title: Antillatoxin is a marine cyanobacterial toxin that potently activates voltage-gated sodium channels.
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.
authors: Department of Physiology and Pharmacology, College of Veterinary Medicine, University of Georgia, Athens, GA 30602-7389, USA.
authors: W I
authors: WI
authors: Li
authors: F W
authors: FW
authors: Berman
authors: T
authors: T
authors: Okino
authors: F
authors: F
authors: Yokokawa
authors: T
authors: T
authors: Shioiri
authors: W H
authors: WH
authors: Gerwick
authors: T F
authors: TF
authors: Murray
mesh_terms: D000818:Animals; D001496:Batrachotoxins / Q000493:pharmacokinetics; D001667:Binding, Competitive; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000502:physiology; D000458:Cyanobacteria; D007700:Kinetics; D055666:Lipopeptides; D008074:Lipoproteins / Q000494:pharmacology*; D008387:Marine Toxins / Q000494:pharmacology*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D009570:Nitriles; D010456:Peptides, Cyclic; D011722:Pyrethrins / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012615:Sea Anemones; D015222:Sodium Channels / Q000187:drug effects / Q000502:physiology*; D013779:Tetrodotoxin / Q000494:pharmacology
chemical_list: D001496:Batrachotoxins; D055666:Lipopeptides; D008074:Lipoproteins; D008387:Marine Toxins; D009570:Nitriles; D010456:Peptides, Cyclic; D011722:Pyrethrins; D015222:Sodium Channels; C121886:antillatoxin; C017180:decamethrin; D013779:Tetrodotoxin; D002118:Calcium