Anomalous enhancement of resurgent Na+ currents at high temperatures by SCN9A mutations underlies the episodic heat-enhanced pain in inherited erythromelalgia
Anomalous enhancement of resurgent Na+ currents at high temperatures by SCN9A mutations underlies the episodic heat-enhanced pain in inherited erythromelalgia
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DOI：
10.1038/s41598-019-48672-6
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发表时间：
2019-08-22
影响因子：
4.6
通讯作者：
Kuo, Chung-Chin
中科院分区：
文献类型：
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作者：
Huang, Chiung-Wei;Lai, Hsing-Jung;Kuo, Chung-Chin
遗传性红斑性肢痛症（IEM）是由Na（v）1.7通道突变引起的，其特征是发作性神经病理性疼痛，尤其是在温暖的温度下。然而，IEM的温度依赖性发作的机制仍然难以捉摸。我们研究了温度变化对Na（v）1.7通道的电生理效应，这些通道具有三种不同的突变，p.I136V，p.I848T和p.V1316A，在体外和体内。突变通道的体外生物物理学研究显示，如果归一化为瞬时电流，则相对复苏电流的一致温度依赖性增强，以及复苏电流的峰值时间和衰减动力学的温度依赖性变化，但在稳态参数中没有一致的温度依赖性变化，例如激活/激活的偏移。失活曲线和窗口或复苏电流的绝对大小的变化。IEM患者的体内神经兴奋性测试（NET）显示在单一刺激下NET的基本正常指数。然而，如果用预处理脉冲进行评估，则存在明显的异常，例如超极化阈值电紧张的阈值升高降低（50-100 ms）、电流-电压曲线内向整流增加、恢复周期脉冲间间隔2-6 ms不应期增加，可能也暗示了突变通道失活和失活恢复的温度依赖性紊乱。IEM中热增强疼痛的发病机制可归因于负责复活电流产生的Na（v）1.7通道的温度依赖性紊乱。
Inherited erythromelalgia (IEM), caused by mutations in Na(v)1.7 channel is characterized by episodic neuropathic pain triggered especially by warm temperature. However, the mechanism underlying the temperature-dependent episodic attacks of IEM remains elusive. We investigated the electrophysiological effect of temperature changes on Na(v)1.7 channels with three different mutations, p.I136V, p.I848T, and p.V1316A, both in vitro and in vivo. In vitro biophysical studies of the mutant channels show consistent temperature-dependent enhancement of the relative resurgent currents if normalized to the transient currents, as well as temperature-dependent changes in the time to peak and the kinetics of decay of the resurgent currents, but no congruent temperature-dependent changes in steady-state parameters such as shift of activation/inactivation curves and changes of the absolute size of the window or resurgent currents. In vivo nerve excitability tests (NET) in IEM patients reveal the essentially normal indices of NET at a single stimulus. However, there are evident abnormalities if assessed with preconditioning pulses, such as the decrease of threshold elevation in hyperpolarizing threshold electrotonus (50-100 ms), the increase of inward rectification in current-voltage curve, and the increase of refractoriness at the interpulse interval of 2-6 ms in recovery cycle, probably also implicating derangements in temperature dependence of inactivation and of recovery from inactivation in the mutant channels. The pathogenesis of heat-enhanced pain in IEM could be attributed to deranged temperature dependence of Na(v)1.7 channels responsible for the genesis of resurgent currents.