Review
Asymmetry of GPCR oligomers supports their functional relevance

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G protein-coupled receptors (GPCRs) can exist as dimers or as larger oligomeric clusters that enable intercommunication between different receptor protomers within the same complex. This phenomenon is observed at three distinct levels: (i) at the level of ligand binding where the activation of one protomer can allosterically inhibit or facilitate ligand binding to the second protomer; (ii) at the level of ligand-induced conformational switches, which occur between transmembrane domains of the two protomers; and (iii) within GPCR-associated protein complexes, either directly at the level of GPCR-interacting proteins or at further downstream levels of the complex. Intercommunication at these different levels introduces asymmetry within GPCR dimers wherein each protomer fulfills its specific task. In this review, we discuss how the asymmetric behavior of GPCRs highlights the advantage of oligomeric receptor organization and supports the functional relevance of GPCR dimerization.

Section snippets

Dimerization of G protein-coupled receptors

The superfamily of seven-transmembrane-spanning G protein-coupled receptors (GPCRs) is of particular interest for pharmacologists. GPCRs constitute the largest family of membrane receptors, and the 400 non-odorant members are privileged drug targets [1]. Organization of GPCRs into di(oligo)meric clusters has been considered for more than 10 years and is now supported by numerous functional studies [2], in vivo complementation assays [3] and the crystal structure of two GPCRs 4, 5. For

Asymmetry of GPCR dimers at the level of ligand binding and conformational changes

GPCRs are subject to multiple allosteric modulations [12]. Binding of endogenous ligands to the orthosteric ligand binding site may be modulated by molecules binding a distinct, allosteric, site on the same receptor. In the context of GPCR dimers, similar allosteric modulations can be envisioned between the two protomers of the dimer. Each protomer possesses an orthosteric binding pocket that may exert allosteric effects on the orthosteric site of the other protomer, resulting in either

Asymmetry of GPCR dimers at the level of GIPs

GPCRs are part of large protein networks comprising principally membrane-spanning and cytosolic proteins, including heterotrimeric G proteins. Despite extensive characterization of this privileged GIP, the receptor/G protein stoichiometry remains a matter of debate. Recent studies using purified and reconstituted GPCRs showed that monomeric receptors potently activate G proteins, demonstrating that a receptor monomer is fully functional in this respect, and therefore implying a 1:1

Future developments and concluding remarks

GPCR dimerization is a topic of interest because of the potential importance of the functional consequences of such interactions. Evidence presented in this review on the asymmetric nature of GPCRs provides clues to the potential advantage of a dimeric organization of receptors in a context in which receptor dimers were shown to be dispensable for G protein coupling, GRK and arrestin recruitment. Asymmetry at the level of ligand binding was demonstrated for multiple receptors. However, many of

Acknowledgements

We thank Dr Thierry Durroux (Institut de Génomique Fonctionnelle, Montpellier) and Dr Mark Scott and Dr Julie Dam (Institut Cochin, Paris) for expert advice. This work was supported by grants from SERVIER, the Fondation pour la Recherche Médicale (Equipe FRM), the Association pour la Recherche sur le Cancer (no. 5051), the Institut National de la Santé et de la Recherche Médicale and the Centre National de la Recherche Scientifique.

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