The γ-aminobutyric acid (GABA) receptor is an important site of action of a variety of chemicals, including barbiturates, benzodiazepines, picrotoxin, bicuculline, general anesthetics, alcohols, and certain insecticides. Fipronil is the first phenylpyrazole insecticide introduced for pest control. It is effective against some insects that have become resistant to the existing insecticides. To elucidate the mechanism of fipronil interaction with the mammalian GABA system, whole-cell patch-clamp experiments were performed using rat dorsal root ganglion neurons in primary culture. Fipronil suppressed the GABA-induced whole-cell currents reversibly in both closed and activated states. The IC50 values and Hill coefficients for fipronil block of the GABAA receptor were estimated to be 1.66 ± 0.18 μM and 1.23 ± 0.14 for the closed receptor, respectively, and 1.61 ± 0.14 μM and 0.96 ± 0.06 for the activated receptor, respectively. The association rate and dissociation rate constants of fipronil effect were estimated to be 673 ± 220 M-1 s-1 and 0.018 ± 0.0035 s-1 for the closed GABAA receptor, respectively, and 6600 ± 380 M-1 s-1 and 0.11 ± 0.0054 s-1 for the activated GABAA receptor, respectively. Thus, both the association and dissociation rate constants of fipronil for the activated GABAA receptor are approximately 10 times as large as those for the closed receptor. Experiments with coapplication of fipronil and picrotoxinin indicated that they did not compete for the same binding site to block the receptor. It is concluded that although fipronil binds to the GABAA receptor without activation, channel opening facilitates fipronil binding to and unbinding from the receptor.
|Original language||English (US)|
|Number of pages||8|
|Journal||Journal of Pharmacology and Experimental Therapeutics|
|State||Published - 2001|
ASJC Scopus subject areas
- Molecular Medicine