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

Cell Signal. 2003 Feb;15(2):151-9. doi: 10.1016/s0898-6568(02)00085-2.


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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • Action Potentials / drug effects*
  • Action Potentials / physiology
  • Animals
  • Humans
  • Ion Channel Gating / physiology
  • Lipid Metabolism
  • Neurotoxins / chemistry
  • Neurotoxins / metabolism
  • Neurotoxins / toxicity*
  • Sodium Channels / chemistry
  • Sodium Channels / metabolism*
  • Solubility


  • Neurotoxins
  • Sodium Channels