Abstract

Native GABAA receptors containing different γ-subunit variants were distinguished immunobiochemically with antisera selectively recognizing the γ1-, γ2- and γ3-subunits. While GABAA receptors containing the γ2-subunit were confirmed to be rather ubiquitous in the adult brain, receptors characterized by the γ1- or γ3-subunit were of low abundance, as shown by immunoprecipitation. The three receptor populations differed strikingly in their benzodiazepine (BZ) site ligand binding profiles. The γ3-receptor population displayed reduced affinity for the full agonists clonazepam and flunitrazepam and virtually lacked sensitivity to zolpidem. The γ1-receptor population displayed low affinity for all benzodiazepine site ligands tested, except for flunitrazepam, and could be differentiated from the γ2- and γ3-receptors by its low affinity for the inverse agonist βCCM and its lack of affinity for the partial inverse agonist Ro 15-4513 and the antagonist flumazenil. Since flumazenil antagonizes all major effects of BZ agonists, γ1-receptors are not involved in mediating these actions in vivo. In immunopurified receptors, the γ-subunit variants were found to be assembled with different variants of α- and β-subunits, indicating that not only the γ2-subunit but also the γ1- and γ3-subunits are part of various receptor subtypes. In addition, the γ2- and γ3-subunits can be co-assembled in native receptors, consistent with the subunit stoichiometry of two α-, one β- and two γ-subunits proposed previously for recombinant receptors. Copyright © 1996 Elsevier Science Ltd

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