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 α₁-, α₂-, and α₃-subunits, coexpression of this new α-subunit (α₅) with a β- and γ₂-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 α₂-, α₃- or α₅-subunits have low affinities for several type I-selective compounds. However, α₅-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 α₂- or α₃-subunits. Based on these findings, a reclassification of the GABA_A/benzodiazepine receptors is warranted.