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  • Review Article
  • Published:

Oligomerization of G-protein-coupled transmitter receptors

Nature Reviews Neuroscience volume 2, pages 274–286 (2001)Cite this article

Key Points

  • Since their biochemical purification in the 1970s and molecular cloning in the late 1980s, G-protein-coupled receptors (GPCRs) have generally been shown as monomeric transmembrane proteins that allosterically interact with heterotrimeric G proteins upon ligand binding. However, the complexity of radio-ligand binding properties of some receptors, combined with indirect biochemical data, provide evidence that GPCRs exist as oligomeric complexes.

  • The observation that receptor mutants can have dominant-negative effect on wild-type receptors, and that receptor function can be rescued by coexpressing receptors inactivated by mutations in distinct domains, implied that GPCRs can function as dimers. Co-immunoprecipitation of differentially tagged receptors provided the first direct biochemical evidence for this; however, GPCRs are very hydrophobic and could form artefactual aggregates resembling dimers. Biophysical approaches such as bioluminescence or fluorescence energy transfer (BRET or FRET) have confirmed that GPCRs exist as dimers in living cells.

  • The metabotropic GABAB receptor illustrates a convincing role for GPCR dimerization. The expression of a functional GABAB receptor at the cell surface depends entirely on heterodimerization between the GABABR1 and GABABR2 isoforms. When these are co-expressed, the heterodimer formed is trafficked at the cell surface as a functional receptor, indicating that dimerization could play a role in both chaperoning and signalling. Additional evidence for a role of dimerization in signal transduction includes the observation that preventing dimer formation abrogates β2-adrenergic receptor signal transduction.

  • Heterodimers can form between other receptor subtypes; for example, between δ- and μ- or κ-opioid receptors, or between receptors for different transmitters; for example, between the dopamine and somatostatin, the angiotensin and bradykinin, and the opioid and adrenergic receptors. Heterodimerization often gives different pharmacological and/or functional properties to the individual receptors, implying a diversity that was not anticipated. Heterodimerization might also be one of the mechanisms underlying cross-talk signalling between receptor systems.

  • Heterodimerization between GPCRs and non-GPCR proteins is also important. For the calcitonin-receptor-like-receptor, stable association with receptor-activity-modifying-proteins (RAMPs) is necessary for cell-surface targeting and determines its pharmacological properties. A direct interaction between a dopamine receptor and the ionotropic GABAA receptor leads to a reciprocal regulation of the two receptors. Heterotypic oligomeric assemblies might be the rule rather than the exception in GPCR-mediated signalling.

  • Relatively little is known about the dynamics and regulation of GPCR dimer formation. One of the most debated issues is whether ligands promote assembly or disassembly of dimers, or whether they bind to preformed dimers and change their conformation.

  • GPCRs might use different dimerization interfaces to associate. For example, hydrophobic packing of transmembrane domains has been suggested for monoamine receptors such as the β2-adrenergic and dopamine receptors. A coiled-coil interaction between the carboxyl-terminal domains causes heterodimerization of GABABR1 and R2, whereas dimers between calcium-sensing and metabotropic glutamate receptors are stabilized by disulphide bonds within their amino-terminal portions. It remains to be determined whether this diversity reflects the existence of multiple sites of interaction for all GPCR dimers, or indicates distinct strategies used by different classes of receptor.

Abstract

Examples of G-protein-coupled receptors that can be biochemically detected in homo- or heteromeric complexes are emerging at an accelerated rate. Biophysical approaches have confirmed the existence of several such complexes in living cells and there is strong evidence to support the idea that dimerization is important in different aspects of receptor biogenesis and function. While the existence of G-protein-coupled-receptor homodimers raises fundamental questions about the molecular mechanisms involved in transmitter recognition and signal transduction, the formation of heterodimers raises fascinating combinatorial possibilities that could underlie an unexpected level of pharmacological diversity, and contribute to cross-talk regulation between transmission systems. Because G-protein-coupled receptors are major pharmacological targets, the existence of dimers could have important implications for the development and screening of new drugs. Here, we review the evidence supporting the existence of G-protein-coupled-receptor dimerization and discuss its functional importance.

