CLONING OF CDNA SEQUENCES ENCODING HUMAN ALPHA-2 AND ALPHA-3 GAMMA-AMINOBUTYRIC ACID(A) RECEPTOR SUBUNITS AND CHARACTERIZATION OF THE BENZODIAZEPINE PHARMACOLOGY OF RECOMBINANT ALPHA-1-CONTAINING, ALPHA-2-CONTAINING, ALPHA-3-CONTAINING, AND ALPHA-5-CONTAINING HUMAN GAMMA-AMINOBUTYRIC ACID(A) RECEPTORS

cDNAs encoding human alpha2 and alpha3 gamma-aminobutyric acid(A) rece ptor subunits have been cloned. Their deduced amino acid sequences sho w much sequence identity with the published bovine sequences (98.2% an d 97.0% for alpha2 and alpha3, respectively). Human alpha1beta1gamma2, alpha2beta1gamma2, alpha3beta1gamma2, and alpha5beta1gamma2 subunit c ombinations were expressed in transiently transfected cells and their pharmacologies were characterized using a series of benzodiazepine (BZ ) binding site ligands. Human alpha1-containing receptors exhibited a BZ1-type pharmacology, and alpha2-, alpha3-, and alpha5-containing rec eptors exhibited a broadly BZ2-type pharmacology. The partial inverse agonist Ro15-4513 showed an approximately 10-15-fold higher affinity f or alpha5-containing than for alpha1-, alpha2-, or alpha3-containing r eceptors and is thus the first compound shown to have a significantly higher affinity for another receptor subtype than for alpha1beta1gamma 2.