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Several major insecticides, including α-endosulfan, lindane, and fipronil, and the botanical picrotoxinin are noncompetitive antagonists (NCAs) for the GABA receptor. We showed earlier that human β3 homopentameric GABAA receptor recognizes all of the important GABAergic insecticides and reproduces the high insecticide sensitivity and structure-activity relationships of the native insect receptor. Despite large structural diversity, the NCAs are proposed to fit a single binding site in the chloride channel lumen lined by five transmembrane 2 segments. This hypothesis is examined with the β3 homopentamer by mutagenesis, pore structure studies, NCA binding, and molecular modeling. The 15 amino acids in the cytoplasmic half of the pore were mutated to cysteine, serine, or other residue for 22 mutants overall. Localization of A-1′C, A2′C, T6′C, and L9′C (index numbers for the transmembrane 2 region) in the channel lumen was established by disulfide cross-linking. Binding of two NCA radioligands [3 H]1-(4-ethynylphenyl)-4-n -propyl-2,6,7-trioxabicyclo[2.2.2]octane and [3 H] 3,3-bis-trifluoromethyl-bicyclo[2,2,1]heptane-2,2-dicarbonitrile was dramatically reduced with 8 of the 15 mutated positions, focusing attention on A2′, T6′, and L9′ as proposed binding sites, consistent with earlier mutagenesis studies. The cytoplasmic half of the β3 homopentamer pore was modeled as an α-helix. The six NCAs listed above plus t-butylbicyclophosphorothionate fit the 2′ to 9′ pore region forming hydrogen bonds with the T6′ hydroxyl and hydrophobic interactions with A2′, T6′, and L9′ alkyl substituents, thereby blocking the channel. Thus, widely diverse NCA structures fit the same GABA receptor β subunit site with important implications for insecticide cross-resistance and selective toxicity between insects and mammals.

Structural model for γ-aminobutyric acid receptor noncompetitive antagonist binding: Widely diverse structures fit the same site