GABA receptor subunit composition relative to insecticide potency and selectivity

Abstract

Three observations on the 4-[ 3H]propyl-4′-ethynylbicycloorthobenzoate ([ 3H]EBOB) binding site in the γ-aminobutyric acid (GABA) receptor indicate the specific target for insecticide action in human brain and a possible mechanism for selectivity. First, from published data, α-endosulfan, lindane and fipronil compete for the [ 3H]EBOB binding site with affinities of 0.3–7 nM in both human recombinant homooligomeric β3 receptors and housefly head membranes. Second, from structure-activity studies, including new data, GABAergic insecticide binding potency on the pentameric receptor formed from the β3 subunit correlates well with that on the housefly receptor ( r=0.88, n=20). This conserved inhibitor specificity is consistent with known sequence homologies in the housefly GABA receptor and the human GABA A receptor β3 subunit. Third, as mostly new findings, various combinations of α1, α6, and γ2 subunits coexpressed with a β1 or β3 subunit confer differential insecticide binding sensitivity, particularly to fipronil, indicating that subunit composition is a major factor in insecticide selectivity.