Sodium channels caught in the act.
Sodium channels caught in the act.
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钠通道当场被捕。
DOI：
10.1126/science.aaw8645
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Chanda,Baron
中科院分区：
文献类型：
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作者：
Chowdhury,Sandipan;Chanda,Baron
电压门控钠通道 (VGSC) 主要负责许多可兴奋细胞（例如神经和肌肉）动作电位的启动。哺乳动物有九种 VGSC 亚型（Nav1.1 至 1.9），具有截然不同的表达模式和生理作用。这些通道的功能障碍会导致从癫痫到慢性疼痛的病理生理学变化 (1)。这些蛋白质是蜘蛛和蝎子等动物毒液中发现的强效毒素的目标，这些毒素通过两种广泛的机制调节其活性：它们要么堵塞渗透途径，要么结合在这些蛋白质的电压感应域 (VSD) 的变构位点并调节通道开放（门控修饰毒素，GMT）。 VGSC 包含四个同源结构域，每个结构域对通道门控、药理学和离子选择性的贡献不同。例如，第四个结构域 (DIV) 对通道开放贡献不大，但对于快速失活至关重要 (3)。与不同域的 VSD 结合的 GMT 对门控表现出不同的功能影响。 GMT 的这种域特异性为开发治疗方法提供了一个有价值的模板，以治疗由导致功能获得或功能丧失表型的突变引起的疾病。在本期第 1302、1309 和 1303 页，Clairfeuilleet al.(4)、Panet al.(5) 和 Shenet al.(6) 分别提供了不同 VGSC 在激活状态下的详细视图，与孔阻塞毒素和 GMT 结合，以及与 GMT 结合的失活状态通道的结构。此外，Xuet al.(7) 报告了工程钠通道变体的毒素结合静息和激活状态的结构。总之，这些研究为 VGSC 的药理学和门控机制提供了前所未有的见解。
Voltage-gated sodium channels (VGSCs) are primarily responsible for initiation of action potentials in many excitable cells such as nerves and muscles. Mammals have nine isoforms of VGSCs, Nav1.1 to 1.9, with largely distinct expression patterns and physiological roles. Dysfunction of these channels leads to pathophysiologies ranging from epilepsies to chronic pain (1). These proteins are targets of potent toxins found in the venoms of animals such as spiders and scorpions (2), which modulate their activity by two broad mechanisms: They either clog the permeation pathway or bind at allosteric sites in the voltage-sensing domains (VSDs) of these proteins and modulate channel opening (gating modifier toxins, GMTs). VGSCs comprise four homologous domains, each of which contribute differently to channel gating, pharmacology, and ion selectivity. For instance, the fourth domain (DIV) contributes little to channel opening but is critical for fast inactivation (3). GMTs that bind to the VSDs of different domains exhibit different functional impacts on gating. This domain specificity of GMTs offers a valuable template to develop therapeutics to treat diseases arising from mutations causing gain-of-function or loss-of-function phenotypes. On pages 1302, 1309, and 1303 of this issue, Clairfeuilleet al.(4), Panet al.(5), and Shenet al.(6), respectively, provide detailed views of different VGSCs in their activated states, bound to pore-blocking toxins and GMTs, as well as a structure of a GMT-bound deactivated state of the channel. Additionally, Xuet al.(7) report structures of toxin-bound resting and activated states of an engineered sodium channel variant. Together, these studies provide unprecedented insights into the pharmacology and gating mechanisms of VGSCs.