RT Journal Article SR Electronic T1 Sulfone Metabolite of Fipronil Blocks γ-Aminobutyric Acid- and Glutamate-Activated Chloride Channels in Mammalian and Insect Neurons JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 363 OP 373 DO 10.1124/jpet.104.077891 VO 314 IS 1 A1 Xilong Zhao A1 Jay Z. Yeh A1 Vincent L. Salgado A1 Toshio Narahashi YR 2005 UL http://jpet.aspetjournals.org/content/314/1/363.abstract AB Fipronil sulfone, a major metabolite of fipronil in both insects and mammals, binds strongly to GABA receptors and is thought to play a significant role in poisoning by fipronil. To better understand the mechanism of selective insecticidal action of fipronil, we examined the effects of its sulfone metabolite on GABA- and glutamate-activated chloride channels (GluCls) in cockroach thoracic ganglion neurons and on GABAA receptors in rat dorsal root ganglion neurons using the whole-cell patch-clamp technique. Fipronil sulfone blocked both desensitizing and nondesensitizing GluCls in the cockroach. Activation was required for block and unblock of desensitizing GluCls. In contrast, activation was not prerequisite for block and unblock of nondesensitizing channels. After repetitive activation of the receptors, the IC50 of fipronil sulfone to block the desensitizing GluCls was reduced from 350 to 25 nM and that for blocking nondesensitizing GluCls was reduced from 31.2 to 8.8 nM. This use-dependent block may be explained by its slow unbinding rate. In cockroach and rat neurons, fipronil sulfone blocked GABA receptors in both activated and resting states, with IC50 values ranging from 20 to 70 nM. In conclusion, although fipronil sulfone is a potent inhibitor of cockroach GABA receptors, desensitizing and nondesensitizing GluCls, and rat GABAA receptors, its selective toxicity in insects over mammals appears to be associated with its potent blocking action on both desensitizing and nondesensitizing GluCls, which are lacking in mammals. The American Society for Pharmacology and Experimental Therapeutics