Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

G-Protein-coupled receptor oligomerization and its potential for drug discovery

Nature Reviews Drug Discovery volume 1, pages 808–820 (2002)Cite this article

Key Points

  • The human genome encodes more than 1,000 G-protein-coupled receptors (GPCRs), making these protein the largest class of drug targets, and it has been estimated that 50% of all modern drugs modulate GPCR activity. Despite the recent realization that these receptors form homo-oligomeric and hetero-oligomeric complexes, virtually all therapeutics directed towards GPCRs have been designed using assays that presume these receptors are monomeric, and this important aspect of GPCR biology remains largely unincorporated into schemes to search for new therapeutics.

  • Although it is not known how large GPCR oligomers are or whether receptors can exist in multiple oligomeric states, the assembly of correctly formed oligomers seems to be a requirement for proper cellular transport to the cell surface. Oligomerization of a receptor with mutant or variant forms of itself can result in attenuation of receptor expression, and might, therefore, represent a potential disease mechanism or a means of cellular self-regulatory modulation of receptor function.

  • Traditionally, signal amplification is generally thought to occur only at the level of the G protein or the effector, and not at the receptor level. However, both homo- and hetero-oligomerization might provide a means for signal amplification through the activation of many receptors by the action of a single ligand molecule.

  • GPCR hetero-oligomerization can result in the formation of receptor complexes that have ligand-binding and signalling properties distinct from their constituent receptors. It represents a novel aspect of GPCR biology that has exciting potential to generate new drug targets. Heteromeric interactions might also mask the individual properties of one of the constituent receptors.

  • Altered levels of GPCR hetero-oligomerization could represent the molecular basis of some clinical disorders.

  • Little is known about the dynamics and regulation of GPCR oligomer formation; that is, whether ligands promote association or dissociation of oligomers, or whether they bind to pre-formed oligomers and change the oligomeric receptor conformation. However, resonance-energy-transfer assays in live cells have indicated that agonist-induced oligomerization might occur.

  • There is evidence that the oligomeric nature of GPCRs can be exploited to improve drugs by developing dimeric ligands. Several dimeric ligands have been shown to have increased affinity and altered potency compared with their constituent ligands, potentially because dimeric ligands might more readily induce or stabilize the dimeric conformation of the receptors, which in some manner increases the efficacy of signal transduction.

  • Contemporary drug discovery for GPCRs has largely been based on using a single GPCR of interest expressed in a recombinant cell line. For future lead-compound identification, the current understanding of GPCR oligomerization mandates that hetero-oligomeric receptors must be considered as novel targets in the screening of compounds as drug candidates. Drugs that can enhance or disrupt GPCR oligomer formation as a means to regulate oligomerization-dependent functions will also have to be explored.

  • Given what is known about GPCR oligomerization so far, it is plausible that the development of 'new' therapies could be as simple as creating novel regimens with 'old' drugs.

  • The consideration of GPCR quaternary structure has been slow to permeate into the thinking of the drug discovery mainstream despite the potential to exploit it for improved therapies.

Abstract

G-protein-coupled receptors (GPCRs) represent by far the largest class of targets for modern drugs. Virtually all therapeutics that are directed towards GPCRs have been designed using assays that presume that these receptors are monomeric. The recent realization that these receptors form homo-oligomeric and hetero-oligomeric complexes has added a new dimension to rational drug design. However, this important aspect of GPCR biology remains largely unincorporated into schemes to search for new therapeutics. This review provides a synopsis of the current thinking surrounding GPCR homo-oligomerization and hetero-oligomerization and shows how new models point towards unexplored avenues in the development of new therapies.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Bivalent and dimeric ligands.

Similar content being viewed by others

References

  1. Howard, A. D. et al. Orphan G protein-coupled receptors and natural ligand discovery. Trends Pharmacol. Sci. 22, 132–140 (2001).

    CAS  PubMed  Google Scholar 

  2. Spiegel, A. M. Defects in G protein-coupled signal transduction in human disease. Annu. Rev. Physiol. 58, 143–170 (1996).

    Article  CAS  PubMed  Google Scholar 

  3. Rana, B. K., Shiina, T. & Insel, P. A. Genetic variations and polymorphisms of G protein-coupled receptors: functional and therapeutic implications. Annu. Rev. Pharmacol. Toxicol. 41, 593–624 (2001).

    CAS  PubMed  Google Scholar 

  4. Bailey, W. J. et al. Patent status of therapeutically important G protein-coupled receptors. Expert Opin. Ther. Patents 11, 1861–1887 (2001).

    CAS  Google Scholar 

  5. Bockaert, J. & Pin, J. P. Molecular tinkering of G protein-coupled receptors: an evolutionary success. EMBO J. 18, 1723–1729 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Gether, U. Uncovering molecular mechanisms involved in activation of G protein-coupled receptors. Endocr. Rev. 21, 90–113 (2000).References 5 and 6 are general reviews that, among other things, outline several key structural features of the different families of GPCRs.

