Ahern Christopher A, Payandeh Jian, Bosmans Frank, Chanda Baron
Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA 52242
Department of Structural Biology, Genentech, Inc., South San Francisco, CA 94080
J Gen Physiol. 2016 Jan;147(1):1-24. doi: 10.1085/jgp.201511492.
Eukaryotic voltage-gated sodium (Nav) channels contribute to the rising phase of action potentials and served as an early muse for biophysicists laying the foundation for our current understanding of electrical signaling. Given their central role in electrical excitability, it is not surprising that (a) inherited mutations in genes encoding for Nav channels and their accessory subunits have been linked to excitability disorders in brain, muscle, and heart; and (b) Nav channels are targeted by various drugs and naturally occurring toxins. Although the overall architecture and behavior of these channels are likely to be similar to the more well-studied voltage-gated potassium channels, eukaryotic Nav channels lack structural and functional symmetry, a notable difference that has implications for gating and selectivity. Activation of voltage-sensing modules of the first three domains in Nav channels is sufficient to open the channel pore, whereas movement of the domain IV voltage sensor is correlated with inactivation. Also, structure-function studies of eukaryotic Nav channels show that a set of amino acids in the selectivity filter, referred to as DEKA locus, is essential for Na(+) selectivity. Structures of prokaryotic Nav channels have also shed new light on mechanisms of drug block. These structures exhibit lateral fenestrations that are large enough to allow drugs or lipophilic molecules to gain access into the inner vestibule, suggesting that this might be the passage for drug entry into a closed channel. In this Review, we will synthesize our current understanding of Nav channel gating mechanisms, ion selectivity and permeation, and modulation by therapeutics and toxins in light of the new structures of the prokaryotic Nav channels that, for the time being, serve as structural models of their eukaryotic counterparts.
真核生物电压门控钠（Nav）通道参与动作电位的上升期，是生物物理学家早期的研究对象，为我们当前对电信号的理解奠定了基础。鉴于它们在电兴奋性中的核心作用，编码Nav通道及其辅助亚基的基因发生（a）遗传性突变与脑、肌肉和心脏的兴奋性障碍有关，以及（b）Nav通道是各种药物和天然毒素的作用靶点，也就不足为奇了。尽管这些通道的整体结构和行为可能与研究更深入的电压门控钾通道相似，但真核生物Nav通道缺乏结构和功能对称性，这一显著差异对门控和选择性有影响。Nav通道中前三个结构域的电压感应模块的激活足以打开通道孔，而结构域IV电压传感器的移动与失活相关。此外，真核生物Nav通道的结构-功能研究表明，选择性过滤器中一组被称为DEKA位点的氨基酸对于Na(+)选择性至关重要。原核生物Nav通道的结构也为药物阻断机制提供了新的线索。这些结构呈现出足够大的侧向开孔，允许药物或亲脂性分子进入内部前庭，这表明这可能是药物进入关闭通道的途径。在本综述中，我们将根据原核生物Nav通道的新结构，综合我们目前对Nav通道门控机制、离子选择性和通透以及治疗药物和毒素调节的理解，目前原核生物Nav通道的结构可作为其真核生物对应物的结构模型。
