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Vol. 54, Issue 5, 928-933, November 1998

Rat and Human Hippocampal alpha 5 Subunit-Containing gamma -Aminobutyric AcidA Receptors Have alpha 5beta 3gamma 2 Pharmacological Characteristics

Cyrille Sur, Kathleen Quirk, Deborah Dewar, John Atack, and Ruth McKernan

Department of Biochemistry, Merck Sharp and Dohme Research Laboratories, Harlow, Essex, CM20 2QR, UK (C.S., K.Q., J.A., R.M.) and Wellcome Surgical Institute, University of Glasgow, Glasgow, UK (D.D.)

The gamma -aminobutyric acid (GABA)A receptor is a hetero-oligomer consisting of five subunits, the combination of which confers unique pharmacological properties to the receptor. To understand the physiological role of native GABAA receptors, it is critical to determine their subunit compositions. The pharmacological characteristics of human alpha 5beta 3gamma 2 and alpha 5beta 3gamma 3 GABAA receptors stably expressed in L(tk-) cells were characterized with the alpha 5-selective ligand [3H]L-655,708 and compared with the pharmacological characteristics of [3H]L-655,708 binding sites from rat and human hippocampus. Saturation analyses revealed a 9-fold selective affinity of [3H]L-655,708 for alpha 5beta 3gamma 2 receptors (Kd = 1.7 ± 0.4 nM), compared with alpha 5beta 3gamma 3 receptors (Kd = 15 ± 3 nM). Rat and human hippocampal [3H]L-655,708 binding sites had affinities of 2.2 ± 0.6 and 1.0 ± 0.2 nM, respectively, comparable to the affinity of alpha 5beta 3gamma 2 receptors. Pharmacological analysis of [3H]L-655,708 binding sites in rat and human hippocampi revealed a strong correlation with the affinities of seven benzodiazepine site ligands for alpha 5beta 3gamma 2 but not alpha 5beta 3gamma 3 receptors. Immunoprecipitation of [3H]L-655,708 binding sites from rat hippocampus with a gamma 2-selective antibody yielded 19 ± 4% of total benzodiazepine binding sites measured using [3H]Ro15-1788, whereas no specific binding was measured after immunoprecipitation with an anti-gamma 3 antibody. Combinatorial immunoprecipitations of [3H]muscimol binding sites with anti-alpha 5 and anti-gamma 2 or anti-alpha 5 and anti-gamma 3 antibodies established the preferential expression of alpha 5gamma 2 receptors, accounting for 22 ± 2% of total rat hippocampal GABAA receptors. These observations provide pharmacological and structural evidence for the prevalence of alpha 5beta 3gamma 2 GABAA receptors in rat hippocampus, despite the clustering of alpha 5 and gamma 3 loci on the same chromosome.

Copyright © 1998 by The American Society for Pharmacology and Experimental Therapeutics


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