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

W. I. Li, F. W. Berman, T. Okino, F. Yokokawa, T. Shioiri, W. H. Gerwick, Thomas F. Murray

Research output: Contribution to journalArticle

69 Citations (Scopus)

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 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 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.

Original languageEnglish
Pages (from-to)7599-7604
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume98
Issue number13
DOIs
StatePublished - Jun 19 2001
Externally publishedYes

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Marine Toxins
Voltage-Gated Sodium Channels
Tetrodotoxin
Batrachotoxins
Lipopeptides
Voltage-Gated Sodium Channel Agonists
N-Methyl-D-Aspartate Receptors
antillatoxin
cyanobacterial toxin
Scorpions
Pyrethrins
Sodium Channels
Neurotoxins
Cyanobacteria

All Science Journal Classification (ASJC) codes

  • Genetics
  • General

Cite this

Antillatoxin is a marine cyanobacterial toxin that potently activates voltage-gated sodium channels. / Li, W. I.; Berman, F. W.; Okino, T.; Yokokawa, F.; Shioiri, T.; Gerwick, W. H.; Murray, Thomas F.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 98, No. 13, 19.06.2001, p. 7599-7604.

Research output: Contribution to journalArticle

Li, W. I. ; Berman, F. W. ; Okino, T. ; Yokokawa, F. ; Shioiri, T. ; Gerwick, W. H. ; Murray, Thomas F. / Antillatoxin is a marine cyanobacterial toxin that potently activates voltage-gated sodium channels. In: Proceedings of the National Academy of Sciences of the United States of America. 2001 ; Vol. 98, No. 13. pp. 7599-7604.
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AU - Li, W. I.

AU - Berman, F. W.

AU - Okino, T.

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AU - Shioiri, T.

AU - Gerwick, W. H.

AU - Murray, Thomas F.

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AB - 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 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.

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