Fipronil is a potent open channel blocker of glutamate-activated chloride channels in cockroach neurons.

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.

• Authors: Xilong Zhao, Jay Z Yeh, Vincent L Salgado, Toshio Narahashi
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 310 Issue 1 Pg. 192-201 (Jul 2004) ISSN: 0022-3565 [Print] United States
• PMID: 15014137 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Chloride Channels
• Insecticides
• Pyrazoles
• glutamate-gated chloride channels
• Glutamic Acid
• fipronil

Topics

• Animals
• Chloride Channels (drug effects, metabolism)
• Cockroaches
• Glutamic Acid (metabolism)
• Insecticides (pharmacology)
• Kinetics
• Neurons (drug effects, metabolism)
• Pyrazoles (pharmacology)