Abstract
Binding sites for t-[35S]butylbicyclophosphorothionate ([35S]TBPS) were detected in well-washed membranes from the brain of trout; γ-aminobutyric acid (GABA) acted as an uncompetitive inhibitor of the binding of [35S]TBPS, decreasing both the number of binding sites and the affinity of TBPS. Inhibition of the binding of [35S]TBPS by deltamethrin, a Type II pyrethroid, was modulated by GABA; both the affinity and the efficacy of this insecticide increased with incremental concentrations of GABA. Deltamethrin also enhanced the potency of GABA as an inhibitor of the binding of [35S]TBPS. The interaction of 4′-chlorodiazepam (Ro5-4864) with [35S]TBPS was dependent on GABA: in the absence of GABA, Ro5-4864 inhibited up to 40% of the binding: in the presence of 10 μM GABA, Ro5-4864 enhanced binding to a maximum value of 170% of control. However, the same absolute amount of binding was observed with both of these effects at micromolar concentrations of Ro5-4864. Also, Ro5-4864 caused a rtghtward shift in GABA dose-response curves, increasing the IC50 value for GABA more than 6 fold. These results indicate the reciprocal allosteric interactions between a binding site for pyrethroids, a binding site for Ro5-4864, the GABA recognition moiety and the binding site for TBPS in the brain of trout. The similarity of these findings to previous results in preparations of rodent brain highlight the conservation of the modulation of GABAA receptor function during the evolution of vertebrates.