Molecular and kinetic determinants of local anaesthetic action on sodium channels

Autor: Iván E. Sierralta, Gerald W. Zamponi, Robert J. French
Rok vydání: 1998
Předmět:
Zdroj: Toxicology Letters. :247-254
ISSN: 0378-4274
DOI: 10.1016/s0378-4274(98)00192-1
Popis: (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.
Databáze: OpenAIRE