The insecticide fipronil and its metabolite fipronil sulphone inhibit the rat alpha1beta2gamma2L GABA(A) receptor.
OBJECTIVE
Fipronil is the active ingredient in a number of widely used insecticides. Human exposure to fipronil leads to symptoms (headache, nausea and seizures) typically associated with the antagonism of GABA(A) receptors in the brain. In this study, we have examined the modulation of the common brain GABA(A) receptor subtype by fipronil and its major metabolite, fipronil sulphone.


METHODS
Whole-cell and single-channel recordings were made from HEK 293 cells transiently expressing rat alpha1beta2gamma2L GABA(A) receptors.


RESULTS
The major effect of fipronil was to increase the rate of current decay in macroscopic recordings. In single-channel recordings, the presence of fipronil resulted in shorter cluster durations without affecting the intracluster open and closed time distributions or the single-channel conductance. The alpha1V256S mutation, previously shown alleviate channel inhibition by inhibitory steroids and several insecticides, had a relatively small effect on channel block by fipronil. The mode of action of fipronil sulphone was similar to that of its parent compound but the metabolite was less potent at inhibiting the alpha1beta2gamma2L receptor.


CONCLUSIONS
We conclude that exposure to fipronil induces accumulation of receptors in a novel, long-lived blocked state. This process proceeds in parallel with and independently of, channel desensitization. The lower potency of fipronil sulphone indicates that the conversion serves as a detoxifying process in mammalian brain.
Li
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Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
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D000818:Animals; D002460:Cell Line; D003001:Cloning, Molecular; D004594:Electrophysiology; D058787:GABA-A Receptor Antagonists; D006801:Humans; D007306:Insecticides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D015640:Ion Channel Gating / Q000187:drug effects; D015394:Molecular Structure; D018408:Patch-Clamp Techniques; D011720:Pyrazoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D011963:Receptors, GABA-A / Q000096:biosynthesis; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors
D058787:GABA-A Receptor Antagonists; C546240:GABRA1 protein, human; C546279:GABRG2 protein, human; C546242:Gabra1 protein, rat; C502185:Gabrb2 protein, rat; C546281:Gabrg2 protein, rat; D007306:Insecticides; D011720:Pyrazoles; D011963:Receptors, GABA-A; D011994:Recombinant Proteins; C534368:fipronil sulfone; C082360:fipronil