Protonation underlies tonic vs. use-dependent block.
Protonation underlies tonic vs. use-dependent block.
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质子化是强直性阻滞与使用依赖性阻滞的基础。
DOI：
10.1073/pnas.1802178115
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发表时间：
2018
影响因子：
11.1
通讯作者：
Carnevale,Vincenzo
中科院分区：
文献类型：
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作者：
Carnevale,Vincenzo
真核细胞电压门控钠选择性通道（VGSC）能够响应跨膜电位的变化将Na+流入可兴奋细胞。离子的这种运动导致在动作电位的上升阶段期间发生的膜去极化，并且因此是神经元中电信号传播的基础。VGSC的跨膜区的特征在于四重假对称结构。特别地，通道由四个同源重复序列（称为结构域，DI至DIV）构成，每个同源重复序列包含六个螺旋区段（S1至S6）。每个域的前四个螺旋（S1-S4）组装成单独的螺旋束，即所谓的电压传感器域，其响应于膜去极化而经历构象转变。所有结构域中剩余的S5和S6螺旋形成四聚体组装体，即孔结构域，其中心含有内腔。后者构成了连接细胞外和细胞内区室的通路，使得水分子和离子能够穿过膜扩散。沿着这条途径的关键里程碑沿着是选择性过滤器，一个可渗透Na+但不能渗透K+的部分，以及激活门，一个疏水塞，当通道处于关闭状态时，它阻碍了沃茨和离子的通过。这种生物纳米机器的主要特征在进化过程中沿着保持着显著的保守性：来自所有生命王国的电压门控离子通道都有一个共同的“蓝图”，具有相同的结构和基本的功能规则。特别是，VGSC是一个大的系统发育家族，六跨膜家族的成员，也包含来自细菌的VGSC。尽管有很大程度的序列相似性，但原核VGSC的结构不如真核VGSC复杂。后者由含有四个同源重复的单链多肽组成，而前者是真正的同源四聚体。此外，原核VGSC几乎完全缺乏表征真核VGSC的大的细胞内和细胞外结构域。换句话说，细菌拥有极简版本的VGSC。这种固有的简单性使得大量的结构和功能研究成为可能，这些研究产生了VGSC激活机制的详细显微图像（1-3）JGSC的分子细节的理解不仅揭示了电信号的基本方面，而且还揭示了与可兴奋细胞功能障碍相关的许多疾病的原因。VGSC功能障碍涉及例如心律失常、癫痫和疼痛综合征（4-7）。因此，VGSC的小分子调节是治疗这些疾病的主要治疗策略之一。然而，这些药物的安全性和生存能力往往受到缺乏选择性的限制。人类基因组包含9个VGSC基因，在心脏、中枢神经系统和外周神经系统之间具有不同的表达谱。同时抑制几种VGSC亚型，如在局部麻醉剂的情况下，增加了危及生命的副作用的风险，因此严重限制了可能的给药途径。因此，开发选择性抑制剂是发现有效而安全的药物的必要策略。然而，这奋进的成功仍然是偶然的，尚未导致批准的药物（8-10）。部分问题是缺乏对VGSC抑制剂作用机制的详细了解。自第一个开创性研究以来，VGSC抑制表现为一个复杂的过程，有几个令人困惑的方面。例如，VGSC以两种不同的方式被抑制：通过...
Eukaryotic voltage gated sodium-selective channels (VGSCs) enable influx of Na+ into excitable cells in response to a change in the transmembrane potential. This movement of ions causes the membrane depolarization occurring during the rising phase of the action potential and, as such, underlies propagation of electrical signals in neurons. The transmembrane region of VGSCs is characterized by a fourfold pseudosymmetrical architecture. In particular, the channel is constituted of four homologous repeats (referred to as domains, DI through DIV), each comprising six helical segments (S1 through S6). The first four helices (S1–S4) of each domain assemble into a separate helix bundle, the so-called voltage sensor domain, which undergoes a conformational transition in response to membrane depolarization. The remaining S5 and S6 helices from all of the domains form a tetrameric assembly, the pore domain, containing a lumen in its center. The latter constitutes a pathway connecting the extracellular and intracellular compartments, enabling diffusion of water molecules and ions across the membrane. Crucial milestones along this pathway are the selectivity filter, a section permeable to Na+ but not K+, and the activation gate, a hydrophobic plug that hinders the passage of waters and ions when the channel is in the closed state. The major features of this biological nanomachine are remarkably conserved along evolution: Voltagegated ion channels from all kingdoms of life share a common “blueprint” with the same architecture and basic rules of functioning. In particular, VGSCs are members of a large phylogenetic family, the sixtransmembrane family, also containing VGSCs from bacteria. Despite the large degree of sequence similarity, the structure of prokaryotic VGSCs is less complex than that of eukaryotic ones. While the latter are constituted of a single polypeptide chain containing four homologous repeats, the former are genuine homotetramers. Moreover, prokaryotic VGSCs lack almost completely the large intracellular and extracellular domains characterizing eukaryotic VGSCs. In other words, bacteria possess a minimalist version of VGSCs. This inherent simplicity enabled a wealth of structural and functional studies that resulted in a detailed microscopic picture of the VGSC activation mechanism (1–3).Understanding the molecular details of VGSCs sheds light not only on fundamental aspects of electrical signaling but also on the causes of many diseases associated with disorders of excitable cell function. VGSC malfunctioning is involved, for instance, in cardiac arrhythmias, epilepsy, and pain syndromes (4–7). Accordingly, small-molecule modulation of VGSCs is one of the major therapeutic strategies to treat these diseases. Often, however, the safety, and thus the viability, of these drugs is limited by their lack of selectivity. The human genome contains nine VGSC genes with distinct expression profiles between the heart, central nervous system, and peripheral nervous system. Simultaneous inhibition of several VGSC subtypes, as in the case of local anesthetics, increases the risk of life-threatening side effects, and thus severely limits the possible routes of administration. Developing selective inhibitors is thus a necessary strategy to discover effective yet safe drugs. However, success in this endeavor is still episodic and has not yet resulted in approved drugs (8–10). Part of the problem is the lack of a detailed understanding of VGSC inhibitor mechanism of action. Since the first pioneering studies, VGSC inhibition appeared as a complex process with several puzzling aspects. For instance, VGSCs are inhibited in two distinct ways: through a …