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.
Hadingham
K L
KL
Merck Sharp & Dohme Research Laboratories, Harlow, Essex, England.
Wingrove
P
P
Le Bourdelles
B
B
Palmer
K J
KJ
Ragan
C I
CI
Whiting
P J
PJ
D000595:Amino Acid Sequence; D001386:Azides / Q000378:metabolism; D001483:Base Sequence; D001569:Benzodiazepines / Q000378:metabolism*; D001665:Binding Sites; D002460:Cell Line; D003001:Cloning, Molecular; D004247:DNA / Q000737:chemistry / Q000235:genetics; D006801:Humans; D008969:Molecular Sequence Data; D011963:Receptors, GABA-A / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D016415:Sequence Alignment; D014162:Transfection
D001386:Azides; D011963:Receptors, GABA-A; D011994:Recombinant Proteins; D001569:Benzodiazepines; D004247:DNA; C042957:Ro 15-4513