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Research ArticleNEUROPHARMACOLOGY

Fipronil Is a Potent Open Channel Blocker of Glutamate-Activated Chloride Channels in Cockroach Neurons

Xilong Zhao, Jay Z. Yeh, Vincent L. Salgado and Toshio Narahashi
Journal of Pharmacology and Experimental Therapeutics July 2004, 310 (1) 192-201; DOI: https://doi.org/10.1124/jpet.104.065516
Xilong Zhao
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Jay Z. Yeh
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Vincent L. Salgado
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Toshio Narahashi
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Abstract

Fipronil, a phenylpyrazole insecticide, displays high insecticidal activity and reduced mammalian toxicity. To better elucidate the mechanism of its selective toxicity between insects and mammals and activity against dieldrin-resistant insects, we studied fipronil action on glutamate-gated chloride channels (GluCls), unique invertebrate ligand-gated chloride channels, in cockroach thoracic ganglion neurons, using the whole-cell patch clamp technique. Glutamate evoked two types of chloride currents, a desensitizing current and a nondesensitizing current. Fipronil differentially inhibited these two types of currents with different potencies and with different rates of reversibility. Fipronil inhibited the desensitizing and nondesensitizing GluCls with IC50 values of 801 and 10 nM, respectively. Kinetic analysis revealed that fipronil blocks required channel opening. Recovery of the desensitizing current from fipronil block required channel opening, whereas recovery of nondesensitizing current from block was independent of channel opening. The high potency of fipronil against the nondesensitizing current was due to a slow unblocking rate constant. In addition, when the nondesensitizing GluCls were occupied by picrotoxinin, the receptors became less sensitive to fipronil block. It is concluded that GluCls are a critical target for fipronil, especially for the selective toxicity between mammals and insects, and that fipronil block of GluCls may play a role in the lack of the cross-resistance with dieldrin.

Footnotes

  • This work was supported by a grant from the National Institutes of Health (NS 14143).

  • DOI: 10.1124/jpet.104.065516.

  • ABBREVIATIONS: Rdl, dieldrin; GluCl, glutamate receptor chloride channel.

    • Received January 14, 2004.
    • Accepted March 10, 2004.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 310 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 310, Issue 1
1 Jul 2004
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Research ArticleNEUROPHARMACOLOGY

Fipronil Is a Potent Open Channel Blocker of Glutamate-Activated Chloride Channels in Cockroach Neurons

Xilong Zhao, Jay Z. Yeh, Vincent L. Salgado and Toshio Narahashi
Journal of Pharmacology and Experimental Therapeutics July 1, 2004, 310 (1) 192-201; DOI: https://doi.org/10.1124/jpet.104.065516

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Research ArticleNEUROPHARMACOLOGY

Fipronil Is a Potent Open Channel Blocker of Glutamate-Activated Chloride Channels in Cockroach Neurons

Xilong Zhao, Jay Z. Yeh, Vincent L. Salgado and Toshio Narahashi
Journal of Pharmacology and Experimental Therapeutics July 1, 2004, 310 (1) 192-201; DOI: https://doi.org/10.1124/jpet.104.065516
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