Brevetoxin derivatives act as partial agonists at neurotoxin site 5 on the voltage-gated Na+ channel

K. T. LePage, D. G. Baden, Thomas F. Murray

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Brevetoxins (PbTx-1 to PbTx-10) are potent lipid-soluble polyether neurotoxins produced by the marine dinoflagellate Karina brevis, an organism associated with 'red tide' blooms in the Gulf of Mexico. Ingestion of shellfish contaminated with K. brevis produces neurotoxic shellfish poisoning (NSP) in humans. NSP symptoms emanate from brevetoxin activation of neurotoxin site 5 on voltage-gated sodium channels (VGSC) [Toxicon 20 (1982) 457]. In primary cultures of rat cerebellar granule neurons (CGN), brevetoxins produce acute neuronal injury and death. The ability of a series of naturally occurring and synthetic brevetoxins to trigger Ca2+ influx in CGN was explored in the present study. Intracellular Ca2+ concentration was monitored in fluo-3-loaded CGN using a fluorescent laser imaging plate reader. The naturally occurring derivatives PbTx-1, PbTx-2 and PbTx-3 all produced a rapid and concentration-dependent increase in cytosolic [Ca2+]. The maximum response to PbTx-1 was approximately two-fold greater than that of either PbTx-2 or PbTx-3. Two synthetic derivatives of PbTx-3, α-naphthoyl-PbTx-3 and β-naphthoyl-PbTx-3, were also tested. Both α- and β-naphthoyl-PbTx-3 stimulated a rapid and concentration-dependent Ca2+ influx that was, however, less efficacious than that of PbTx-3. These data indicate that, analogous to neurotoxin site 2 ligands, activators of neurotoxin site 5 display a range of efficacies, with PbTx-1 being a full agonist and other derivatives acting as partial agonists.

Original languageEnglish
Pages (from-to)120-127
Number of pages8
JournalBrain Research
Volume959
Issue number1
DOIs
StatePublished - Jan 3 2003
Externally publishedYes

Fingerprint

Shellfish Poisoning
Neurotoxins
Neurons
Harmful Algal Bloom
Gulf of Mexico
Voltage-Gated Sodium Channels
Dinoflagellida
Shellfish
Lasers
Eating
Ligands
Lipids
pelamitoxin
brevetoxin
Wounds and Injuries
Ptychodiscus brevis T2 toxin

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

Cite this

Brevetoxin derivatives act as partial agonists at neurotoxin site 5 on the voltage-gated Na+ channel. / LePage, K. T.; Baden, D. G.; Murray, Thomas F.

In: Brain Research, Vol. 959, No. 1, 03.01.2003, p. 120-127.

Research output: Contribution to journalArticle

@article{81468921811b4607a9e99f366f20988c,
title = "Brevetoxin derivatives act as partial agonists at neurotoxin site 5 on the voltage-gated Na+ channel",
abstract = "Brevetoxins (PbTx-1 to PbTx-10) are potent lipid-soluble polyether neurotoxins produced by the marine dinoflagellate Karina brevis, an organism associated with 'red tide' blooms in the Gulf of Mexico. Ingestion of shellfish contaminated with K. brevis produces neurotoxic shellfish poisoning (NSP) in humans. NSP symptoms emanate from brevetoxin activation of neurotoxin site 5 on voltage-gated sodium channels (VGSC) [Toxicon 20 (1982) 457]. In primary cultures of rat cerebellar granule neurons (CGN), brevetoxins produce acute neuronal injury and death. The ability of a series of naturally occurring and synthetic brevetoxins to trigger Ca2+ influx in CGN was explored in the present study. Intracellular Ca2+ concentration was monitored in fluo-3-loaded CGN using a fluorescent laser imaging plate reader. The naturally occurring derivatives PbTx-1, PbTx-2 and PbTx-3 all produced a rapid and concentration-dependent increase in cytosolic [Ca2+]. The maximum response to PbTx-1 was approximately two-fold greater than that of either PbTx-2 or PbTx-3. Two synthetic derivatives of PbTx-3, α-naphthoyl-PbTx-3 and β-naphthoyl-PbTx-3, were also tested. Both α- and β-naphthoyl-PbTx-3 stimulated a rapid and concentration-dependent Ca2+ influx that was, however, less efficacious than that of PbTx-3. These data indicate that, analogous to neurotoxin site 2 ligands, activators of neurotoxin site 5 display a range of efficacies, with PbTx-1 being a full agonist and other derivatives acting as partial agonists.",
author = "LePage, {K. T.} and Baden, {D. G.} and Murray, {Thomas F.}",
year = "2003",
month = "1",
day = "3",
doi = "10.1016/S0006-8993(02)03737-X",
language = "English",
volume = "959",
pages = "120--127",
journal = "Brain Research",
issn = "0006-8993",
publisher = "Elsevier",
number = "1",

}

TY - JOUR

T1 - Brevetoxin derivatives act as partial agonists at neurotoxin site 5 on the voltage-gated Na+ channel

AU - LePage, K. T.

