title: The oligomeric state sets GABA(B) receptor signalling efficacy.
abstract: G protein-coupled receptors (GPCRs) have key roles in cell-cell communication. Recent data suggest that these receptors can form large complexes, a possibility expected to expand the complexity of this regulatory system. Among the brain GPCRs, the heterodimeric GABA(B) receptor is one of the most abundant, being distributed in most brain regions, on either pre- or post-synaptic elements. Here, using specific antibodies labelled with time-resolved FRET compatible fluorophores, we provide evidence that the heterodimeric GABA(B) receptor can form higher-ordered oligomers in the brain, as suggested by the close proximity of the GABA(B1) subunits. Destabilizing the oligomers using a competitor or a GABA(B1) mutant revealed different G protein coupling efficiencies depending on the oligomeric state of the receptor. By examining, in heterologous system, the G protein coupling properties of such GABA(B) receptor oligomers composed of a wild-type and a non-functional mutant heterodimer, we provide evidence for a negative functional cooperativity between the GABA(B) heterodimers.
authors.affiliation: CNRS, UMR5203, Institut de Génomique Fonctionnelle, Department of Molecular Pharmacology, Montpellier, France.
authors.forename: Laëtitia
authors.initials: L
authors.lastname: Comps-Agrar
authors.forename: Julie
authors.initials: J
authors.lastname: Kniazeff
authors.forename: Lenea
authors.initials: L
authors.lastname: Nørskov-Lauritsen
authors.forename: Damien
authors.initials: D
authors.lastname: Maurel
authors.forename: Martin
authors.initials: M
authors.lastname: Gassmann
authors.forename: Nathalie
authors.initials: N
authors.lastname: Gregor
authors.forename: Laurent
authors.initials: L
authors.lastname: Prézeau
authors.forename: Bernhard
authors.initials: B
authors.lastname: Bettler
authors.forename: Thierry
authors.initials: T
authors.lastname: Durroux
authors.forename: Eric
authors.initials: E
authors.lastname: Trinquet
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Pin
mesh_terms: D000494:Allosteric Regulation / Q000235:genetics; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D016297:Mutagenesis, Site-Directed; D020033:Protein Isoforms / Q000737:chemistry / Q000172:deficiency / Q000235:genetics; D055503:Protein Multimerization / Q000235:genetics; D055550:Protein Stability; D018080:Receptors, GABA-B / Q000737:chemistry* / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*
chemical_list: D020033:Protein Isoforms; D018080:Receptors, GABA-B