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. © 2011 European Molecular Biology Organization | All Rights Reserved.