Fenestrations control resting-state block of a voltage-gated sodium channel

Significance Voltage-gated sodium channels initiate electrical signals in nerve and cardiac muscle, where their hyperactivity causes pain and cardiac arrhythmia. Local anesthetics and antiarrhythmic drugs selectively block sodium channels in rapidly firing nerve and muscle cells to relieve these conditions. We studied an ancestral bacterial sodium channel to elucidate the structure of the drug-binding site and the pathway for drug entry to the receptor site. We found that the drug-binding site is located in the center of the transmembrane pore, through which sodium ions move and fenestrations form an access pathway for drug entry directly from the cell membrane. These results show how these widely used drugs block the sodium channel and have important implications for structure-based design of next-generation drugs.