Cloning of cDNA sequences encoding human alpha 2 and alpha 3 gamma-aminobutyric acidA receptor subunits and characterization of the benzodiazepine pharmacology of recombinant alpha 1-, alpha 2-, alpha 3-, and alpha 5-containing human gamma-aminobutyric acidA receptors.

cDNAs encoding human alpha 2 and alpha 3 gamma-aminobutyric acidA receptor subunits have been cloned. Their deduced amino acid sequences show much sequence identity with the published bovine sequences (98.2% and 97.0% for alpha 2 and alpha 3, respectively). Human alpha 1 beta 1 gamma 2, alpha 2 beta 1 gamma 2, alpha 3 beta 1 gamma 2, and alpha 5 beta 1 gamma 2 subunit combinations were expressed in transiently transfected cells and their pharmacologies were characterized using a series of benzodiazepine (BZ) binding site ligands. Human alpha 1-containing receptors exhibited a BZ1-type pharmacology, and alpha 2-, alpha 3-, and alpha 5-containing receptors exhibited a broadly BZ2-type pharmacology. The partial inverse agonist Ro15-4513 showed an approximately 10-15-fold higher affinity for alpha 5-containing than for alpha 1-, alpha 2-, or alpha 3-containing receptors and is thus the first compound shown to have a significantly higher affinity for another receptor subtype than for alpha 1 beta 1 gamma 2.