Voltage-gated sodium channels as primary targets of diverse lipid-soluble neurotoxins [Review]

摘要

Voltage-gated Na+ channels are heteromeric membrane glycoproteins responsible for the generation of action potentials. A number of diverse lipid-soluble neurotoxins, such as batrachotoxin, veratridine, aconitine, grayanotoxins, pyrethroid insecticides, brevetoxins and ciguatoxin, target voltage-gated Na+ channels for their primary actions. These toxins promote Na+ channel opening, induce depolarization of the resting membrane potential, and thus drastically affect the excitability of nerve, muscle and cardiac tissues. Poisoning by these lipid-soluble neurotoxins causes hyperexcitability of excitable tissues, followed by convulsions, paralysis and death in animals. How these lipid-soluble neurotoxins alter Na+ channel gating mechanistically remains unknown. Recent mapping of receptor sites within the Na+ channel protein for these neurotoxins using site-directed mutagenesis has provided important clues on this subject. Paradoxically, the receptor site for batrachotoxin and veratridine on the voltage-gated Na+ channel alpha-subunit appears to be adjacent to or overlap with that for therapeutic drugs such as local anaesthetics (LAs), antidepressants and anticonvulsants. This article reviews the physiological actions of lipid-soluble neurotoxins on voltage-gated Na+ channels, their receptor sites on the S6 segments of the Na+ channel alpha-subunit and a possible linkage between their receptors and the gating function of Na+ channels. (C) 2003 Elsevier Science Inc. All rights reserved. [References: 68]