title: Gambierol, a toxin produced by the dinoflagellate Gambierdiscus toxicus, is a potent blocker of voltage-gated potassium channels.
abstract: In this study, we pharmacologically characterized gambierol, a marine polycyclic ether toxin which is produced by the dinoflagellate Gambierdiscus toxicus. Besides several other polycyclic ether toxins like ciguatoxins, this scarcely studied toxin is one of the compounds that may be responsible for ciguatera fish poisoning (CFP). Unfortunately, the biological target(s) that underlies CFP is still partly unknown. Today, ciguatoxins are described to specifically activate voltage-gated sodium channels by interacting with their receptor site 5. But some dispute about the role of gambierol in the CFP story shows up: some describe voltage-gated sodium channels as the target, while others pinpoint voltage-gated potassium channels as targets. Since gambierol was never tested on isolated ion channels before, it was subjected in this work to extensive screening on a panel of 17 ion channels: nine cloned voltage-gated ion channels (mammalian Na(v)1.1-Na(v)1.8 and insect Para) and eight cloned voltage-gated potassium channels (mammalian K(v)1.1-K(v)1.6, hERG and insect ShakerIR) expressed in Xenopus laevis oocytes using two-electrode voltage-clamp technique. All tested sodium channel subtypes are insensitive to gambierol concentrations up to 10 microM. In contrast, K(v)1.2 is the most sensitive voltage-gated potassium channel subtype with almost full block (>97%) and an half maximal inhibitory concentration (IC(50)) of 34.5 nM. To the best of our knowledge, this is the first study where the selectivity of gambierol is tested on isolated voltage-gated ion channels. Therefore, these results lead to a better understanding of gambierol and its possible role in CFP and they may also be useful in the development of more effective treatments.
authors.affiliation: Laboratorium voor Toxicologie, Campus Gasthuisberg, Onderwijs en Navorsing 2, Herestraat 49, Bus 922, KULeuven B-3000, Belgium.
authors.forename: Eva
authors.initials: E
authors.lastname: Cuypers
authors.forename: Yousra
authors.initials: Y
authors.lastname: Abdel-Mottaleb
authors.forename: Ivan
authors.initials: I
authors.lastname: Kopljar
authors.forename: Jon D
authors.initials: JD
authors.lastname: Rainier
authors.forename: Adam L
authors.initials: AL
authors.lastname: Raes
authors.forename: Dirk J
authors.initials: DJ
authors.lastname: Snyders
authors.forename: Jan
authors.initials: J
authors.lastname: Tytgat
mesh_terms: D000818:Animals; D036841:Ciguatera Poisoning; D002922:Ciguatoxins / Q000737:chemistry / Q000494:pharmacology*; D004141:Dinoflagellida / Q000737:chemistry*; D004305:Dose-Response Relationship, Drug; D009865:Oocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D024642:Potassium Channels, Voltage-Gated / Q000187:drug effects* / Q000378:metabolism; D015222:Sodium Channels / Q000187:drug effects* / Q000378:metabolism; D014982:Xenopus laevis; D035964:Oxocins
chemical_list: D002922:Ciguatoxins; D026902:Potassium Channel Blockers; D024642:Potassium Channels, Voltage-Gated; D015222:Sodium Channels; C435770:gambierol; D035964:Oxocins