Expression and pharmacology of human GABAA receptors containing γ3 subunits

Abstract

A cDNA encoding the γ3 subunit of the human GABA_A receptor has been obtained by molecular cloning. Its deduced amino acid sequence shows a high level of sequence identity with the published mouse and rat sequences (96%). The ligand binding pharmacology of the benzodiazepine site formed by stably-expressed human α5β3γ2S GABA_A receptor subtypes have been compared for a number of ligands. Benzodiazepine site ligands were found to be either non-selective or γ2-selective, with the exception of CL218,872, which was found to be 10-fold selective for the α5β3γ3-containing subtype. Two benzodiazepine site ligands, Rol15-4513 and FG8205 were more efficacious at α5β3β3 receptors than αβ3γ2 receptors expressed in Xenopus oocytes. CL218,872, which is partial agonist at α1 containing receptors, had no intrinsic activity at either α5β3γ2 or α5β3γ3. α1β2γ2S and α1β2γ3 human GABA_A receptors were also expressed in Xenopus oocytes and their benzodiazepine pharmacology investigated. Both in the EC₅₀ and efficacy of benzodiazepine site ligands were influence by the type of γ subunit coexpressed with α1 β2.