    CAS  PubMed  Google Scholar 

  7. Heldin, C. H. Dimerization of cell surface receptors in signal transduction. Cell 80, 213–223 (1995).

    CAS  PubMed  Google Scholar 

  8. Salahpour, A., Angers, S. & Bouvier, M. Functional significance of oligomerization of G-protein-coupled receptors. Trends Endocrinol. Metab. 11, 163–168 (2000).

    CAS  PubMed  Google Scholar 

  9. Lee, D. K., George, S. R., Evans, J. F., Lynch, K. R. & O'Dowd, B. F. Orphan G protein-coupled receptors in the CNS. Curr. Opin. Pharmacol. 1, 31–39 (2001).

    CAS  PubMed  Google Scholar 

  10. Nimchinsky, E. A., Hof, P. R., Janssen, W. G., Morrison, J. H. & Schmauss, C. Expression of dopamine D3 receptor dimers and tetramers in brain and in transfected cells. J. Biol. Chem. 272, 29229–29237 (1997).

    CAS  PubMed  Google Scholar 

  11. George, S. R. et al. A transmembrane domain-derived peptide inhibits D1 dopamine receptor function without affecting receptor oligomerization. J. Biol. Chem. 273, 30244–30248 (1998).

    CAS  PubMed  Google Scholar 

  12. Lee, S. P. et al. Inhibition of cell surface expression by mutant receptors demonstrates that D2 dopamine receptors exist as oligomers in the cell. Mol. Pharmacol. 58, 120–128 (2000).

    CAS  PubMed  Google Scholar 

  13. Chidiac, P., Green, M. A., Pawagi, A. B. & Wells, J. W. Cardiac muscarinic receptors. Cooperativity as the basis for multiple states of affinity. Biochemistry 36, 7361–7379 (1997).

    CAS  PubMed  Google Scholar 

  14. Romano, C., Yang, W. L. & O'Malley, K. L. Metabotropic glutamate receptor 5 is a disulfide-linked dimer. J. Biol. Chem. 271, 28612–28616 (1996).

    CAS  PubMed  Google Scholar 

  15. Bai, M., Trivedi, S. & Brown, E. M. Dimerization of the extracellular calcium-sensing receptor (CaR) on the cell surface of CaR-transfected HEK293 cells. J. Biol. Chem. 273, 23605–23610 (1998).

    CAS  PubMed  Google Scholar 

  16. Kunishima, N. et al. Structural basis of glutamate recognition by a dimeric metabotropic glutamate receptor. Nature 407, 971–977 (2000).This paper details the crystal structure of the amino terminus of mGluR1, directly showing that this receptor is a covalently linked constitutive dimer.

    CAS  PubMed  Google Scholar 

  17. Hebert, T. E. et al. A peptide derived from a β2-adrenergic receptor transmembrane domain inhibits both receptor dimerization and activation. J. Biol. Chem. 271, 16384–16392 (1996).

    CAS  PubMed  Google Scholar 

  18. Cvejic, S. & Devi, L. A. Dimerization of the δ-opioid receptor: implication for a role in receptor internalization. J. Biol. Chem. 272, 26959–26964 (1997).

    CAS  PubMed  Google Scholar 

  19. Ng, G. Y. et al. Identification of a GABAB receptor subunit, GB2, required for functional GABAB receptor activity. J. Biol. Chem. 274, 7607–7610 (1999).

    CAS  PubMed  Google Scholar 

  20. Rocheville, M. et al. Subtypes of the somatostatin receptor assemble as functional homo- and heterodimers. J. Biol. Chem. 275, 7862–7869 (2000).

    CAS  PubMed  Google Scholar 

  21. Jordan, B. A. & Devi, L. A. G-protein-coupled receptor heterodimerization modulates receptor function. Nature 399, 697–700 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. George, S. R. et al. Oligomerization of μ- and δ-opioid receptors. Generation of novel functional properties. J. Biol. Chem. 275, 26128–26135 (2000).

    CAS  PubMed  Google Scholar 

  23. Schulz, A., Grosse, R., Schultz, G., Gudermann, T. & Schoneberg, T. Structural implication for receptor oligomerization from functional reconstitution studies of mutant V2 vasopressin receptors. J. Biol. Chem. 275, 2381–2389 (2000).

    CAS  PubMed  Google Scholar 

  24. Mellado, M. et al. Chemokine receptor homo- or heterodimerization activates distinct signaling pathways. EMBO J. 20, 2497–2507 (2001).A study that demonstrates agonist-induced homo- and hetero-oligomerization of chemokine receptors. The formation of hetero-oligomers was detected at 100-fold lower concentration of agonist than required for the formation of homo-oligomers.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Casey, J. R. & Reithmeier, R. A. Detergent interaction with band 3, a model polytopic membrane protein. Biochemistry 32, 1172–1179 (1993).

    CAS  PubMed  Google Scholar 

  26. Whitfield, G. K., Jurutka, P. W., Haussler, C. A. & Haussler, M. R. Steroid hormone receptors: evolution, ligands, and molecular basis of biologic function. J. Cell. Biochem. 33 (Suppl. 32), 110–122 (1999).

