title: Potentiation of gamma-aminobutyric acid-induced chloride currents by various benzodiazepine site agonists with the alpha 1 gamma 2, beta 2 gamma 2 and alpha 1 beta 2 gamma 2 subtypes of cloned gamma-aminobutyric acid type A receptors.
abstract: Previous studies with cloned gamma-aminobutyric acid type A receptors expressed in human embryonic kidney cells have indicated that the alpha 1 beta 2 gamma 2 and alpha 1 gamma 2 (but not alpha 1 beta 2) subtypes have benzodiazepine sites. We found in this study that even the beta 2 gamma 2 subtype displays gamma-aminobutyric acid-induced Cl- currents that are potentiated by triazolam (a triazolobenzodiazepine). The maximal efficacy of the drug among the subtypes was highest with the alpha 1 beta 2 gamma 2 subtype, followed by the alpha 1 gamma 2 and beta 2 gamma 2 subtypes. These observations led us to compare the ability of several benzodiazepine site agonists of diverse chemical structures to potentiate Cl- currents with these subtypes. With the alpha 1 gamma 2 subtype, diazepam, alpidem, zolpidem, Cl-218872, zopiclone, U-79098 (an imidazoquinoxaline derivative), and U-90167 (a diimidazoquinazoline derivative) at 5 microM potentiated Cl- currents to essentially similar levels (slightly lower for a few ligands), compared with those with the alpha 1 beta 2 gamma 2 subtype. With the beta 2 gamma 2 subtype, the type 1 ligands zolpidem, alpidem, and Cl-218872 showed no or very low levels of potentiation, whereas less selective ligands such as diazepam, zopiclone, U-78098, and U-90167 displayed levels of Cl- current potentiation comparable to those observed with the subtypes containing the alpha 1 and gamma 2 subunits. These data indicate that, in the presence of gamma 2, beta 2 may substitute for alpha 1 in forming the benzodiazepine site of limited sensitivity to the type 1 ligands. It appears that individual ligands for benzodiazepine sites have their own sets of interacting domains, which are distributed in alpha 1 and gamma 2, and the agonistic activity of type 1 ligands may be more dependent on the alpha 1-specific domains than is that of less selective ligands.
authors.affiliation: Upjohn Company, Kalamazoo, Michigan 49001.
authors.forename: H K
authors.initials: HK
authors.lastname: Im
authors.forename: W B
authors.initials: WB
authors.lastname: Im
authors.forename: B J
authors.initials: BJ
authors.lastname: Hamilton
authors.forename: D B
authors.initials: DB
authors.lastname: Carter
authors.forename: P F
authors.initials: PF
authors.lastname: Vonvoigtlander
mesh_terms: D014151:Anti-Anxiety Agents / Q000494:pharmacology; D053961:Azabicyclo Compounds; D001569:Benzodiazepines / Q000378:metabolism*; D001665:Binding Sites; D002478:Cells, Cultured; D018118:Chloride Channels / Q000187:drug effects* / Q000502:physiology; D003001:Cloning, Molecular; D004357:Drug Synergism; D005442:Flumazenil / Q000494:pharmacology; D006801:Humans; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D007668:Kidney / Q000166:cytology; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D010879:Piperazines / Q000494:pharmacology; D011724:Pyridazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000145:classification* / Q000187:drug effects / Q000502:physiology*; D014229:Triazolam / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
chemical_list: D014151:Anti-Anxiety Agents; D053961:Azabicyclo Compounds; D018118:Chloride Channels; D006993:Hypnotics and Sedatives; D007093:Imidazoles; D010879:Piperazines; D011724:Pyridazines; D011725:Pyridines; D011963:Receptors, GABA-A; C515050:zopiclone; D001569:Benzodiazepines; D014229:Triazolam; D005442:Flumazenil; D005680:gamma-Aminobutyric Acid; C021604:CL 218872