title: PNU-107484A with alpha isoform-dependent functional changes in alpha(x)beta2gamma2 subtypes of rat recombinant GABA(A) receptors.
abstract: 1. We discovered a novel gamma-aminobutyric acidA (GABA(A)) receptor ligand displaying seemingly opposite functionalities, depending on the alpha isoform of the alpha(x)beta2gamma2 subtypes. PNU-107484A enhanced GABA-induced Cl- currents in the alpha1beta2gamma2 subtype, but inhibited the currents in the alpha3beta2gamma2 and alpha6beta2gamma2 subtypes, and its half-maximal concentrations in the subtypes were 3.1 +/- 0.5, 4.2 +/- 1, and 3.5 +/- 0.2 microM, respectively, without showing much dependency on alpha isoforms. 2. In the alpha1beta2 subtype, the drug at concentrations up to 40 microM showed no effect on GABA-induced Cl- currents, suggesting the requirement of the gamma subunit for its action. 3. PNU-107484A behaved like a positive allosteric modulator of the alpha1beta2gamma2 subtype with its binding site distinct from those for benzodiazepines, barbiturates and neurosteroids. With the alpha3beta2gamma2 subtype, the drug behaved like a non-competitive inhibitor of GABA, thus blocking Cl- currents by GABA alone or in the presence of pentobarbitone and neurosteroids. 4. It appears that PNU-107484A is a unique GABA(A) receptor ligand with alpha isoform-dependent functionalities, which may provide a basis for development of alpha isoform-selective ligands, and it could be useful as a probe to investigate the physiological roles of the various alpha isoform subtypes.
authors.affiliation: CNS Diseases Research and Discovery Chemistry, Pharmacia & Upjohn, Inc., Kalamazoo, MI 49001, U.S.A.
authors.forename: H K
authors.initials: HK
authors.lastname: Im
authors.forename: W B
authors.initials: WB
authors.lastname: Im
authors.forename: D B
authors.initials: DB
authors.lastname: Carter
authors.forename: T M
authors.initials: TM
authors.lastname: Schwartz
authors.forename: G L
authors.initials: GL
authors.lastname: Bundy
authors.forename: P F
authors.initials: PF
authors.lastname: VonVoigtlander
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D015152:Blotting, Northern; D002460:Cell Line; D018118:Chloride Channels / Q000187:drug effects; D018682:GABA Agents / Q000494:pharmacology*; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000196:embryology; D018408:Patch-Clamp Techniques; D010424:Pentobarbital / Q000494:pharmacology; D011725:Pyridines / Q000378:metabolism* / Q000494:pharmacology*; D011743:Pyrimidines / Q000378:metabolism* / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
chemical_list: D018118:Chloride Channels; D018682:GABA Agents; D011725:Pyridines; D011743:Pyrimidines; D012333:RNA, Messenger; D011963:Receptors, GABA-A; D011994:Recombinant Proteins; C114356:PNU 107484A; D005680:gamma-Aminobutyric Acid; D010424:Pentobarbital