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Research ArticleArticle

Differential Actions of Pacific Ciguatoxin-1 on Sodium Channel Subtypes in Mammalian Sensory Neurons

Liesl C. Strachan, Richard J. Lewis and Graham M. Nicholson
Journal of Pharmacology and Experimental Therapeutics January 1999, 288 (1) 379-388;
Liesl C. Strachan
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Richard J. Lewis
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Graham M. Nicholson
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Abstract

Pacific ciguatoxin-1 (P-CTX-1), is a highly lipophilic cyclic polyether molecule originating from the marine dinoflagellateGambierdiscus toxicus. Its effects were investigated on sodium channel subtypes present in acutely dissociated rat dorsal root ganglion neurons, using whole-cell patch clamp techniques. Concentrations of P-CTX-1 ranging from 0.2 to 20 nM had no effect on the kinetics of tetrodotoxin-sensitive (TTX-S) or tetrodotoxin-resistant (TTX-R) sodium channel activation and inactivation, however, a concentration-dependent reduction in peak current amplitude occurred in both channel types. The main actions of 5 nM P-CTX-1 on TTX-S sodium channels were a 13-mV hyperpolarizing shift in the voltage dependence of sodium channel activation and a 22-mV hyperpolarizing shift in steady-state inactivation (h∞). In addition, P-CTX-1 caused a rapid rise in the membrane leakage current in cells expressing TTX-S sodium channels. This effect was blocked by 200 nM TTX, indicating an action mediated through TTX-S sodium channels. In contrast, the main action of P-CTX-1 (5 nM) on TTX-R sodium channels was a significant increase in the rate of recovery from sodium channel inactivation. These results indicate that P-CTX-1 acts to modify voltage-gated sodium channels present in peripheral sensory neurons consistent with its action to increase nerve excitability. This provides an explanation for the sensory neurological disturbances associated with ciguatera fish poisoning.

Footnotes

  • Send reprint requests to: Graham M. Nicholson, Department of Health Sciences, University of Technology, Sydney, P.O. Box 123, Broadway NSW 2007, Australia. E-mail:Graham.Nicholson{at}uts.edu.au.

  • 1 This work was supported by an Australian Postgraduate Award to Liesl Strachan and a UTS internal research grant.

  • Abbreviations:
    CTX
    ciguatoxin
    P-CTX-1
    Pacific CTX-1
    PbTX
    brevetoxin
    TTX-S
    tetrodotoxin-sensitive
    TTX-R
    tetrodotoxin-resistant
    DRG
    dorsal root ganglia
    DMEM
    Dulbecco’s modified Eagle’s medium
    HEPES
    N-(2-hydroxyethyl)piperazine-N′-(2-ethanesulfonic acid)
    TEA-Cl
    tetraethylammonium chloride
    TMA-Cl
    tetramethylammonium chloride
    TTX
    tetrodotoxin
    DDT
    1,1′-(2,2,2-trichloroethylidene)bis[4-chlorobenzene]
    • Received March 23, 1998.
    • Accepted July 31, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 288 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 288, Issue 1
1 Jan 1999
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Research ArticleArticle

Differential Actions of Pacific Ciguatoxin-1 on Sodium Channel Subtypes in Mammalian Sensory Neurons

Liesl C. Strachan, Richard J. Lewis and Graham M. Nicholson
Journal of Pharmacology and Experimental Therapeutics January 1, 1999, 288 (1) 379-388;

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Research ArticleArticle

Differential Actions of Pacific Ciguatoxin-1 on Sodium Channel Subtypes in Mammalian Sensory Neurons

Liesl C. Strachan, Richard J. Lewis and Graham M. Nicholson
Journal of Pharmacology and Experimental Therapeutics January 1, 1999, 288 (1) 379-388;
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