title: The human GABA(B1b) and GABA(B2) heterodimeric recombinant receptor shows low sensitivity to phaclofen and saclofen.
abstract: 1. The aim of this study was to characterize the pharmacological profile of the GABA(B1)/GABA(B2) heterodimeric receptor expressed in Chinese hamster ovary (CHO) cells. We have compared receptor binding affinity and functional activity for a series of agonists and antagonists. 2. The chimeric G-protein, G(qi5), was used to couple receptor activation to increases in intracellular calcium for functional studies on the Fluorimetric Imaging Plate Reader (FLIPR), using a stable GABA(B1)/GABA(B2)/G(qi5) CHO cell line. [(3)H]-CGP-54626 was used in radioligand binding studies in membranes prepared from the same cell line. 3. The pharmacological profile of the recombinant GABA(B1/B2) receptor was consistent with that of native GABA(B) receptors in that it was activated by GABA and baclofen and inhibited by CGP-54626A and SCH 50911. 4. Unlike native receptors, the GABA(B1)/GABA(B2)/G(qi5) response was not inhibited by high microMolar concentration of phaclofen, saclofen or CGP 35348. 5. This raises the possibility that the GABA(B1)/GABA(B2)/G(qi5) recombinant receptor may represent the previously described GABA(B) receptor subtype which is relatively resistant to inhibition by phaclofen.
authors.affiliation: Department of Neuroscience Research, SmithKline Beecham Pharmaceuticals, New Frontiers Science Park, Third Avenue, Harlow, Essex, CM19 5AW. Martyn_Wood-1@sbphrd.com
authors.forename: M D
authors.initials: MD
authors.lastname: Wood
authors.forename: K L
authors.initials: KL
authors.lastname: Murkitt
authors.forename: S Q
authors.initials: SQ
authors.lastname: Rice
authors.forename: T
authors.initials: T
authors.lastname: Testa
authors.forename: P K
authors.initials: PK
authors.lastname: Punia
authors.forename: M
authors.initials: M
authors.lastname: Stammers
authors.forename: O
authors.initials: O
authors.lastname: Jenkins
authors.forename: N A
authors.initials: NA
authors.lastname: Elshourbagy
authors.forename: U
authors.initials: U
authors.lastname: Shabon
authors.forename: S J
authors.initials: SJ
authors.lastname: Taylor
authors.forename: T L
authors.initials: TL
authors.lastname: Gager
authors.forename: J
authors.initials: J
authors.lastname: Minton
authors.forename: W D
authors.initials: WD
authors.lastname: Hirst
authors.forename: G W
authors.initials: GW
authors.lastname: Price
authors.forename: M
authors.initials: M
authors.lastname: Pangalos
mesh_terms: D000818:Animals; D001418:Baclofen / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D016466:CHO Cells; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D018755:GABA Agonists / Q000378:metabolism*; D018756:GABA Antagonists / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D018079:Receptors, GABA / Q000378:metabolism*; D018080:Receptors, GABA-B / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D018755:GABA Agonists; D018756:GABA Antagonists; C485503:GABBR2 protein, human; D018079:Receptors, GABA; D018080:Receptors, GABA-B; C052329:phaclofen; D005680:gamma-Aminobutyric Acid; D001418:Baclofen; C080629:saclofen