    Google Scholar 

  27. Jahangeer, S. & Rodbell, M. The disaggregation theory of signal transduction revisited: further evidence that G proteins are multimeric and disaggregate to monomers when activated. Proc. Natl Acad. Sci. USA 90, 8782–8786 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Yan, K., Greene, E., Belga, F. & Rasenick, M. M. Synaptic membrane G proteins are complexed with tubulin in situ. J. Neurochem. 66, 1489–1495 (1996).

    CAS  PubMed  Google Scholar 

  29. Limbird, L. E., Meyts, P. D. & Lefkowitz, R. J. β-Adrenergic receptors: evidence for negative cooperativity. Biochem. Biophys. Res. Commun. 64, 1160–1168 (1975).

    CAS  PubMed  Google Scholar 

  30. Henis, Y. I. & Sokolovsky, M. Muscarinic antagonists induce different receptor conformations in rat adenohypophysis. Mol. Pharmacol. 24, 357–365 (1983).

    CAS  PubMed  Google Scholar 

  31. Hirschberg, B. T. & Schimerlik, M. I. A kinetic model for oxotremorine M binding to recombinant porcine M2 muscarinic receptors expressed in Chinese hamster ovary cells. J. Biol. Chem. 269, 26127–26135 (1994).

    CAS  PubMed  Google Scholar 

  32. Mattera, R., Pitts, B. J., Entman, M. L. & Birnbaumer, L. Guanine nucleotide regulation of a mammalian myocardial muscarinic receptor system. Evidence for homo- and heterotropic cooperativity in ligand binding analyzed by computer-assisted curve fitting. J. Biol. Chem. 260, 7410–7421 (1985).

    CAS  PubMed  Google Scholar 

  33. Boyer, J. L., Martinez-Carcamo, M., Monroy-Sanchez, J. A., Posadas, C. & Garcia-Sainz, J. A. Guanine nucleotide-induced positive cooperativity in muscarinic-cholinergic antagonist binding. Biochem. Biophys. Res. Commun. 134, 172–177 (1986).

    CAS  PubMed  Google Scholar 

  34. Potter, L. T. et al. Evidence of paired M2 muscarinic receptors. Mol. Pharmacol. 39, 211–221 (1991).

    CAS  PubMed  Google Scholar 

  35. Sinkins, W. G. & Wells, J. W. G protein-linked receptors labeled by [3H]histamine in guinea pig cerebral cortex. II. Mechanistic basis for multiple states of affinity [corrected]. Mol. Pharmacol. 43, 583–594 (1993).

    CAS  PubMed  Google Scholar 

  36. Wreggett, K. A. & Wells, J. W. Cooperativity manifest in the binding properties of purified cardiac muscarinic receptors. J. Biol. Chem. 270, 22488–22499 (1995).

    CAS  PubMed  Google Scholar 

  37. Chazenbalk, G. D., Kakinuma, A., Jaume, J. C., McLachlan, S. M. & Rapoport, B. Evidence for negative cooperativity among human thyrotropin receptors overexpressed in mammalian cells. Endocrinology 137, 4586–4591 (1996).

    CAS  PubMed  Google Scholar 

  38. Armstrong, D. & Strange, P. G. Dopamine D2 receptor dimer formation: evidence from ligand binding. J. Biol. Chem. 276, 22621–22629 (2001).

    CAS  PubMed  Google Scholar 

  39. Pizard, A., Marchetti, J., Allegrini, J., Alhenc-Gelas, F. & Rajerison, R. M. Negative cooperativity in the human bradykinin B2 receptor. J. Biol. Chem. 273, 1309–1315 (1998).

    CAS  PubMed  Google Scholar 

  40. AbdAlla, S., Lother, H. & Quitterer, U. AT1-receptor heterodimers show enhanced G-protein activation and altered receptor sequestration. Nature 407, 94–98 (2000).

    CAS  PubMed  Google Scholar 

  41. Hurtley, S. M. & Helenius, A. Protein oligomerization in the endoplasmic reticulum. Annu. Rev. Cell Biol. 5, 277–307 (1989).

    CAS  PubMed  Google Scholar 

  42. Brown, D. & Breton, S. Sorting proteins to their target membranes. Kidney Int. 57, 816–824 (2000).

    CAS  PubMed  Google Scholar 

  43. Karpa, K. D., Lin, R., Kabbani, N. & Levenson, R. The dopamine D3 receptor interacts with itself and the truncated D3 splice variant D3nf: D3–D3nf interaction causes mislocalization of D3 receptors. Mol. Pharmacol. 58, 677–683 (2000).

    CAS  PubMed  Google Scholar 

  44. Benkirane, M., Jin, D. Y., Chun, R. F., Koup, R. A. & Jeang, K. T. Mechanism of transdominant inhibition of CCR5-mediated HIV-1 infection by CCR5Δ32. J. Biol. Chem. 272, 30603–30606 (1997).

    CAS  PubMed  Google Scholar 

  45. Zhu, X. & Wess, J. Truncated V2 vasopressin receptors as negative regulators of wild-type V2 receptor function. Biochemistry 37, 15773–15784 (1998).

