title: Gambierol acts as a functional antagonist of neurotoxin site 5 on voltage-gated sodium channels in cerebellar granule neurons.
abstract: The marine toxin gambierol, a polyether ladder toxin derived from the marine dinoflagellate Gambierdiscus toxicus, was evaluated for interaction with voltage-gated sodium channels (VGSCs) in cerebellar granule neuron (CGN) cultures. At concentrations ranging from 10 nM to 10 microM, gambierol alone had no effect on the intracellular Ca2+ concentration [Ca2+]i of exposed CGN cultures. Furthermore, there was no evidence of neurotoxicity in CGN cultures exposed for 2 h to gambierol (1 nM-10 microM). However, gambierol was a potent inhibitor (IC50 = 189 nM) of the elevation of [Ca2+]i that accompanies exposure of CGN cultures to the VGSC activator brevetoxin-2 (PbTx-2). To further explore the potential interaction of gambierol with VGSCs, the influence of gambierol on PbTx-2-induced neurotoxicity was assessed. Gambierol reduced the PbTx-2-induced efflux of lactate dehydrogenase in exposed CGN cultures in a concentration-dependent manner (IC50 = 471 nM). It is noteworthy that the potencies of gambierol as an inhibitor of both PbTx-2-induced Ca2+ influx and cytotoxicity were coincident. Finally, the inhibitory effects of gambierol on PbTx-2-induced elevation of [Ca2+]i were compared with those of brevenal, a natural inhibitor of the toxic effects of brevetoxin isolated from cultures of Karina brevis. Like gambierol, brevenal inhibited PbTx-2-induced elevation of [Ca2+]i in a concentration-dependent manner (IC50 = 108.6 nM). These results provide evidence for gambierol acting as a functional antagonist of neurotoxin site 5 on neuronal VGSCs.
authors.affiliation: Department of Biology, Xavier University of Louisiana, New Orleans, Louisiana, USA.
authors.forename: K T
authors.initials: KT
authors.lastname: LePage
authors.forename: J D
authors.initials: JD
authors.lastname: Rainier
authors.forename: H W B
authors.initials: HW
authors.lastname: Johnson
authors.forename: D G
authors.initials: DG
authors.lastname: Baden
authors.forename: T F
authors.initials: TF
authors.lastname: Murray
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002531:Cerebellum / Q000187:drug effects* / Q000378:metabolism; D002922:Ciguatoxins / Q000494:pharmacology*; D004988:Ethers, Cyclic / Q000494:pharmacology*; D008387:Marine Toxins / Q000494:pharmacology; D015394:Molecular Structure; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D035964:Oxocins; D011083:Polycyclic Compounds / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D026941:Sodium Channel Blockers / Q000494:pharmacology*; D015222:Sodium Channels / Q000378:metabolism*; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
chemical_list: D004988:Ethers, Cyclic; D008387:Marine Toxins; D035964:Oxocins; D011083:Polycyclic Compounds; C051732:Ptychodiscus brevis T2 toxin; D026941:Sodium Channel Blockers; D015222:Sodium Channels; C435770:gambierol; D002922:Ciguatoxins; D002118:Calcium