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

Abstract 

Molecular modeling predicts that a local anesthetic (LA) lidocaine binds to the resting and open Na_v1.5 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.

Abbreviations: LA, local anesthetic, MC, Monte Carlo, DEKA, the circular locus of residues Asp, Glu, Lys, and Ala from P-loops in domains D1–D4, respectively, which form the Na⁺ channel selectivity filter, D1S6–D4S6, the inner helices in domains D1–D4, respectively, D3P, the pore helix in domain 3

Keywords: Homology modeling, Lidocaine, QX-314, Monte Carlo-minimization, Ion permeation, Channel block, Slow inactivation