    CAS  PubMed  Google Scholar 

  46. Elmhurst, J. L., Xie, Z., O'Dowd, B. F. & George, S. R. The splice variant D3nf reduces ligand binding to the D3 dopamine receptor: evidence for heterooligomerization. Brain Res. Mol. Brain Res. 80, 63–74 (2000).

    CAS  PubMed  Google Scholar 

  47. Okuda-Ashitaka, E. et al. Suppression of prostaglandin E receptor signaling by the variant form of EP1 subtype. J. Biol. Chem. 271, 31255–31261 (1996).

    CAS  PubMed  Google Scholar 

  48. Osuga, Y. et al. Co-expression of defective luteinizing hormone receptor fragments partially reconstitutes ligand-induced signal generation. J. Biol. Chem. 272, 25006–25012 (1997).

    CAS  PubMed  Google Scholar 

  49. Grosse, R., Schoneberg, T., Schultz, G. & Gudermann, T. Inhibition of gonadotropin-releasing hormone receptor signaling by expression of a splice variant of the human receptor. Mol. Endocrinol. 11, 1305–1318 (1997).

    CAS  PubMed  Google Scholar 

  50. Kuner, R. et al. Role of heteromer formation in GABAB receptor function. Science 283, 74–77 (1999).

    CAS  PubMed  Google Scholar 

  51. Kaupmann, K. et al. GABA(B)-receptor subtypes assemble into functional heteromeric complexes. Nature 396, 683–687 (1998).

    CAS  PubMed  Google Scholar 

  52. White, J. H. et al. Heterodimerization is required for the formation of a functional GABA(B) receptor. Nature 396, 679–682 (1998).

    CAS  PubMed  Google Scholar 

  53. Couve, A. et al. Intracellular retention of recombinant GABAB receptors. J. Biol. Chem. 273, 26361–26367 (1998).

    CAS  PubMed  Google Scholar 

  54. Margeta-Mitrovic, M., Jan, Y. N. & Jan, L. Y. A trafficking checkpoint controls GABA(B) receptor heterodimerization. Neuron 27, 97–106 (2000).

    CAS  PubMed  Google Scholar 

  55. Levac, B. A., O'Dowd, B. F. & George, S. R. Oligomerization of opioid receptors: generation of novel signaling units. Curr. Opin. Pharmacol. 2, 76–81 (2002).

    CAS  PubMed  Google Scholar 

  56. Pfeiffer, M. et al. Homo- and heterodimerization of somatostatin receptor subtypes. Inactivation of SST(3) receptor function by heterodimerization with SST(2A). J. Biol. Chem. 276, 14027–14036 (2001).

    CAS  PubMed  Google Scholar 

  57. AbdAlla, S., Lother, H., el Massiery, A. & Quitterer, U. Increased AT(1) receptor heterodimers in preeclampsia mediate enhanced angiotensin II responsiveness. Nature Med. 7, 1003–1009 (2001).It is shown that there is a potential relationship between the level of AT 1 – B 2 receptor hetero-oligomerization and pre-eclampsia.

    CAS  PubMed  Google Scholar 

  58. Robbins, M. J. et al. GABA(B2) is essential for G-protein coupling of the GABA(B) receptor heterodimer. J. Neurosci. 21, 8043–8052 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Palczewski, K. et al. Crystal structure of rhodopsin: a G protein-coupled receptor. Science 289, 739–745 (2000).This landmark paper showing the crystal structure of rhodopsin represents the first and only determination of a high-resolution, three-dimensional structure for a family 1 GPCR.

    CAS  PubMed  Google Scholar 

  60. Zeng, F. Y. & Wess, J. Identification and molecular characterization of M3 muscarinic receptor dimers. J. Biol. Chem. 274, 19487–19497 (1999).

    CAS  PubMed  Google Scholar 

  61. Lee, S. P. et al. Oligomerization of dopamine and serotonin receptors. Neuropsychopharmacology 23, S32–S40 (2000).

    CAS  PubMed  Google Scholar 

  62. Ng, G. Y. et al. Dopamine D2 receptor dimers and receptor-blocking peptides. Biochem. Biophys. Res. Commun. 227, 200–204 (1996).

    CAS  PubMed  Google Scholar 

  63. Lemmon, M. A. et al. Glycophorin A dimerization is driven by specific interactions between transmembrane α-helices. J. Biol. Chem. 267, 7683–7689 (1992).

    CAS  PubMed  Google Scholar 

  64. Fan, G. F., Ray, K., Zhao, X. M., Goldsmith, P. K. & Spiegel, A. M. Mutational analysis of the cysteines in the extracellular domain of the human Ca2+ receptor: effects on cell surface expression, dimerization and signal transduction. FEBS Lett. 436, 353–356 (1998).

    CAS  PubMed  Google Scholar 

  65. Ward, D. T., Brown, E. M. & Harris, H. W. Disulfide bonds in the extracellular calcium-polyvalent cation-sensing receptor correlate with dimer formation and its response to divalent cations in vitro. J. Biol. Chem. 273, 14476–14483 (1998).

