transitional kinetics between the open and the inactivated states. The sustained and resurgent Na+ currents may therefore be correlatively enhanced by specific mutations involving this linker and relevant regions, and thus marked hyperexcitability in corresponding neural tissues as well as IEM symptomatology.
Nav1.7通道对感觉神经元的兴奋性起着关键作用，该通道的功能获得性突变已被证明会导致伴有神经性疼痛的遗传性红斑性肢痛症（IEM）。在本研究中，我们报告了一例由Nav1.7通道中p.V1316A突变引起的严重IEM表型病例。从机制上讲，我们首先证明Navβ4肽作为一种门控修饰剂，而非与失活肽竞争的开放通道阻滞剂，从而在Nav1.7通道中产生复苏电流。此外，复苏性Na+电流的产生存在两种不同的开放状态和两种相应的快速失活状态。一种负责复苏途径，实际上仅在存在Navβ4肽时存在，而另一种负责从失活中恢复的“沉默”途径。在这方面，p.V1316A突变使激活曲线发生超极化偏移，失活曲线发生去极化偏移，从而使失活与激活明显解偶联。就分子门控操作而言，p.V1316A突变引起的最重要变化是从失活状态到激活状态的转变加速以及反向转变减速，导致持续和复苏的Na+电流都大得多。总之，Nav1.7通道中复苏电流的产生归因于由Navβ4肽促进的一种独特且新颖的开放状态的短暂存在。此外，V1316所在的结构域III中的S4-5连接子似乎在激活-失活偶联中起关键作用，主要是通过直接调节开放状态和失活状态之间的过渡动力学。因此，涉及该连接子及相关区域的特定突变可能会相应增强持续和复苏的Na+电流，进而导致相应神经组织中明显的过度兴奋性以及IEM症状。
