GPCR oligomer

Crystallographic structure of the human κ-opioid receptor homo dimer (4djh) imbedded in a cartoon representation of a lipid bilayer. Each protomer is individually rainbow colored (N-terminus = blue, C-terminus = red). The receptor is complexed with the ligand JDTic that is depicted as a space-filling model (carbon = white, oxygen = red, nitrogen = blue).[1]

A GPCR oligomer is a complex of a small number of G protein-coupled receptors, which is held together by covalent bonds or by intermolecular forces. Receptors within this complex are called protomers, while unconnected receptors are called monomers. Receptor homomers consist of identical, heteromers of different protomers.

The existence of receptor oligomers is a general phenomenon, whose discovery has superseded the prevailing paradigmatic concept of the function of receptors as plain monomers, and has far-reaching implications for the understanding of neurobiological diseases as well as for the development of drugs.[2][3]


For a long time it was assumed that receptors transmitted their effects exclusively from their basic functional forms – as monomers. The first clue to the existence of GPCR oligomers goes back to 1975 when Robert Lefkowitz observed that β-adrenoceptors display negative binding cooperativity.[4] At the beginning of the 1980s, it was hypothesized, receptors could form larger complexes, the so-called mosaic form,[5] where two receptors may interact directly with each other.[6] Mass determination of β-adrenoceptors (1982)[7] and muscarinic receptors (1983),[8] supported the existence of homodimer or tetrameric complexes. In 1991, the phenomenon of receptor crosstalk was observed between adenosine A2A (A2A) and dopamine D2 receptor (DRD2) thus suggesting the formation of heteromers.[9] Maggio and co-workers showed in 1993 the ability of the muscarinic M3 receptor and α2C-adrenoceptor to heterodimerize.[10] The first direct evidence that GPCRs functioned as oligomers in vivo came from Overton and Blumer in 2000 by fluorescence resonance energy transfer (FRET) analysis of the α-factor receptor in the yeast Saccharomyces cerevisiae.[11] In 2005, further evidence was provided that receptor oligomizeration plays a functional role in a living organism with regulatory implication.[12] The crystal structure of CXCR4 dimer was published in 2010.[13] While initially thought to be a heterodimer, a 2015 review indicated that the A2A-DRD2 complex is a heterotetramer composed of A2A and DRD2 homodimers (i.e., a complex of 4 GPCRs composed of 2 adenosine A2A receptors and 2 dopamine D2 receptors).[14]

Consequences of oligomerization

First order GPCR oligomers are monomers, i.e., individual G-protein coupled receptors. Second and higher order GPCR oligomers consist of dimers, trimers, tetramers, and higher complexes. These oligomers have properties that differ from those of the monomers in several ways.[15] The functional character of a receptor is dependent on its tertiary or quaternary structure. Touch receptors located on a larger area or at sensitive places, then, forces, which alter the shape as well as the internal mobility of the reorganized protomers; short, protomers act as allosteric modulators of another. This has consequences for:

See also


  1. PDB: 4DJH; Wu H, Wacker D, Mileni M, Katritch V, Han GW, Vardy E, Liu W, Thompson AA, Huang XP, Carroll FI, Mascarella SW, Westkaemper RB, Mosier PD, Roth BL, Cherezov V, Stevens RC (March 2012). "Structure of the human κ-opioid receptor in complex with JDTic". Nature. 485 (7398): 327–32. doi:10.1038/nature10939. PMC 3356457Freely accessible. PMID 22437504.
  2. Albizu L, Moreno JL, González-Maeso J, Sealfon SC (November 2010). "Heteromerization of G protein-coupled receptors: relevance to neurological disorders and neurotherapeutics". CNS Neurol Disord Drug Targets. 9 (5): 636–50. doi:10.2174/187152710793361586. PMC 3066024Freely accessible. PMID 20632964.
  3. Rozenfeld R, Devi LA (March 2010). "Receptor heteromerization and drug discovery". Trends Pharmacol. Sci. 31 (3): 124–30. doi:10.1016/ PMC 2834828Freely accessible. PMID 20060175.
  4. Limbird LE, Meyts PD, Lefkowitz RJ (June 1975). "Beta-adrenergic receptors: evidence for negative cooperativity". Biochem. Biophys. Res. Commun. 64 (4): 1160–8. doi:10.1016/0006-291x(75)90815-3. PMID 1137592.
  5. Fuxe K, Borroto-Escuela DO, Marcellino D, Romero-Fernandez W, Frankowska M, Guidolin D, Filip M, Ferraro L, Woods AS, Tarakanov A, Ciruela F, Agnati LF, Tanganelli S (2012). "GPCR heteromers and their allosteric receptor-receptor interactions". Curr. Med. Chem. 19 (3): 356–63. doi:10.2174/092986712803414259. PMID 22335512.
  6. Birdsall NJM (1982). "Can different receptors interact directly with each other?". Trends in Neurosciences. 5: 137–138. doi:10.1016/0166-2236(82)90081-9.
  7. Fraser CM, Venter JC (November 1982). "The size of the mammalian lung beta 2-adrenergic receptor as determined by target size analysis and immunoaffinity chromatography". Biochem. Biophys. Res. Commun. 109 (1): 21–9. doi:10.1016/0006-291x(82)91560-1. PMID 6297476.
  8. Avissar S, Amitai G, Sokolovsky M (January 1983). "Oligomeric structure of muscarinic receptors is shown by photoaffinity labeling: subunit assembly may explain high- and low-affinity agonist states". Proc. Natl. Acad. Sci. U.S.A. 80 (1): 156–9. doi:10.1073/pnas.80.1.156. PMC 393329Freely accessible. PMID 6571990.
  9. Ferre S, von Euler G, Johansson B, Fredholm BB, Fuxe K (August 1991). "Stimulation of high-affinity adenosine A2 receptors decreases the affinity of dopamine D2 receptors in rat striatal membranes". Proc. Natl. Acad. Sci. U.S.A. 88 (16): 7238–41. doi:10.1073/pnas.88.16.7238. PMC 52269Freely accessible. PMID 1678519.
  10. Maggio R, Vogel Z, Wess J (April 1993). "Coexpression studies with mutant muscarinic/adrenergic receptors provide evidence for intermolecular "cross-talk" between G-protein-linked receptors". Proc. Natl. Acad. Sci. U.S.A. 90 (7): 3103–7. doi:10.1073/pnas.90.7.3103. PMC 46245Freely accessible. PMID 8385357.
  11. Overton MC, Blumer KJ (2000). "G-protein-coupled receptors function as oligomers in vivo.". Curr Biol. 10 (6): 341–4. doi:10.1016/S0960-9822(00)00386-9. PMID 10744981.
  12. Waldhoer M, Fong J, Jones RM, Lunzer MM, Sharma SK, Kostenis E, Portoghese PS, Whistler JL (June 2005). "A heterodimer-selective agonist shows in vivo relevance of G protein-coupled receptor dimers". Proc. Natl. Acad. Sci. U.S.A. 102 (25): 9050–5. doi:10.1073/pnas.0501112102. PMC 1157030Freely accessible. PMID 15932946.
  13. Wu B, Chien EY, Mol CD, Fenalti G, Liu W, Katritch V, Abagyan R, Brooun A, Wells P, Bi FC, Hamel DJ, Kuhn P, Handel TM, Cherezov V, Stevens RC (November 2010). "Structures of the CXCR4 chemokine GPCR with small-molecule and cyclic peptide antagonists". Science. 330 (6007): 1066–71. doi:10.1126/science.1194396. PMC 3074590Freely accessible. PMID 20929726.
  14. Ferré S, Bonaventura J, Tomasi D, Navarro G, Moreno E, Cortés A, Lluís C, Casadó V, Volkow ND (June 2015). "Allosteric mechanisms within the adenosine A2A-dopamine D2 receptor heterotetramer". Neuropharmacology. doi:10.1016/j.neuropharm.2015.05.028. PMID 26051403.
  15. Wnorowski, A; Jozwiak, K (2014). "Homo- and hetero-oligomerization of β2-adrenergic receptor in receptor trafficking, signaling pathways and receptor pharmacology". Cellular Signalling. 26 (10): 2259–65. doi:10.1016/j.cellsig.2014.06.016. PMID 25049076.

Further reading

External links

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