    CAS  PubMed  Google Scholar 

  66. Tsuji, Y. et al. Cryptic dimer interface and domain organization of the extracellular region of metabotropic glutamate receptor subtype 1. J. Biol. Chem. 275, 28144–28151 (2000).A non-covalent dimerization interface between the amino termini of mGluR1 receptors revealed that an intermolecular disulphide bond might not be the only mechanism of interaction in family 3 receptor dimerization.

    CAS  PubMed  Google Scholar 

  67. AbdAlla, S., Zaki, E., Lother, H. & Quitterer, U. Involvement of the amino terminus of the B2 receptor in agonist-induced receptor dimerization. J. Biol. Chem. 274, 26113–26119 (1999).

    Google Scholar 

  68. Bowery, N. G. et al. International Union of Pharmacology. XXXIII. Mammalian γ-aminobutyric acid(B) receptors: structure and function. Pharmacol. Rev. 54, 247–264 (2002).

    CAS  PubMed  Google Scholar 

  69. Pagano, A. et al. C-terminal interaction is essential for surface trafficking but not for heteromeric assembly of GABA(B) receptors. J. Neurosci. 21, 1189–1202 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Ng, G. Y. et al. Resistance of the dopamine D2L receptor to desensitization accompanies the up-regulation of receptors on to the surface of Sf9 cells. Endocrinology 138, 4199–4206 (1997).

    CAS  PubMed  Google Scholar 

  71. McVey, M. et al. Monitoring receptor oligomerization using time-resolved fluorescence resonance energy transfer and bioluminescence resonance energy transfer. The human δ-opioid receptor displays constitutive oligomerization at the cell surface, which is not regulated by receptor occupancy. J. Biol. Chem. 276, 14092–14099 (2001).

    CAS  PubMed  Google Scholar 

  72. Himeno, A., Shigematsu, K., Taguchi, T. & Niwa, M. Endothelin-1 binding to endothelin receptors in the rat anterior pituitary gland: interaction in the recognition of endothelin-1 between ETA and ETB receptors. Cell. Mol. Neurobiol. 18, 447–452 (1998).

    CAS  PubMed  Google Scholar 

  73. Angers, S. et al. Detection of β2-adrenergic receptor dimerization in living cells using bioluminescence resonance energy transfer (BRET). Proc. Natl Acad. Sci. USA 97, 3684–3689 (2000).

    CAS  PubMed Central  PubMed  Google Scholar 

  74. Kroeger, K. M., Hanyaloglu, A. C., Seeber, R. M., Miles, L. E. & Eidne, K. A. Constitutive and agonist-dependent homo-oligomerization of the thyrotropin-releasing hormone receptor. Detection in living cells using bioluminescence resonance energy transfer. J. Biol. Chem. 276, 12736–12743 (2001).

    CAS  PubMed  Google Scholar 

  75. Rocheville, M. et al. Receptors for dopamine and somatostatin: formation of hetero-oligomers with enhanced functional activity. Science 288, 154–157 (2000).

    CAS  PubMed  Google Scholar 

  76. Cornea, A., Janovick, J. A., Maya-Nunez, G. & Conn, P. M. Gonadotropin-releasing hormone receptor microaggregation. Rate monitored by fluorescence resonance energy transfer. J. Biol. Chem. 276, 2153–2158 (2001).

    CAS  PubMed  Google Scholar 

  77. Dupuis, D. S., Perez, M., Halazy, S., Colpaert, F. C. & Pauwels, P. J. Magnitude of 5-HT1B and 5-HT1A receptor activation in guinea-pig and rat brain: evidence from sumatriptan dimer-mediated [35S]GTPγS binding responses. Brain Res. Mol. Brain Res. 67, 107–123 (1999).

    CAS  PubMed  Google Scholar 

  78. Halazy, S. et al. Serotonin dimers: application of the bivalent ligand approach to the design of new potent and selective 5-HT(1B/1D) agonists. J. Med. Chem. 39, 4920–4927 (1996).

    CAS  PubMed  Google Scholar 

  79. Perez, M. et al. Dimerization of sumatriptan as an efficient way to design a potent, centrally and orally active 5-HT1B agonist. Bioorg. Med. Chem. Lett. 8, 675–680 (1998).Dimeric sumatriptan, a clinically used treatment for migraine headaches, was shown to be more potent than monomeric sumitriptan, possibly because it behaves as a bivalent ligand.

    CAS  PubMed  Google Scholar 

  80. Yano, K., Kimura, S. & Imanishi, Y. Simultaneous activation of two different receptor systems by enkephalin/neurotensin conjugates having spacer chains of various lengths. Eur. J. Pharm. Sci. 7, 41–48 (1998).

    CAS  PubMed  Google Scholar 

  81. Portoghese, P. S. Bivalent ligands and the message-address concept in the design of selective opioid receptor antagonists. Trends Pharmacol. Sci. 10, 230–235 (1989).The linking of opioid peptides with various chemical spacers generated opioid ligands with varying properties.

