G protein activation by serotonin type 4 receptor dimers: evidence that turning on two protomers is more efficient |
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Authors: | Pellissier Lucie P Barthet Gaël Gaven Florence Cassier Elisabeth Trinquet Eric Pin Jean-Philippe Marin Philippe Dumuis Aline Bockaert Joël Banères Jean-Louis Claeysen Sylvie |
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Institution: | Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS UMR5203, F-34094 Montpellier, France. |
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Abstract: | The discovery that class C G protein-coupled receptors (GPCRs) function as obligatory dimeric entities has generated major interest in GPCR oligomerization. Oligomerization now appears to be a common feature among all GPCR classes. However, the functional significance of this process remains unclear because, in vitro, some monomeric GPCRs, such as rhodopsin and β(2)-adrenergic receptors, activate G proteins. By using wild type and mutant serotonin type 4 receptors (5-HT(4)Rs) (including a 5-HT(4)-RASSL) expressed in COS-7 cells as models of class A GPCRs, we show that activation of one protomer in a dimer was sufficient to stimulate G proteins. However, coupling efficiency was 2 times higher when both protomers were activated. Expression of combinations of 5-HT(4), in which both protomers were able to bind to agonists but only one could couple to G proteins, suggested that upon agonist occupancy, protomers did not independently couple to G proteins but rather that only one G protein was activated. Coupling of a single heterotrimeric G(s) protein to a receptor dimer was further confirmed in vitro, using the purified recombinant WT RASSL 5-HT(4)R obligatory heterodimer. These results, together with previous findings, demonstrate that, differently from class C GPCR dimers, class A GPCR dimers have pleiotropic activation mechanisms. |
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Keywords: | Cyclic AMP (cAMP) G Protein-coupled Receptors (GPCR) G Proteins Neurotransmitter Receptors Signal Transduction 5-HT4 Receptor Dimerization Oligomerization |
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