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

TLDR

Characteristic of GABA A/benzodiazepine type II sites, receptors containing α2, α3, or α5 subunits have low affinities for several type I‑selective compounds. A cDNA encoding a protein 70 % identical to known GABA A receptor α‑subunits was isolated from a rat brain library, and coexpression of this α5 subunit with β and γ2 subunits in cultured cells produced receptors with high‑affinity muscimol and benzodiazepine binding sites. Receptors assembled with the α5 subunit exhibit high‑affinity muscimol and benzodiazepine binding but display markedly lower affinities for zolpidem (30‑fold) and Cl218872 (three‑fold) compared to α2/α3 receptors, indicating a need to reclassify GABA A/benzodiazepine receptors.

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.