    CAS  PubMed  Google Scholar 

  82. Hazum, E. & Keinan, D. Gonadotropin releasing hormone activation is mediated by dimerization of occupied receptors. Biochem. Biophys. Res. Commun. 133, 449–456 (1985).

    CAS  PubMed  Google Scholar 

  83. Hillion, J. et al. Coaggregation, cointernalization, and codesensitization of adenosine A2A receptors and dopamine D2 receptors. J. Biol. Chem. 277, 18091–18097 (2002).

    CAS  PubMed  Google Scholar 

  84. Jordan, B. A., Trapaidze, N., Gomes, I., Nivarthi, R. & Devi, L. A. Oligomerization of opioid receptors with β2-adrenergic receptors: a role in trafficking and mitogen-activated protein kinase activation. Proc. Natl Acad. Sci. USA 98, 343–348 (2001).

    CAS  PubMed  Google Scholar 

  85. Tarasova, N. I., Rice, W. G. & Michejda, C. J. Inhibition of G-protein-coupled receptor function by disruption of transmembrane domain interactions. J. Biol. Chem. 274, 34911–34915 (1999).

    CAS  PubMed  Google Scholar 

  86. Yudt, M. R. & Koide, S. Preventing estrogen receptor action with dimer-interface peptides. Steroids 66, 549–558 (2001).

    CAS  PubMed  Google Scholar 

  87. Salim, K. et al. Oligomerization of G-protein-coupled receptors shown by selective co-immunoprecipitation. J. Biol. Chem. 277, 15482–15485 (2002).

    CAS  PubMed  Google Scholar 

  88. Pfeiffer, M. et al. Heterodimerization of somatostatin and opioid receptors cross-modulates phosphorylation, internalization, and desensitization. J. Biol. Chem. 277, 19762–19772 (2002).

    CAS  PubMed  Google Scholar 

  89. Rodriguez-Frade, J. M. et al. The chemokine monocyte chemoattractant protein-1 induces functional responses through dimerization of its receptor CCR2. Proc. Natl Acad. Sci. USA 96, 3628–3633 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Gines, S. et al. Dopamine D1 and adenosine A1 receptors form functionally interacting heteromeric complexes. Proc. Natl Acad. Sci. USA 97, 8606–8611 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Gouldson, P. R., Snell, C. R. & Reynolds, C. A. A new approach to docking in the β2-adrenergic receptor that exploits the domain structure of G protein-coupled receptors. J. Med. Chem. 40, 3871–3886 (1997).

    CAS  PubMed  Google Scholar 

  92. Maggio, R., Vogel, Z. & Wess, J. Coexpression studies with mutant muscarinic/adrenergic receptors provide evidence for intermolecular 'cross-talk' between G-protein-linked receptors. Proc. Natl Acad. Sci. USA 90, 3103–3107 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Monnot, C. et al. Polar residues in the transmembrane domains of the type 1 angiotensin II receptor are required for binding and coupling. Reconstitution of the binding site by co-expression of two deficient mutants. J. Biol. Chem. 271, 1507–1513 (1996).

    CAS  PubMed  Google Scholar 

  94. Baldwin, J. M. The probable arrangement of the helices in G protein-coupled receptors. EMBO J. 12, 1693–1703 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Hadac, E. M. et al. A peptide agonist acts by occupation of a monomeric G protein-coupled receptor: dual sites of covalent attachment to domains near TM1 and TM7 of the same molecule make biologically significant domain-swapped dimerization unlikely. J. Med. Chem. 42, 2105–2111 (1999).

    CAS  PubMed  Google Scholar 

  96. Ciruela, F. et al. Immunological identification of A1 adenosine receptors in brain cortex. J. Neurosci. Res. 42, 818–828 (1995).

    CAS  PubMed  Google Scholar 

  97. Vila-Coro, A. J. et al. HIV-1 infection through the CCR5 receptor is blocked by receptor dimerization. Proc. Natl Acad. Sci. USA 97, 3388–3393 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Vila-Coro, A. J. et al. The chemokine SDF-1α triggers CXCR4 receptor dimerization and activates the JAK/STAT pathway. FASEB J. 13, 1699–1710 (1999).

    CAS  PubMed  Google Scholar 

  99. Ng, G. Y. et al. Desensitization, phosphorylation and palmitoylation of the human dopamine D1 receptor. Eur. J. Pharmacol. 267, 7–19 (1994).

    CAS  PubMed  Google Scholar 

  100. Fukushima, Y. et al. Oligomer formation of histamine H2 receptors expressed in Sf9 and COS7 cells. FEBS Lett. 409, 283–286 (1997).

    CAS  PubMed  Google Scholar 

  101. Nguyen, T. et al. Discovery of a novel member of the histamine receptor family. Mol. Pharmacol. 59, 427–433 (2001).

    CAS  PubMed  Google Scholar 

  102. Indrapichate, K. et al. Biological actions of monoclonal luteinizing hormone/human chorionic gonadotropin receptor antibodies. Biol. Reprod. 46, 265–278 (1992).

    CAS  PubMed  Google Scholar 

  103. Ayoub, M. A. et al. Monitoring of ligand-independent dimerization and ligand-induced conformational changes of melatonin receptors in living cells by bioluminescence resonance energy transfer. J. Biol. Chem. 277, 21522–21528 (2002).

