Biology:GPCR oligomer

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Short description: Class of protein complexes
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 protein complex that consists of a small number (ὀλίγοι oligoi "a few", μέρος méros "part, piece, component") of G protein-coupled receptors (GPCRs). It is held together by covalent bonds or by intermolecular forces. The subunits within this complex are called protomers, while unconnected receptors are called monomers. Receptor homomers consist of identical protomers, while heteromers consist of different protomers.

Receptor homodimers – which consist of two identical GPCRs – are the simplest homomeric GPCR oligomers. Receptor heterodimers – which consist of two different GPCRs – are the simplest heteromeric GPCR oligomers.

The existence of receptor oligomers is a general phenomenon, whose discovery has superseded the prevailing paradigmatic concept of the function of receptors as plain monomers, and has far-reaching implications for the understanding of neurobiological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

Discovery

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] While initially thought to be a receptor heterodimer, a review from 2015 determined that the A2A-DRD2 heteromer is a heterotetramer composed of A2A and DRD2 homodimers (i.e., two adenosine A2A receptors and two dopamine D2 receptors).[10] Maggio and co-workers showed in 1993 the ability of the muscarinic M3 receptor and α2C-adrenoceptor to heterodimerize.[11] 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.[12] In 2005, further evidence was provided that receptor oligomerization plays a functional role in a living organism with regulatory implication.[13] The crystal structure of the CXCR4 dimer was published in 2010.[14]

Consequences of oligomerization

GPCR oligomers consist of receptor dimers, trimers, tetramers, and complexes of higher order. These oligomers are entities with properties that can differ from those of the monomers in several ways.[15] The functional character of a receptor is dependent on its tertiary or quaternary structure. Within the complex protomers act as allosteric modulators of another. This has consequences for:

  • the supply of the cell surface with receptors
  • the ligand binding at corresponding binding sites
  • the G-protein coupling
  • the GPCR-mediated signal transduction
  • modifying the desensitization profile
  • the tendency for endocytosis and internalization
  • the post-endocytotic fate of the receptors

Detection

There are various methods to detect and observe GPCR oligomers.[16][17]

See also

  • D1-D2 dopamine receptor

References

  1. ↑ PDB: 4DJH​; "Structure of the human κ-opioid receptor in complex with JDTic". Nature 485 (7398): 327–32. March 2012. doi:10.1038/nature10939. PMID 22437504. Bibcode: 2012Natur.485..327W. 
  2. ↑ "Heteromerization of G protein-coupled receptors: relevance to neurological disorders and neurotherapeutics". CNS Neurol Disord Drug Targets 9 (5): 636–50. November 2010. doi:10.2174/187152710793361586. PMID 20632964. 
  3. ↑ "Receptor heteromerization and drug discovery". Trends Pharmacol. Sci. 31 (3): 124–30. March 2010. doi:10.1016/j.tips.2009.11.008. PMID 20060175. 
  4. ↑ "Beta-adrenergic receptors: evidence for negative cooperativity". Biochem. Biophys. Res. Commun. 64 (4): 1160–8. June 1975. doi:10.1016/0006-291x(75)90815-3. PMID 1137592. 
  5. ↑ "GPCR heteromers and their allosteric receptor-receptor interactions". Curr. Med. Chem. 19 (3): 356–63. 2012. 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. ↑ "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. November 1982. doi:10.1016/0006-291x(82)91560-1. PMID 6297476. 
  8. ↑ "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. January 1983. doi:10.1073/pnas.80.1.156. PMID 6571990. Bibcode: 1983PNAS...80..156A. 
  9. ↑ "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. August 1991. doi:10.1073/pnas.88.16.7238. PMID 1678519. PMC 52269. Bibcode: 1991PNAS...88.7238F. https://digital.csic.es/bitstream/10261/26347/1/Ferre_Sergi_et_al.pdf. 
  10. ↑ "Allosteric mechanisms within the adenosine A2A-dopamine D2 receptor heterotetramer". Neuropharmacology 104: 154–60. June 2015. doi:10.1016/j.neuropharm.2015.05.028. PMID 26051403. 
  11. ↑ "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. April 1993. doi:10.1073/pnas.90.7.3103. PMID 8385357. Bibcode: 1993PNAS...90.3103M. 
  12. ↑ "G-protein-coupled receptors function as oligomers in vivo.". Curr. Biol. 10 (6): 341–4. 2000. doi:10.1016/S0960-9822(00)00386-9. PMID 10744981. 
  13. ↑ "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. June 2005. doi:10.1073/pnas.0501112102. PMID 15932946. Bibcode: 2005PNAS..102.9050W. 
  14. ↑ "Structures of the CXCR4 chemokine GPCR with small-molecule and cyclic peptide antagonists". Science 330 (6007): 1066–71. November 2010. doi:10.1126/science.1194396. PMID 20929726. Bibcode: 2010Sci...330.1066W. 
  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. https://zenodo.org/record/2649291. 
  16. ↑ "Methods used to study the oligomeric structure of G-protein-coupled receptors". Biosci. Rep. 37 (2). 2017. doi:10.1042/BSR20160547. PMID 28062602. 
  17. ↑ "BRET and Time-resolved FRET strategy to study GPCR oligomerization: from cell lines toward native tissues". Front Endocrinol (Lausanne) 3: 92. 2012. doi:10.3389/fendo.2012.00092. PMID 22837753. 

Further reading

External links



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