The heartbeat is initiated by voltage-gated sodium channel Na_V1.5, which opens rapidly and triggers the cardiac action potential; however, the structural basis for pore opening remains unknown. Here, we blocked fast inactivation with a mutation and captured the elusive open-state structure. The fast inactivation gate moves away from its receptor, allowing asymmetric opening of pore-lining S6 segments, which bend and rotate at their intracellular ends to dilate the activation gate to ∼10 Å diameter. Molecular dynamics analyses predict physiological rates of Na⁺ conductance. The open-state pore blocker propafenone binds in a high-affinity pose, and drug-access pathways are revealed through the open activation gate and fenestrations. Comparison with mutagenesis results provides a structural map of arrhythmia mutations that target the activation and fast inactivation gates. These results give atomic-level insights into molecular events that underlie generation of the action potential, open-state drug block, and fast inactivation of cardiac sodium channels, which initiate the heartbeat.

心跳由电压门控钠通道 Na _V 1.5 启动，快速打开并触发心脏动作电位；然而，孔隙打开的结构基础仍然未知。在这里，我们通过突变阻止了快速失活并捕获了难以捉摸的开放状态结构。快速失活门远离其受体，允许孔衬 S6 片段不对称打开，这些片段在其细胞内末端弯曲和旋转以将激活门扩大到 10 Å 直径。分子动力学分析预测 Na ^{+的生理速率}电导。开放状态的孔阻滞剂普罗帕酮以高亲和力姿势结合，通过开放的激活门和开窗揭示药物进入途径。与诱变结果的比较提供了靶向激活和快速失活门的心律失常突变的结构图。这些结果为分子事件提供了原子水平的见解，这些分子事件是动作电位产生、开放状态药物阻滞和心脏钠通道快速失活的基础，从而引发了心跳。