Antillatoxin is a marine cyanobacterial toxin that potently activates voltage-gated sodium channels

Proc Natl Acad Sci U S A. 2001 Jun 19;98(13):7599-604. doi: 10.1073/pnas.121085898.

Abstract

Antillatoxin (ATX) is a lipopeptide derived from the pantropical marine cyanobacterium Lyngbya majuscula. ATX is neurotoxic in primary cultures of rat cerebellar granule cells, and this neuronal death is prevented by either N-methyl-d-aspartate (NMDA) receptor antagonists or tetrodotoxin. To further explore the potential interaction of ATX with voltage-gated sodium channels, we assessed the influence of tetrodotoxin on ATX-induced Ca2+ influx in cerebellar granule cells. The rapid increase in intracellular Ca2+ produced by ATX (100 nM) was antagonized in a concentration-dependent manner by tetrodotoxin. Additional, more direct, evidence for an interaction with voltage-gated sodium channels was derived from the ATX-induced allosteric enhancement of [3H]batrachotoxin binding to neurotoxin site 2 of the alpha subunit of the sodium channel. ATX, moreover, produced a strong synergistic stimulation of [3H]batrachotoxin binding in combination with brevetoxin, which is a ligand for neurotoxin site 5 on the voltage-gated sodium channel. Positive allosteric interactions were not observed between ATX and either alpha-scorpion toxin or the pyrethroid deltamethrin. That ATX interaction with voltage-gated sodium channels produces a gain of function was demonstrated by the concentration-dependent and tetrodotoxin-sensitive stimulation of 22Na+ influx in cerebellar granule cells exposed to ATX. Together these results demonstrate that the lipopeptide ATX is an activator of voltage-gated sodium channels. The neurotoxic actions of ATX therefore resemble those of brevetoxins that produce neural insult through depolarization-evoked Na+ load, glutamate release, relief of Mg2+ block of NMDA receptors, and Ca2+ influx.

Publication types

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

MeSH terms

  • Animals
  • Batrachotoxins / pharmacokinetics
  • Binding, Competitive
  • Calcium / metabolism
  • Cell Survival / drug effects
  • Cells, Cultured
  • Cerebellum / cytology
  • Cerebellum / physiology
  • Cyanobacteria
  • Kinetics
  • Lipopeptides
  • Lipoproteins / pharmacology*
  • Marine Toxins / pharmacology*
  • Neurons / cytology
  • Neurons / drug effects
  • Neurons / physiology*
  • Nitriles
  • Peptides, Cyclic*
  • Pyrethrins / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Sea Anemones
  • Sodium Channels / drug effects
  • Sodium Channels / physiology*
  • Tetrodotoxin / pharmacology

Substances

  • Batrachotoxins
  • Lipopeptides
  • Lipoproteins
  • Marine Toxins
  • Nitriles
  • Peptides, Cyclic
  • Pyrethrins
  • Sodium Channels
  • antillatoxin
  • decamethrin
  • Tetrodotoxin
  • Calcium