Molecular and kinetic determinants of local anaesthetic action on sodium channels.
(1) Local anaesthetics (LA) rely for their clinical actions on state-dependent inhibition of voltage-dependent sodium channels. (2) Single, batrachoxin-modified sodium channels in planar lipid bilayers allow direct observation of drug-channel interactions. Two modes of inhibition of single-channel current are observed: fast block of the open channels and prolongation of a long-lived closed state, some of whose properties resemble those of the inactivated 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 of fast, open-state block. (5) Site-directed mutagenesis studies suggest that hydrophobic residues in transmembrane segment 6 of repeat domain 4 of sodium channels are critical for both LA binding and stabilization of the inactivated state.
French
R J
RJ
Department of Physiology and Biophysics, The University of Calgary, Alberta, Canada. french@acs.ucalgary.ca
Zamponi
G W
GW
Sierralta
I E
IE
D000779:Anesthetics, Local / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D006801:Humans; D007700:Kinetics; D015222:Sodium Channels / Q000737:chemistry* / Q000187:drug effects*
D000779:Anesthetics, Local; D015222:Sodium Channels