    CAS  PubMed  Google Scholar 

  104. Ng, G. Y. et al. Human serotonin1B receptor expression in Sf9 cells: phosphorylation, palmitoylation, and adenylyl cyclase inhibition. Biochemistry 32, 11727–11733 (1993).

    CAS  PubMed  Google Scholar 

  105. Abe, J., Suzuki, H., Notoya, M., Yamamoto, T. & Hirose, S. Ig-hepta, a novel member of the G protein-coupled hepta-helical receptor (GPCR) family that has immunoglobulin-like repeats in a long N-terminal extracellular domain and defines a new subfamily of GPCRs. J. Biol. Chem. 274, 19957–19964 (1999).

    CAS  PubMed  Google Scholar 

  106. Romano, C. et al. Covalent and noncovalent interactions mediate metabotropic glutamate receptor mGlu5 dimerization. Mol. Pharmacol. 59, 46–53 (2001).

    CAS  PubMed  Google Scholar 

  107. Overton, M. C. & Blumer, K. J. G-protein-coupled receptors function as oligomers in vivo. Curr. Biol. 10, 341–344 (2000).

    CAS  PubMed  Google Scholar 

  108. Yesilaltay, A. & Jenness, D. D. Homo-oligomeric complexes of the yeast α-factor pheromone receptor are functional units of endocytosis. Mol. Biol. Cell 11, 2873–2884 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Xie, Z., Lee, S. P., O'Dowd, B. F. & George, S. R. Serotonin 5-HT1B and 5-HT1D receptors form homodimers when expressed alone and heterodimers when co-expressed. FEBS Lett. 456, 63–67 (1999).

    CAS  PubMed  Google Scholar 

  110. Ciruela, F. et al. Metabotropic glutamate 1α and adenosine A1 receptors assemble into functionally interacting complexes. J. Biol. Chem. 276, 18345–18351 (2001).

    CAS  PubMed  Google Scholar 

  111. Yoshioka, K., Saitoh, O. & Nakata, H. Heteromeric association creates a P2Y-like adenosine receptor. Proc. Natl Acad. Sci. USA 98, 7617–7622 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. AbdAlla, S., Lother, H., Abdel-Tawab, A. M. & Quitterer, U. The angiotensin II AT2 receptor is an AT1 receptor antagonist. J. Biol. Chem. 276, 39721–39726 (2001).

    CAS  PubMed  Google Scholar 

  113. Scarselli, M. et al. D2/D3 dopamine receptor heterodimers exhibit unique functional properties. J. Biol. Chem. 276, 30308–30314 (2001).

    CAS  PubMed  Google Scholar 

  114. Jones, K. A. et al. GABA(B) receptors function as a heteromeric assembly of the subunits GABA(B)R1 and GABA(B)R2. Nature 396, 674–679 (1998).

    CAS  PubMed  Google Scholar 

  115. Maggio, R. et al. G protein-linked receptors: pharmacological evidence for the formation of heterodimers. J. Pharmacol. Exp. Ther. 291, 251–257 (1999).

    CAS  PubMed  Google Scholar 

  116. Nelson, G. et al. An amino-acid taste receptor. Nature 416, 199–202 (2002).

    CAS  PubMed  Google Scholar 

  117. Nelson, G. et al. Mammalian sweet taste receptors. Cell 106, 381–390 (2001).

    CAS  PubMed  Google Scholar 

  118. Perez, M., Jorand-Lebrun, C., Pauwels, P. J., Pallard, I. & Halazy, S. Dimers of 5HT1 ligands preferentially bind to 5HT1B/1D receptor subtypes. Bioorg. Med. Chem. Lett. 8, 1407–1412 (1998).

    CAS  PubMed  Google Scholar 

  119. Jacobson, K. A., Xie, R., Young, L., Chang, L. & Liang, B. T. A novel pharmacological approach to treating cardiac ischemia. Binary conjugates of A1 and A3 adenosine receptor agonists. J. Biol. Chem. 275, 30272–30279 (2000).

    CAS  PubMed  Google Scholar 

  120. Carrithers, M. D. & Lerner, M. R. Synthesis and characterization of bivalent peptide ligands targeted to G-protein-coupled receptors. Chem. Biol. 3, 537–542 (1996).

    CAS  PubMed  Google Scholar 

  121. Moser, U. et al. Aliphatic and heterocyclic analogues of arecaidine propargyl ester. Structure–activity relationships of mono- and bivalent ligands at muscarinic M1 (M4), M2 and M3 receptor subtypes. Arzneimittelforschung 45, 449–455 (1995).

    CAS  PubMed  Google Scholar 

  122. Portoghese, P. S. From models to molecules: opioid receptor dimers, bivalent ligands, and selective opioid receptor probes. J. Med. Chem. 44, 2259–2269 (2001).

    CAS  PubMed  Google Scholar 

  123. Bolognesi, M. L. et al. Opioid antagonist activity of naltrexone-derived bivalent ligands: importance of a properly oriented molecular scaffold to guide 'address' recognition at κ opioid receptors. J. Med. Chem. 39, 1816–1822 (1996).

