Atomic determinants of state‐dependent block of sodium channels by charged local anesthetics and benzocaine

Molecular modeling predicts that a local anesthetic (LA) lidocaine binds to the resting and open Na v 1.5 in different modes, interacting with LA‐sensing residues known from experiments. Besides the major pathway via the open activation gate, LAs can reach the inner pore via a “sidewalk” between D3S6, D4S6, and D3P. The ammonium group of a cationic LA binds in the focus of the pore‐helices macrodipoles, which also stabilize a Na + ion chelated by two benzocaine molecules. The LA's cationic group and a Na + ion in the selectivity filter repel each other suggesting that the Na + depletion upon slow inactivation would stabilize a LA, while a LA would stabilize slow‐inactivated states.