Optical Control of the Cardiac Rhythm with Photoswitchable NaV1.5 Channel Blockers

Voltage-gated sodium channel Na _V 1.5 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 _V 1.5 is implicated in life-threatening arrhythmias, making it a critical therapeutic target. Acting as a Na _V 1.5 open-state blocker, quinidine demonstrates efficacy in arrhythmia treatment, but its low specificity restricts its clinical application. Here, we reported an optopharmacological strategy which enables a precise and optical control of Na _V 1.5 function by means of photoswitchable quinidine derivatives. Through systematic structural optimization, we identified 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 was observed under 365 nm light irradiation ( cis isomer). Of note, azo-Q2a demonstrated exceptional selectivity for Na _V 1.5 over other cardiac ion channels, minimizing potential off-target effects. Furthermore, by solving the cryo-EM structure of the Na _V 1.5 in complex with the cis -active isomer azo-Q2a (3.1 Å resolution), we revealed the essential binding site that is responsible for the optical control of Na _V 1.5. Finally, azo-Q2a also attenuates 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 _V 1.5 but also provides a structural blueprint for the rational design of next-generation optopharmacological antiarrhythmic agents.