    CAS  PubMed  Google Scholar 

  124. Portoghese, P. S. The bivalent ligand approach in the design of highly selective opioid receptor antagonists. NIDA Res. Monogr. 96, 3–20 (1990).

    CAS  PubMed  Google Scholar 

  125. Lambrecht, G. et al. The novel heteromeric bivalent ligand SB9 potently antagonizes P2Y(1) receptor-mediated responses. J. Auton. Nerv. Syst. 81, 171–177 (2000).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors receive support from the Canadian Institutes of Health Research and the National Institute on Drug Abuse.

Author information

Authors and Affiliations

  1. Department of Pharmacology, University of Toronto, 1 King's College Circle, Toronto, M5S 1A8, Ontario, Canada

    Susan R. George, Brian F. O'Dowd & Samuel P. Lee

  2. Department of Medicine, University of Toronto, 1 King's College Circle, Toronto, M5S 1A8, Ontario, Canada

    Susan R. George

  3. Centre for Addiction and Mental Health, 250 College Street, Toronto, M5T 1A8, Ontario, Canada

    Susan R. George & Brian F. O'Dowd

Authors
  1. Susan R. George
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Brian F. O'Dowd
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Samuel P. Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Susan R. George.

Related links

Related links

DATABASES

LocusLink

A1 receptor

A2A receptor

A3 receptor

adenylyl cyclase

β2-adrenoceptor

angiotensin II

AT1 receptor

AT2 receptor

B2 receptor

bradykinin

Ca2+-sensing receptor

CCR2

CCR5

cholecystokinin receptor

CXCR4

D1 receptor

D2 receptor

D3 receptor

enkephalin

EP1 receptor

ET-1

ETA receptor

ETB receptor

GABAB(1)

GABAB(2)

glucagon

gonadotropin-releasing hormone

gonadotropin-releasing-hormone receptor

H2 receptor

H4 receptor

5-HT1B

5-HT1D

luteinizing-hormone receptor

M2 receptor

M3 receptor

α-melanocyte-stimulating-hormone receptor

mGlu1

mGlu5

MT1 receptor

MT2 receptor

neurotensin

oestrogen receptor

δ-opioid receptor

κ-opioid receptor

μ-opioid receptor

P2Y1 receptor

parathyroid hormone

rhodopsin

SSTR1A

SSTR1B

SSTR1C

SSTR2A

T1R1

T1R2

T1R3

thyrotropin-releasing-hormone receptor

V2 receptor

Medscape DrugInfo

levodopa

sumatriptan

OMIM

nephrogenic diabetes insipidus

FURTHER INFORMATION

Encyclopedia of Life Sciences

G protein-coupled receptors

GPCR database

Glossary

POLYMORPHISM

The occurrence in a population of two or more variant alleles of a gene, for which the frequency of the rarer alleles is greater than can be explained by recurrent mutation alone.

RADIATION INACTIVATION

A technique in which proteins are inactivated with high-energy particles to determine the molecular mass of functional oligomers.

PALMITOYLATION

A post-translationlational modification in which palmitic acid, a fatty carbon chain, is attached to a cysteine residue by a thio-ester bond.

ORPHAN RECEPTOR

A receptor for which no endogenous ligand has been identified.

COOPERATIVITY

A property of receptors that have interacting binding sites, for which the binding of a ligand to one site modulates the binding of a second ligand to another site.

CO-IMMUNOPRECIPITATION

A process that uses antibodies to isolate a protein that interacts with the protein of interest.

DIFFERENTIALLY TAGGED

Having two unlike epitope tags.

DESENSITIZATION

The mechanism by which a ligand becomes less effective at activating a receptor during prolonged application.

ALTERNATIVE SPLICING

Different products can be generated from a single gene by, for example, combining alternative forms of particular exons.

PERTUSSIS TOXIN

A toxin that ADP ribosylates the inhibitory G protein Gi, thereby causing it to uncouple from G-protein-coupled receptors.

CROSS-TALK

An informal term that refers to the interaction or reciprocal modulation between two proteins.

PRE-ECLAMPSIA

A hypertensive disorder of pregnancy for which the cause is unknown.

CRYSTAL STRUCTURE

The three-dimensional arrangement of atoms in a protein that is determined by inducing the protein to form crystals.

CROSSLINKING AGENT

A chemical compound that forms a covalent link between two closely associated proteins.

DYSKINESIA

An impairment in the ability to control movements — characterized by spasmodic or repetitive motions or lack of coordination.

PARKINSONISM

Any of a group of nervous disorders that are similar to Parkinson's disease — characterized by muscular rigidity, tremor and impaired motor control.

Rights and permissions

Reprints and permissions

About this article

Cite this article

George, S., O'Dowd, B. & Lee, S. G-Protein-coupled receptor oligomerization and its potential for drug discovery. Nat Rev Drug Discov 1, 808–820 (2002). https://doi.org/10.1038/nrd913

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrd913

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing