GPCR oligomer
A GPCR oligomer is a
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The existence of receptor oligomers is a general phenomenon, whose discovery has superseded the prevailing paradigmatic concept of the function of receptors as plain monomers, and has far-reaching implications for the understanding of neurobiological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
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
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-proteincoupling
- 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
Further reading
- Smith NJ, Milligan G (December 2010). "Allostery at G protein-coupled receptor homo- and heteromers: uncharted pharmacological landscapes". Pharmacol. Rev. 62 (4): 701–25. PMID 21079041.
- González-Maeso J (2011). "GPCR oligomers in pharmacology and signaling". Mol Brain. 4 (1): 20. PMID 21619615.
- Saenz del Burgo L, Milligan G (2011). "Ligand Regulation of GPCR Quaternary Structure". In Giraldo J, Pin JP (eds.). G protein-coupled receptors: from structure to function. Cambridge: Royal Society of Chemistry. pp. 111–152. ISBN 978-1-84973-183-6.
- Gilchrist A (2010). GPCR molecular pharmacology and drug targeting: shifting paradigms and new directions. Hoboken, N.J.: John Wiley & Sons. ISBN 978-0-470-30778-6.
- Borroto-Escuela DO, Brito I, Romero-Fernandez W, et al. (2014). "The G protein-coupled receptor heterodimer network (GPCR-HetNet) and its hub components". Int J Mol Sci. 15 (5): 8570–90. PMID 24830558.
External links
- "The G Protein Coupled Receptor - Oligomerization Knowledge Base Project". Weill Medical College of Cornell University. Archived from the original on 2012-04-28.
- "GRIP Server". Archived from the original on 2012-06-07. – Nemoto W, Fukui K, Toh H (December 2009). "GRIP: a server for predicting interfaces for GPCR oligomerization". J. Recept. Signal Transduct. Res. 29 (6): 312–7. S2CID 11683830.
- "GRIP Database". Archived from the original on 2012-06-10. – Nemoto W, Fukui K, Toh H (June 2011). "GRIPDB - G protein coupled Receptor Interaction Partners DataBase". J. Recept. Signal Transduct. Res. 31 (3): 199–205. S2CID 23109701.
- "GRIP Server". Archived from the original on 2012-06-07. – Nemoto W, Fukui K, Toh H (December 2009). "GRIP: a server for predicting interfaces for GPCR oligomerization". J. Recept. Signal Transduct. Res. 29 (6): 312–7.