title: Impact of beta and gamma variants on ligand-binding properties of gamma-aminobutyric acid type A receptors.
abstract: We expressed in cultured cells recombinant gamma-aminobutyric acid type A (GABAA) receptors of the subunit compositions alpha 1 beta j gamma k and alpha 5 beta j gamma k (j = 1, 2, or 3 and k = 2 or 3). A comparison of ligand-binding properties revealed a functional role for individual beta variants, which depended on the alpha subunit in the GABAA receptor. Recombinant alpha 5 beta x gamma 2/3 receptors recognized the cage convulsant t-butylbicyclophosphoro[35S]thionate, as well as the benzodiazepine (BZ) receptor inverse agonist [3H]Ro 15-4513, only with the beta 3 variant. In contrast, the exchange of beta variants in alpha 1 beta x gamma 2 receptors imparted differential modulation of t-butyl-bicyclophosphoro[35S]thionate binding by BZ receptor ligands. The BZ site of gamma 3-containing receptors was partially independent of the accompanying alpha and beta variants. alpha 1/5 beta 3 gamma 3 receptors were zolpidem insensitive but distinguished from alpha 5 beta 3 gamma 2 receptors by high affinity for the partial BZ receptor agonist CI 218,872. The distinct affinities of recombinant receptors for CI 218,872 suggested that the alpha 5 beta 3 gamma 2 receptor is the dominant zolpidem-insensitive GABAA receptor in the brain. Hence, alpha 5 beta 3 gamma 3 recpetors are not a major fraction of the native zolpidem-insensitive receptors, even though their genes are colocalized on mouse chromosome 7 and on human chromosome 15.
authors.affiliation: Laboratory of Molecular Neuroendocrinology, Center for Molecular Biology, Heidelberg, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Lüddens
authors.forename: P H
authors.initials: PH
authors.lastname: Seeburg
authors.forename: E R
authors.initials: ER
authors.lastname: Korpi
mesh_terms: D001386:Azides / Q000378:metabolism; D001569:Benzodiazepines / Q000378:metabolism; D001667:Binding, Competitive; D001643:Bridged Bicyclo Compounds / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002478:Cells, Cultured; D006801:Humans; D007700:Kinetics; D008024:Ligands; D010446:Peptide Fragments / Q000378:metabolism; D011869:Radioligand Assay; D011963:Receptors, GABA-A / Q000378:metabolism*
chemical_list: D001386:Azides; D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D008024:Ligands; D010446:Peptide Fragments; D011963:Receptors, GABA-A; D001569:Benzodiazepines; C037476:tert-butylbicyclophosphorothionate; C042957:Ro 15-4513