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Figure 1: Role of homo- and heterodimerization in the transport of G-protein-coupled receptors.
Figure 2: Molecular determinants of G-protein-coupled-receptor dimerization.
Figure 3: Alternative three-dimensional models showing dimers of G-protein-coupled receptors.

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Acknowledgements

The author is grateful to Stephane Angers, Ali Salahpour, Jean-François Mercier, Sandrine Hilairet, Lynda Adam and Momique Lagacé for the numerous discussions and their critical reading of the manuscript.

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Authors and Affiliations

  1. Department of Biochemistry and Groupe de Recherche sur le système Nerveux Autonome, Faculté de Médecine Université de Montréal, P.O. Box 6128, Down-Town Station, Montréal, H3C 3J7 , Quebec, Canada

    Michel Bouvier

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DATABASE LINKS

EGF

PDGF

interferon-γ

muscarinic receptors

α-adrenegic receptors

β-adrenegic receptors

gonadotropin-releasing hormone receptor

dopamine receptors

adenosine A1 receptor

glucagon receptor

α2-adrenergic receptor

M3 muscarinic receptor

angiotensin II receptor

β2-adrenergic receptor

M2 muscarinic receptor

GABAB receptor

mGluR5

δ-opioid receptor

SSTR5

CCR5

κ-opioid receptor

μ-opioid receptor

SSTR1

angiotensin I receptor

bradykinin B2 receptor

RAMP

mGluR1

FURTHER INFORMATION

Domain swapping in G-protein-coupled-receptor dimers

ENCYCLOPEDIA OF LIFE SCIENCES

G-protein-coupled receptors

Glossary

BIOGENIC AMINES

A series of molecules that can act as neurotransmitters and include noradrenaline and adrenaline.

ALLOSTERIC

A term to describe proteins that have two or more receptor sites, one of which (the active site) binds the principal substrate, whereas the other(s) bind(s) effector molecules that can influence its biological activity.

DOMINANT-NEGATIVE

A mutant protein that can form a heteromeric complex with the normal molecule, knocking out the activity of the entire complex.

SDS–PAGE

(Sodium dodecyl sulphate–polyacrylamide gel electrophoresis). A method for resolving a protein into its subunits and determining their separate molecular weights.

MOLECULAR CHAPERONE

A protein that assists in the non-covalent assembly of a protein complex but does not participate in its function.

COILED-COIL INTERACTION

A type of protein–protein interaction that involves interlacing of two helical domains.

VASOPRESSIN

Antidiuretic hormone.

FAB FRAGMENT

The antigen-binding portion of an antibody.

CALCITONIN

A polypeptide hormone, consisting of 32 amino-acid residues, that regulates calcium and phosphate levels in the blood.

HOMOTROPIC

Interaction between proteins of the same class.

ADRENOMEDULLIN

A hypotensive peptide hormone secreted by the medulla of the adrenal gland.

AMYLIN

A peptide consisting of 37 amino-acid residues that is secreted with insulin and might act to modulate its stimulatory effects on glucose metabolism in muscle. Also known as islet amyloid peptide.

VINBLASTIN

An alkaloid that arrests mitosis in metaphase by binding to spindle microtubules.

CYTOCHALASIN

Any of a group of fungal metabolites that interfere with the assembly and diassembly of actin filaments. One of the consequences of treating cells with these agents is that cleavage of the cytoplasm after nuclear division is prevented.

DYNAMIN

A protein involved in the formation of microtubule bundles and in membrane transport.

PROTOMERS

Identical subunits in an oligomeric protein complex.

GLYCOPHORIN A

A carbohydrate-rich sialoglycoprotein that is abundant in erythrocyte membranes.

ANXIOLYTIC AGENT

A drug used to reduce anxiety, such as benzodiazepines.

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Bouvier, M. Oligomerization of G-protein-coupled transmitter receptors. Nat Rev Neurosci 2, 274–286 (2001). https://doi.org/10.1038/35067575

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