γ‐Aminobutyric AcidA Receptor α5‐Subunit Creates Novel Type II Benzodiazepine Receptor Pharmacology

Abstract

Abstract: A cDNA encoding a protein with 70% amino acid identity to the previously characterized γ‐aminobutyric acid A (GABA A receptor α‐subunits was isolated from a rat brain cDNA library by homology screening. As observed for α 1‐, α 2‐, and α 3‐subunits, coexpression of this new α‐subunit (α 5) with a β‐ and γ 2‐subunit in cultured cells produces receptors displaying high‐affinity binding sites for both muscimol, a GABA agonist, and benzodiazepines. Characteristic of GABA A/benzodiazepine type II sites, receptors containing α 2‐, α 3‐ or α 5‐subunits have low affinities for several type I‐selective compounds. However, α 5‐subunit‐containing receptors have lower affinities for zolpidem (30‐fold) and Cl 218 872 (three‐fold) than measured previously using recombinantly expressed type II receptors containing either α 2‐ or α 3‐subunits. Based on these findings, a reclassification of the GABA A/benzodiazepine receptors is warranted.