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

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.