G protein activation by serotonin type 4 receptor dimers: evidence that turning on two protomers is more efficient

Lucie P. Pellissier, Gaël Barthet, Florence Gaven, Elisabeth Cassier, Eric Trinquet, Jean-Philippe Pin, Philippe Marin, Aline Dumuis, Joël Bockaert, Jean-Louis Banères, Sylvie Claeysen
Journal of Biological Chemistry. 2011-03-01; 286(12): 9985-9997
DOI: 10.1074/jbc.m110.201939

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Pellissier LP(1), Barthet G, Gaven F, Cassier E, Trinquet E, Pin JP, Marin P, Dumuis A, Bockaert J, Banères JL, Claeysen S.

Author information:
(1)Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS UMR5203, F-34094 Montpellier, France.

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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