Optical control of the cardiac rhythm with photoswitchable Na_V1.5 channel blockers

Voltage-gated sodium channel Na_V1.5 is essential for cardiac excitability, mediating the rapid depolarization phase of the cardiac action potential (AP) and ensuring proper electrical conduction in the heart. Dysfunction of Na_V1.5 is implicated in life-threatening arrhythmias, making it a critical therapeutic target. Acting as a Na_V1.5 open-state blocker, quinidine demonstrates efficacy in arrhythmia treatment, but its low specificity restricts its clinical application. Here, we report an optopharmacological strategy that enables a precise and optical control of Na_V1.5 function by means of photoswitchable quinidine derivatives. Through systematic structural optimization, we identify azo-Q2a as a high-performance photoswitchable inhibitor, exhibiting low activity in the dark or under 480 nm light irradiation (trans isomer), while approximately 7-fold higher efficacy is observed under 365 nm light irradiation (cis isomer). Of note, azo-Q2a demonstrates exceptional selectivity for Na_V1.5 over cardiac ion channels and other Na_V1 subtypes, minimizing potential off-target effects. Furthermore, by solving the cryo-EM structure of the Na_V1.5 in complex with the cis-active isomer azo-Q2a (3.0 Å resolution), we reveal the essential binding site that is responsible for the optical control of Na_V1.5. Finally, azo-Q2a also attenuates the heart rate of living zebrafish larvae with light, showing its potential in cardiac-related research and treatment. Our work not only establishes azo-Q2a as a robust photoswitchable inhibitor for Na_V1.5 but also provides a structural blueprint for the rational design of next-generation optopharmacological antiarrhythmic agents.