AU - Baden, D. G.

AU - Murray, Thomas F.

PY - 2003/1/3

Y1 - 2003/1/3

N2 - Brevetoxins (PbTx-1 to PbTx-10) are potent lipid-soluble polyether neurotoxins produced by the marine dinoflagellate Karina brevis, an organism associated with 'red tide' blooms in the Gulf of Mexico. Ingestion of shellfish contaminated with K. brevis produces neurotoxic shellfish poisoning (NSP) in humans. NSP symptoms emanate from brevetoxin activation of neurotoxin site 5 on voltage-gated sodium channels (VGSC) [Toxicon 20 (1982) 457]. In primary cultures of rat cerebellar granule neurons (CGN), brevetoxins produce acute neuronal injury and death. The ability of a series of naturally occurring and synthetic brevetoxins to trigger Ca2+ influx in CGN was explored in the present study. Intracellular Ca2+ concentration was monitored in fluo-3-loaded CGN using a fluorescent laser imaging plate reader. The naturally occurring derivatives PbTx-1, PbTx-2 and PbTx-3 all produced a rapid and concentration-dependent increase in cytosolic [Ca2+]. The maximum response to PbTx-1 was approximately two-fold greater than that of either PbTx-2 or PbTx-3. Two synthetic derivatives of PbTx-3, α-naphthoyl-PbTx-3 and β-naphthoyl-PbTx-3, were also tested. Both α- and β-naphthoyl-PbTx-3 stimulated a rapid and concentration-dependent Ca2+ influx that was, however, less efficacious than that of PbTx-3. These data indicate that, analogous to neurotoxin site 2 ligands, activators of neurotoxin site 5 display a range of efficacies, with PbTx-1 being a full agonist and other derivatives acting as partial agonists.

AB - Brevetoxins (PbTx-1 to PbTx-10) are potent lipid-soluble polyether neurotoxins produced by the marine dinoflagellate Karina brevis, an organism associated with 'red tide' blooms in the Gulf of Mexico. Ingestion of shellfish contaminated with K. brevis produces neurotoxic shellfish poisoning (NSP) in humans. NSP symptoms emanate from brevetoxin activation of neurotoxin site 5 on voltage-gated sodium channels (VGSC) [Toxicon 20 (1982) 457]. In primary cultures of rat cerebellar granule neurons (CGN), brevetoxins produce acute neuronal injury and death. The ability of a series of naturally occurring and synthetic brevetoxins to trigger Ca2+ influx in CGN was explored in the present study. Intracellular Ca2+ concentration was monitored in fluo-3-loaded CGN using a fluorescent laser imaging plate reader. The naturally occurring derivatives PbTx-1, PbTx-2 and PbTx-3 all produced a rapid and concentration-dependent increase in cytosolic [Ca2+]. The maximum response to PbTx-1 was approximately two-fold greater than that of either PbTx-2 or PbTx-3. Two synthetic derivatives of PbTx-3, α-naphthoyl-PbTx-3 and β-naphthoyl-PbTx-3, were also tested. Both α- and β-naphthoyl-PbTx-3 stimulated a rapid and concentration-dependent Ca2+ influx that was, however, less efficacious than that of PbTx-3. These data indicate that, analogous to neurotoxin site 2 ligands, activators of neurotoxin site 5 display a range of efficacies, with PbTx-1 being a full agonist and other derivatives acting as partial agonists.

UR - http://www.scopus.com/inward/record.url?scp=0037414734&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0037414734&partnerID=8YFLogxK

U2 - 10.1016/S0006-8993(02)03737-X

DO - 10.1016/S0006-8993(02)03737-X

M3 - Article

VL - 959

SP - 120

EP - 127

JO - Brain Research

JF - Brain Research

SN - 0006-8993

IS - 1

ER -