Gambierol Acts As a Functional Antagonist of Neurotoxin Site 5 on Voltage-gated Sodium Channels in Cerebellar Granule Neurons.
From: Department of Biology, Xavier University of Louisiana, New Orleans, Louisiana, USA.
The Journal of pharmacology and experimental therapeutics
- Publish Date: Oct 2007
- ISSN: 0022-3565
- Volume: 323
- Issue: 1
- Pages: 174-9
- Medium: Print
- Language: English
- Citation (JAMA): LePage K T, Rainier J D, Johnson H W B, et al. Gambierol Acts As a Functional Antagonist of Neurotoxin Site 5 on Voltage-gated Sodium Channels in Cerebellar Granule Neurons.. J. Pharmacol. Exp. Ther. Oct 2007;323:174-9
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.
Mesh Headings (Keywords): Animals, Animals, Newborn, Binding Sites, Calcium, Cell Survival, Cells, Cultured, Cerebellum, Ciguatoxins, Ethers, Cyclic, Marine Toxins, Molecular Structure, Neurons, Polycyclic Compounds, Rats, Rats, Sprague-Dawley, Sodium Channel Blockers, Sodium Channels, Synaptosomes
Check for Full Text / PubMed Unique Identifier (PMID): 17609421
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