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

Citation
Wi. Li et al., Antillatoxin is a marine cyanobacterial toxin that potently activates voltage-gated sodium channels, P NAS US, 98(13), 2001, pp. 7599-7604
Citations number
32
Categorie Soggetti
Multidisciplinary
Journal title
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
ISSN journal
00278424 → ACNP
Volume
98
Issue
13
Year of publication
2001
Pages
7599 - 7604
Database
ISI
SICI code
0027-8424(20010619)98:13<7599:AIAMCT>2.0.ZU;2-C
Abstract
Antillatoxin (ATX) is a lipopeptide derived from the pantropical marine cya nobacterium 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 channel s, 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 tet rodotoxin. Additional, more direct, evidence for an interaction with voltag e-gated sodium channels was derived from the ATX-induced allosteric enhance ment of [H-3]batrachotoxin binding to neurotoxin site 2 of the alpha subuni t of the sodium channel. ATX, moreover, produced a strong synergistic stimu lation of [H-3]batrachotoxin binding in combination with brevetoxin, which is a ligand for neurotoxin site 5 on the voltage-gated sodium channel. Posi tive 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 Na -22(+) influx in cerebellar granule cells exposed to ATX. Together these re sults 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+ l oad, glutamate release, relief of Mg2+ block of NMDA receptors, and Ca2+ in flux.