Molecular and kinetic determinants of local anaesthetic action on sodium channels

(1) Local anaesthetics (LA) rely for their clinical actions on state-depend ent inhibition of voltage-dependent sodium channels. (2) Single, batrachoxi n-modified sodium channels in planar lipid bilayers allow direct observatio n of drug-channel interactions. Two modes of inhibition of single-channel c urrent are observed: fast block of the open channels and prolongation of a long-lived closed state, some of whose properties resemble those of the ina ctivated state of unmodified channels. (3) Analogues of different parts of the LA molecule separately mimic each blocking mode: amines-fast block, and water-soluble aromatics-closed state prolongation. (4) Interaction between a mu-conotoxin derivative and diethylammonium indicate an intrapore site o f fast, open-state block. (5) Site-directed mutagenesis studies suggest tha t hydrophobic residues in transmembrane segment 6 of repeat domain 4 of sod ium channels are critical for both LA binding and stabilization of the inac tivated state. (C) 1998 Published by Elsevier Science Ireland Ltd. All righ ts reserved.