title: Gambierol inhibition of voltage-gated potassium channels augments spontaneous Ca2+ oscillations in cerebrocortical neurons.
abstract: Gambierol is a marine polycyclic ether toxin produced by the marine dinoflagellate Gambierdiscus toxicus and is a member of the ciguatoxin toxin family. Gambierol has been demonstrated to be either a low-efficacy partial agonist/antagonist of voltage-gated sodium channels or a potent blocker of voltage-gated potassium channels (Kvs). Here we examined the influence of gambierol on intact cerebrocortical neurons. We found that gambierol produced both a concentration-dependent augmentation of spontaneous Ca(2+) oscillations, and an inhibition of Kv channel function with similar potencies. In addition, an array of selective as well as universal Kv channel inhibitors mimicked gambierol in augmenting spontaneous Ca(2+) oscillations in cerebrocortical neurons. These data are consistent with a gambierol blockade of Kv channels underlying the observed increase in spontaneous Ca(2+) oscillation frequency. We also found that gambierol produced a robust stimulation of phosphorylation of extracellular signal-regulated kinases 1/2 (ERK1/2). Gambierol-stimulated ERK1/2 activation was dependent on both inotropic [N-methyl-d-aspartate (NMDA)] and type I metabotropic glutamate receptors (mGluRs) inasmuch as MK-801 [NMDA receptor inhibitor; (5S,10R)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate], S-(4)-CGP [S-(4)-carboxyphenylglycine], and MTEP [type I mGluR inhibitors; 3-((2-methyl-4-thiazolyl)ethynyl) pyridine] attenuated the response. In addition, 2-aminoethoxydiphenylborane, an inositol 1,4,5-trisphosphate receptor inhibitor, and U73122 (1-[6-[[(17b)-3-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1H-pyrrole-2,5-dione), a phospholipase C inhibitor, both suppressed gambierol-induced ERK1/2 activation, further confirming the role of type I mGluR-mediated signaling in the observed ERK1/2 activation. Finally, we found that gambierol produced a concentration-dependent stimulation of neurite outgrowth that was mimicked by 4-aminopyridine, a universal potassium channel inhibitor. Considered together, these data demonstrate that gambierol alters both Ca(2+) signaling and neurite outgrowth in cerebrocortical neurons as a consequence of blockade of Kv channels.
authors: State Key Laboratory of Natural Medicines, Department of Complex Prescription of Traditional Chinese Medicine, China Pharmaceutical University, Nanjing, People's Republic of China (Z.C.); Department of Pharmacology, School of Medicine, Creighton University, Omaha, Nebraska (Z.C., Y.C., E.B., S.M., T.F.M.); and Department of Chemistry, University of Utah, Salt Lake City, Utah (J.D.R.).
authors: Zhengyu
authors: Z
authors: Cao
authors: State Key Laboratory of Natural Medicines, Department of Complex Prescription of Traditional Chinese Medicine, China Pharmaceutical University, Nanjing, People's Republic of China (Z.C.); Department of Pharmacology, School of Medicine, Creighton University, Omaha, Nebraska (Z.C., Y.C., E.B., S.M., T.F.M.); and Department of Chemistry, University of Utah, Salt Lake City, Utah (J.D.R.).
authors: Yanjun
authors: Y
authors: Cui
authors: State Key Laboratory of Natural Medicines, Department of Complex Prescription of Traditional Chinese Medicine, China Pharmaceutical University, Nanjing, People's Republic of China (Z.C.); Department of Pharmacology, School of Medicine, Creighton University, Omaha, Nebraska (Z.C., Y.C., E.B., S.M., T.F.M.); and Department of Chemistry, University of Utah, Salt Lake City, Utah (J.D.R.).
authors: Eric
authors: E
authors: Busse
authors: State Key Laboratory of Natural Medicines, Department of Complex Prescription of Traditional Chinese Medicine, China Pharmaceutical University, Nanjing, People's Republic of China (Z.C.); Department of Pharmacology, School of Medicine, Creighton University, Omaha, Nebraska (Z.C., Y.C., E.B., S.M., T.F.M.); and Department of Chemistry, University of Utah, Salt Lake City, Utah (J.D.R.).
authors: Suneet
authors: S
authors: Mehrotra
authors: State Key Laboratory of Natural Medicines, Department of Complex Prescription of Traditional Chinese Medicine, China Pharmaceutical University, Nanjing, People's Republic of China (Z.C.); Department of Pharmacology, School of Medicine, Creighton University, Omaha, Nebraska (Z.C., Y.C., E.B., S.M., T.F.M.); and Department of Chemistry, University of Utah, Salt Lake City, Utah (J.D.R.).
authors: Jon D
authors: JD
authors: Rainier
authors: State Key Laboratory of Natural Medicines, Department of Complex Prescription of Traditional Chinese Medicine, China Pharmaceutical University, Nanjing, People's Republic of China (Z.C.); Department of Pharmacology, School of Medicine, Creighton University, Omaha, Nebraska (Z.C., Y.C., E.B., S.M., T.F.M.); and Department of Chemistry, University of Utah, Salt Lake City, Utah (J.D.R.) tfmurray@creighton.edu.
authors: Thomas F
authors: TF
authors: Murray
mesh_terms: D000818:Animals; D002118:Calcium / Q000502:physiology; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000502:physiology*; D002922:Ciguatoxins / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors / Q000502:physiology*; D035964:Oxocins
chemical_list: D002118:Calcium; D002922:Ciguatoxins; D026902:Potassium Channel Blockers; D024642:Potassium Channels, Voltage-Gated; C435770:gambierol; D035964:Oxocins