Gambierol acts as a functional antagonist of neurotoxin site 5 on voltage-gated sodium channels in cerebellar granule neurons

J Pharmacol Exp Ther. 2007 Oct;323(1):174-9. doi: 10.1124/jpet.107.124271. Epub 2007 Jul 3.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Animals, Newborn
  • Binding Sites
  • Calcium / metabolism
  • Cell Survival / drug effects
  • Cells, Cultured
  • Cerebellum / drug effects*
  • Cerebellum / metabolism
  • Ciguatoxins / pharmacology*
  • Ethers, Cyclic / pharmacology*
  • Marine Toxins / pharmacology
  • Molecular Structure
  • Neurons / drug effects*
  • Neurons / metabolism
  • Oxocins
  • Polycyclic Compounds / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Sodium Channel Blockers / pharmacology*
  • Sodium Channels / metabolism*
  • Synaptosomes / drug effects
  • Synaptosomes / metabolism

Substances

  • Ethers, Cyclic
  • Marine Toxins
  • Oxocins
  • Polycyclic Compounds
  • Ptychodiscus brevis T2 toxin
  • Sodium Channel Blockers
  • Sodium Channels
  • gambierol
  • Ciguatoxins
  • Calcium