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

• Published in: Brain research Vol. 959; no. 1; pp. 120 - 127
• Main Authors: LePage, K.T, Baden, D.G, Murray, T.F
• Format: Journal Article
• Language: English
• Published: London Elsevier B.V 03-01-2003; Amsterdam Elsevier; New York, NY
• Subjects: Animals; Binding, Competitive; Biological and medical sciences; Brevetoxins; Calcium - analysis; Cell membranes. Ionic channels. Membrane pores; Cell structures and functions; Cells, Cultured; Cerebellum - drug effects; Cerebellum - metabolism; Dose-Response Relationship, Drug; Fundamental and applied biological sciences. Psychology; Marine Toxins - pharmacology; Molecular and cellular biology; Neurons - chemistry; Neurons - drug effects; Neurons - metabolism; Neurotoxins - pharmacology; Oxocins - pharmacology; Rats; Rats, Sprague-Dawley; Sodium Channel Agonists; Sodium Channels - drug effects; Sodium Channels - metabolism; Voltage-gated Na + channel; Brevetoxins; Voltage-gated Na + channel; Excitable membranes and synaptic transmission; Cerebellum; Agonist; Granule neuron; Rat; Algae; Rodentia; Central nervous system; Ionic channel; Toxin; Vertebrata; Dinophyta; Mammalia; Sodium; Neurotoxin; Brain (vertebrata); Thallophyta; Voltage-gated Na+ channel
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/S0006-8993(02)03737-X

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 Ca
2+ influx in CGN was explored in the present study. Intracellular Ca
2+ 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 [Ca
2+]. 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 Ca
2+ 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.