Unique insecticide specificity of human homomeric ρ1 GABA_C receptor

Several convulsants and major insecticides block the γ-aminobutyric acid (GABA)-gated chloride channel in brain on binding to the GABA_A receptor. The GABA_C receptor, important in retina and present in brain, is also coupled to a chloride channel and is therefore a potential target for toxicant action examined here in radioligand binding and electrophysiological experiments. Human homomeric ρ1 GABA_C receptor expressed in human embryonic kidney cells (HEK293) undergoes specific and saturable high-affinity binding of 4-n-[³H]propyl-4′-ethynylbicycloorthobenzoate ([³H]EBOB) using a cyano analog (CNBOB) to determine non-specific binding. This GABA_C ρ1 receptor is very sensitive to CNBOB and lindane relative to α-endosulfan, tert-butylbicyclophosphorothionate, picrotoxinin and fipronil (IC₅₀ values of 23, 91, 800, 1080, 4000 and > 10000 nM, respectively, in displacing [³H]EBOB). A similar potency sequence (except for picrotoxinin) is observed for inhibition of GABA-induced currents of ρ1 receptor expressed in Xenopus oocytes. The present study does not consider ρ2 homomeric and ρ1ρ2 heteromeric GABA_C receptors which are known to be more sensitive than ρ1 to picrotoxinin. The inhibitor sensitivity and specificity of this ρ1 GABA_C receptor differ greatly from those of human homomeric β3 and native GABA_A receptors.