Structural basis for inhibition of the cardiac sodium channel by the atypical antiarrhythmic drug ranolazine

Voltage-gated sodium (Na V ) channels generate the upstroke of the cardiac action potential by activating rapidly in response to depolarization and conducting Na + inward across the membrane 1 , 2 . Na V 1.5 is the predominant Na V channel in the heart 3 , 4 . It is the molecular target for class I antiarrhythmic drugs (AADs), which often have unwanted side effects, including arrhythmias 5 , 6 . In contrast, the atypical AAD ranolazine is effective in treatment of atrial arrhythmias and angina pectoris, but with less proarrhythmia than traditional AADs 7 – 11 . Structures of Na V channels from prokaryotes 12 , skeletal muscle 13 , nerve 14 and heart 15 have been determined with AADs bound within the pore to physically block Na + conductance 12 , 15 – 19 . Here we use electrophysiology and cryogenic electron microscopy to define the interaction of ranolazine with Na V 1.5 at high resolution. We reveal ranolazine’s binding pose and elucidate distinct molecular interactions that might underlie its mechanism of action and high therapeutic index relative to traditional class I AADs.