Trends in Pharmacological Sciences
ReviewAsymmetry of GPCR oligomers supports their functional relevance
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.
References (66)
Transducin activation by nanoscale lipid bilayers containing one and two rhodopsins
J. Biol. Chem.
(2007)Monomeric rhodopsin is sufficient for normal rhodopsin kinase (GRK1) phosphorylation and arrestin-1 binding
J. Biol. Chem.
(2011)Monomeric rhodopsin is the minimal functional unit required for arrestin binding
J. Mol. Biol.
(2010)- et al.
Dopamine d2 receptor dimer formation. evidence from ligand binding
J. Biol. Chem.
(2001) - et al.
Cooperative conformational changes in a G-protein-coupled receptor dimer, the leukotriene B(4) receptor BLT1
J. Biol. Chem.
(2004) - et al.
Structure-based analysis of GPCR function: evidence for a novel pentameric assembly between the dimeric leukotriene B4 receptor BLT1 and the G-protein
J. Mol. Biol.
(2003) G protein activation by serotonin type 4 receptor dimers: evidence that turning on two protomers is more efficient
J. Biol. Chem.
(2011)A single subunit (GB2) is required for G-protein activation by the heterodimeric GABA(B) receptor
J. Biol. Chem.
(2002)A G protein-coupled receptor at work: the rhodopsin model
Trends Biochem. Sci.
(2009)Organization of the G protein-coupled receptors rhodopsin and opsin in native membranes
J. Biol. Chem.
(2003)
G protein activation by the leukotriene B4 receptor dimer. Evidence for an absence of trans-activation
J. Biol. Chem.
A generic approach for the purification of signaling complexes that specifically interact with the carboxy-terminal domain of G protein-coupled receptors
Mol. Cell Proteomics
Regulators of G protein signaling proteins as targets for drug discovery
Prog. Mol. Biol. Transl. Sci.
GRKs and beta-arrestins: roles in receptor silencing, trafficking and signaling
Trends Endocrinol. Metab.
Recognition in the face of diversity: interactions of heterotrimeric G proteins and G protein-coupled receptor (GPCR) kinases with activated GPCRs
J. Biol. Chem.
Light causes phosphorylation of nonactivated visual pigments in intact mouse rod photoreceptor cells
J. Biol. Chem.
G protein-coupled receptor kinases promote phosphorylation and beta-arrestin-mediated internalization of CCR5 homo- and hetero-oligomers
J. Biol. Chem.
Heterodimerization of somatostatin and opioid receptors cross-modulates phosphorylation, internalization, and desensitization
J. Biol. Chem.
Heterodimerization of substance P and mu-opioid receptors regulates receptor trafficking and resensitization
J. Biol. Chem.
Facilitation of mu-opioid receptor activity by preventing delta-opioid receptor-mediated codegradation
Neuron
A model for the solution structure of the rod arrestin tetramer
Structure
Complementary roles of the DRY motif and C-terminus tail of GPCRS for G protein coupling and beta-arrestin interaction
Biochem. Biophys. Res. Commun.
The structural basis of arrestin-mediated regulation of G-protein-coupled receptors
Pharmacol. Ther.
Arrestin-rhodopsin binding stoichiometry in isolated rod outer segment membranes depends on the percentage of activated receptors
J. Biol. Chem.
Formation of a ternary complex among NHERF1, beta-arrestin, and parathyroid hormone receptor
J. Biol. Chem.
The asymmetric/symmetric activation of GPCR dimers as a possible mechanistic rationale for multiple signalling pathways
Trends Pharmacol. Sci.
Recent methodological advances in the discovery of GPCR-associated protein complexes
Trends Pharmacol. Sci.
Purification and identification of G protein-coupled receptor protein complexes under native conditions
Mol. Cell Proteomics
The PDZ protein mupp1 promotes Gi coupling and signaling of the Mt1 melatonin receptor
J. Biol. Chem.
GPCR monomers and oligomers: it takes all kinds
Trends Neurosci.
The apparent cooperativity of some GPCRs does not necessarily imply dimerization
Trends Pharmacol. Sci.
The 7 TM G-protein-coupled receptor target family
Chem. Med. Chem.
G protein-coupled receptor hetero-dimerization: contribution to pharmacology and function
Br. J. Pharmacol.
Cited by (87)
Cannabinoid receptor CB<inf>1</inf> and CB<inf>2</inf> interacting proteins: Techniques, progress and perspectives
2021, Methods in Cell BiologyExploring functional consequences of GPCR oligomerization requires a different lens
2020, Progress in Molecular Biology and Translational ScienceDimers of serotonin receptors: Impact on ligand affinity and signaling
2019, BiochimieCitation Excerpt :The possibility of heterodimers formation has been proposed not only within GPCRs responding to one same ligand, but also across different families responding to different ligands. These heterodimers may acquire unique biochemical and functional characteristics, including (i) new pharmacology, orthosteric or allosteric binding sites, (ii) new signaling in response to agonists or antagonists, and (iii) unexpected allosteric-like cross-talk between the protomers, as decribed in previous reviews [9–11]. This review will concentrate on metabotropic serotonin (5-hydroxytryptamine, 5-HT) receptors, which belong to the class A-1 GPCR family, display a widespread expression, and are involved in an important array of physiological and pathological processes.
Dynamic roles for the N-terminus of the yeast G protein-coupled receptor Ste2p
2017, Biochimica et Biophysica Acta - Biomembranes
- *
These authors contributed equally to the manuscript.