Voltage-gated ion channels (VGICs), including those for Na⁺, Ca²⁺ and K⁺, selectively permeate ions across the cell membrane in response to changes in membrane potential, thus participating in physiological processes involving electrical signalling, such as neurotransmission, muscle contraction and hormone secretion. Aberrant function or dysregulation of VGICs is associated with a diversity of neurological, psychiatric, cardiovascular and muscular disorders, and approximately 10% of FDA-approved drugs directly target VGICs. Understanding the structure–function relationship of VGICs is crucial for our comprehension of their working mechanisms and role in diseases. In this Review, we discuss how advances in single-particle cryo-electron microscopy have afforded unprecedented structural insights into VGICs, especially on their interactions with clinical and investigational drugs. We present a comprehensive overview of the recent advances in the structural biology of VGICs, with a focus on how prototypical drugs and toxins modulate VGIC activities. We explore how these structures elucidate the molecular basis for drug actions, reveal novel pharmacological sites, and provide critical clues to future drug discovery.

电压门控离子通道 （VGIC），包括 Na⁺、Ca²⁺ 和 K⁺ 的离子通道，响应膜电位的变化选择性地渗透离子穿过细胞膜，从而参与涉及电信号的生理过程，例如神经传递、肌肉收缩和激素分泌。VGIC 的功能异常或失调与多种神经、精神、心血管和肌肉疾病有关，大约 10% 的 FDA 批准的药物直接靶向 VGIC。了解 VGIC 的结构-功能关系对于我们理解它们的工作机制和在疾病中的作用至关重要。在这篇综述中，我们讨论了单颗粒冷冻电子显微镜的进步如何为 VGIC 提供了前所未有的结构见解，尤其是它们与临床和研究药物的相互作用。我们全面概述了 VGIC 结构生物学的最新进展，重点是原型药物和毒素如何调节 VGIC 活性。我们探讨了这些结构如何阐明药物作用的分子基础，揭示新的药理学位点，并为未来的药物发现提供关键线索。