Zhang Alan H, Sharma Gagan, Undheim Eivind A B, Jia Xinying, Mobli Mehdi
Centre for Advanced Imaging, The University of Queensland, Australia.
Centre for Advanced Imaging, The University of Queensland, Australia.
Neurosci Lett. 2018 Jul 13;679:35-47. doi: 10.1016/j.neulet.2018.04.030. Epub 2018 Apr 21.
Voltage-gated ion channels (VGICs) are specialised ion channels that have a voltage dependent mode of action, where ion conduction, or gating, is controlled by a voltage-sensing mechanism. VGICs are critical for electrical signalling and are therefore important pharmacological targets. Among these, voltage-gated sodium channels (Nas) have attracted particular attention as potential analgesic targets. Nas, however, comprise several structurally similar subtypes with unique localisations and distinct functions, ranging from amplification of action potentials in nociception (e.g. Na1.7) to controlling electrical signalling in cardiac function (Na1.5). Understanding the structural basis of Na function is therefore of great significance, both to our knowledge of electrical signalling and in development of subtype and state selective drugs. An important tool in this pursuit has been the use of peptides from animal venoms as selective Na modulators. In this review, we look at peptides, particularly from spider venoms, that inhibit Nas by binding to the voltage sensing domain (VSD) of this channel, known as gating modifier toxins (GMT). In the first part of the review, we look at the structural determinants of voltage sensing in VGICs, the gating cycle and the conformational changes that accompany VSD movement. Next, the modulation of the analgesic target Na1.7 by GMTs is reviewed to develop bioinformatic tools that, based on sequence information alone, can identify toxins that are likely to inhibit this channel. The same approach is also used to define VSD sequences, other than that from Na1.7, which are likely to be sensitive to this class of toxins. The final section of the review focuses on the important role of the cellular membrane in channel modulation and also how the lipid composition affects measurements of peptide-channel interactions both in binding kinetics measurements in solution and in cell-based functional assays.
电压门控离子通道（VGICs）是一类特殊的离子通道，其作用模式依赖于电压，离子传导或门控由电压传感机制控制。VGICs对电信号传导至关重要，因此是重要的药理学靶点。其中，电压门控钠通道（Nas）作为潜在的镇痛靶点受到了特别关注。然而，Nas由几种结构相似的亚型组成，它们具有独特的定位和不同的功能，从伤害性感受中动作电位的放大（如Na1.7）到心脏功能中电信号的控制（Na1.5）。因此，了解钠通道功能的结构基础对于我们对电信号传导的认识以及亚型和状态选择性药物的开发都具有重要意义。在这一研究过程中，一个重要的工具是使用动物毒液中的肽作为钠通道的选择性调节剂。在本综述中，我们将探讨特别是来自蜘蛛毒液的肽，它们通过与该通道的电压传感结构域（VSD）结合来抑制Nas，这类肽被称为门控修饰毒素（GMT）。在综述的第一部分，我们将研究VGICs中电压传感的结构决定因素、门控循环以及伴随VSD移动的构象变化。接下来，将综述GMTs对镇痛靶点Na1.7的调节作用，以开发仅基于序列信息就能识别可能抑制该通道的毒素的生物信息学工具。同样的方法也用于定义除Na1.7之外可能对这类毒素敏感的VSD序列。综述的最后一部分重点关注细胞膜在通道调节中的重要作用，以及脂质组成如何影响溶液中结合动力学测量和基于细胞的功能测定中肽 - 通道相互作用的测量。
