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
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.