Sodium channel slow inactivation interferes with open channel block.
Sodium channel slow inactivation interferes with open channel block.
复制标题
DOI：
10.1038/srep25974
复制
发表时间：
2016-05-13
影响因子：
4.6
通讯作者：
Lampert A
中科院分区：
文献类型：
--
作者：
Hampl M;Eberhardt E;O'Reilly AO;Lampert A
电压门控钠通道Nav1.7的突变与遗传性疼痛综合征有关，如红斑性肢痛症（IEM）和阵发性极度疼痛障碍（PEPD）。PEPD突变损害Nav1.7快速失活并增加持续电流。PEPD突变还增加了复苏电流，这涉及开放通道阻滞剂的电压依赖性释放。相比之下，IEM突变，无论何时测试，都不会改变复活电流。因此，IEM缺失突变L955（ΔL955）尽管增强了持续电流，但未能产生复苏电流，而持续电流迄今被认为是复苏电流的先决条件。此外，ΔL955表现出显著的缓慢失活（SI）增强。我们将突变引入到Nav1.7和Nav1.6中，增强或损害SI，以研究它们对复活电流的影响。我们的研究结果表明，增强SI伴随着受损的复苏电流，这表明SI可能会干扰开放通道阻滞。
Mutations in the voltage-gated sodium channel Nav1.7 are linked to inherited pain syndromes such as erythromelalgia (IEM) and paroxysmal extreme pain disorder (PEPD). PEPD mutations impair Nav1.7 fast inactivation and increase persistent currents. PEPD mutations also increase resurgent currents, which involve the voltage-dependent release of an open channel blocker. In contrast, IEM mutations, whenever tested, leave resurgent currents unchanged. Accordingly, the IEM deletion mutation L955 (ΔL955) fails to produce resurgent currents despite enhanced persistent currents, which have hitherto been considered a prerequisite for resurgent currents. Additionally, ΔL955 exhibits a prominent enhancement of slow inactivation (SI). We introduced mutations into Nav1.7 and Nav1.6 that either enhance or impair SI in order to investigate their effects on resurgent currents. Our results show that enhanced SI is accompanied by impaired resurgent currents, which suggests that SI may interfere with open-channel block.