Antillatoxin is a Marine Cyanobacterial Toxin That Potently Activates Voltage-Gated Sodium Channels

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 98; no. 13; pp. 7599 - 7604
• Main Authors: Li, W. I., Berman, F. W., Okino, T., Yokokawa, F., Shioiri, T., Gerwick, W. H., Murray, T. F.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 19-06-2001; National Acad Sciences; The National Academy of Sciences
• Subjects: Animals; antillatoxin; Bacteria; Batrachotoxins - pharmacokinetics; Binding, Competitive; Biological Sciences; Calcium - metabolism; Cell Survival - drug effects; Cells, Cultured; Cerebellum - cytology; Cerebellum - physiology; Cultured cells; Cyanobacteria; Cyanophyta; Cytotoxicity; Kinetics; Ligands; Lipopeptides; Lipoproteins - pharmacology; Lyngbya majuscula; Marine Toxins - pharmacology; N methyl D aspartate receptors; N-Nitrosodimethylamine receptors; Neurology; Neurons; Neurons - cytology; Neurons - drug effects; Neurons - physiology; Neurotoxins; Nitriles; Peptides; Peptides, Cyclic; Pharmacology; Poisons; Pyrethrins; Pyrethrins - pharmacology; Rats; Rats, Sprague-Dawley; Receptors; Sea Anemones; Sodium channels; sodium channels (voltage-gated); Sodium Channels - drug effects; Sodium Channels - physiology; Tetrodotoxin - pharmacology; Toxins
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.121085898

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 α 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 α-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 of22Na+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.