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Adenosine A2a receptor
A2A receptor bilayer.png
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols ADORA2A ; A2aR; ADORA2; RDC8
External IDs OMIM: 102776 MGI: 99402 HomoloGene: 20166 IUPHAR: 19 ChEMBL: 251 GeneCards: ADORA2A Gene
RNA expression pattern
PBB GE ADORA2A 205013 s at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 135 11540
Ensembl ENSG00000128271 ENSMUSG00000020178
UniProt P29274 Q60613
RefSeq (mRNA) NM_000675 NM_009630
RefSeq (protein) NP_000666 NP_033760
Location (UCSC) Chr 22:
24.42 – 24.44 Mb		 Chr 10:
75.32 – 75.33 Mb
PubMed search [1] [2]

The adenosine A2A receptor, also known as ADORA2A, is an adenosine receptor, and also denotes the human gene encoding it.[1][2]

Structure[edit]

This protein is a member of the G protein-coupled receptor (GPCR) family which possess seven transmembrane alpha helices. The crystallographic structure of the adenosine A2A receptor reveals a ligand binding pocket distinct from that of other structurally determined GPCRs (i.e., the beta-2 adrenergic receptor and rhodopsin).[3]

Heteromers[edit]

The actions of the A2A receptor are complicated by the fact that a variety of functional heteromers composed of a mixture of A2A subunits with subunits from other unrelated G-protein coupled receptors have been found in the brain, adding a further degree of complexity to the role of adenosine in modulation of neuronal activity. Hetereomers consisting of adenosine A1/A2A,[4][5] dopamine D2/A2A[6] and D3/A2A,[7] glutamate mGluR5/A2A[8] and cannabinoid CB1/A2A[9] have all been observed, as well as CB1/A2A/D2 heterotrimers,[10] and the functional significance and endogenous role of these hybrid receptors is still only starting to be unravelled.[11][12][13]

The receptor's role in immunomodulation in the context of cancer has suggested that it is an important immune checkpoint molecule.[14]

Function[edit]

The gene encodes a protein which is one of several receptor subtypes for adenosine. The activity of the encoded protein, a G protein-coupled receptor family member, is mediated by G proteins which activate adenylyl cyclase, which induce synthesis of intracellular cAMP. The encoded protein is abundant in basal ganglia, vasculature, T lymphocytes, and platelets and it is a major target of caffeine, which is a competitive antagonist of this protein.[15]

Physiological role[edit]

As with the A1, the A2A receptors are believed to play a role in regulating myocardial oxygen consumption and coronary blood flow. In addition, A2A receptor can negatively regulate overreactive immune cells, thereby protecting tissues from collateral inflammatory damage.[16]

The A2A receptor is responsible for regulating myocardial blood flow by vasodilating the coronary arteries, which increases blood flow to the myocardium, but may lead to hypotension. Just as in A1 receptors, this normally serves as a protective mechanism, but may be destructive in altered cardiac function.

The A2A receptor is also expressed in the brain, where it has important roles in the regulation of glutamate and dopamine release, making it a potential therapeutic target for the treatment of conditions such as insomnia, pain, depression, drug addiction and Parkinson's disease.[17][18][19][20][21][22][23]

Ligands[edit]

A number of selective A2A ligands have been developed,[24][25][26][27][28][29][30][31][32][33][34][35] with several possible therapeutic applications.[36][37][38][39][40][41] Older research on adenosine receptor function, and non-selective adenosine receptor antagonists such as aminophylline, focused mainly on the role of adenosine receptors in the heart, and led to several randomized controlled trials using these receptor antagonists to treat bradyasystolic arrest.[42][43][44][45][46][47][48]

However the development of more highly selective A2A ligands has led towards other applications, with the most significant focus of research currently being the potential therapeutic role for A2A antagonists in the treatment of Parkinson's disease.[49][50][51][52]

Agonists[edit]

Antagonists[edit]

Interactions[edit]

Adenosine A2A receptor has been shown to interact with Dopamine receptor D2.[61] As a result, Adenosine receptor A2A decreases activity in the Dopamine D2 receptors.

References[edit]

  1. ^ Libert F, Parmentier M, Lefort A, Dinsart C, Van Sande J, Maenhaut C, Simons MJ, Dumont JE, Vassart G (May 1989). "Selective amplification and cloning of four new members of the G protein-coupled receptor family". Science (New York, N.Y.) 244 (4904): 569–72. doi:10.1126/science.2541503. PMID 2541503. 
  2. ^ Libert F, Passage E, Parmentier M, Simons MJ, Vassart G, Mattei MG (Sep 1991). "Chromosomal mapping of A1 and A2 adenosine receptors, VIP receptor, and a new subtype of serotonin receptor". Genomics 11 (1): 225–7. doi:10.1016/0888-7543(91)90125-X. PMID 1662665. 
  3. ^ PDB: 3EML ; Jaakola VP, Griffith MT, Hanson MA, Cherezov V, Chien EY, Lane JR, Ijzerman AP, Stevens RC (Nov 2008). "The 2.6 angstrom crystal structure of a human A2A adenosine receptor bound to an antagonist". Science (New York, N.Y.) 322 (5905): 1211–7. doi:10.1126/science.1164772. PMC 2586971. PMID 18832607. 
  4. ^ Ciruela F, Casadó V, Rodrigues RJ, Luján R, Burgueño J, Canals M, Borycz J, Rebola N, Goldberg SR, Mallol J, Cortés A, Canela EI, López-Giménez JF, Milligan G, Lluis C, Cunha RA, Ferré S, Franco R (Feb 2006). "Presynaptic control of striatal glutamatergic neurotransmission by adenosine A1-A2A receptor heteromers". The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 26 (7): 2080–7. doi:10.1523/JNEUROSCI.3574-05.2006. PMID 16481441. 
  5. ^ Ferre S, Ciruela F, Borycz J, Solinas M, Quarta D, Antoniou K, Quiroz C, Justinova Z, Lluis C, Franco R, Goldberg SR (2008). "Adenosine A1-A2A receptor heteromers: new targets for caffeine in the brain". Frontiers in Bioscience : A Journal and Virtual Library 13 (13): 2391–9. doi:10.2741/2852. PMID 17981720. 
  6. ^ Fuxe K, Ferré S, Canals M, Torvinen M, Terasmaa A, Marcellino D, Goldberg SR, Staines W, Jacobsen KX, Lluis C, Woods AS, Agnati LF, Franco R (2005). "Adenosine A2A and dopamine D2 heteromeric receptor complexes and their function". Journal of Molecular Neuroscience : MN 26 (2-3): 209–20. doi:10.1385/JMN:26:2-3:209. PMID 16012194. 
  7. ^ Torvinen M, Marcellino D, Canals M, Agnati LF, Lluis C, Franco R, Fuxe K (Feb 2005). "Adenosine A2A receptor and dopamine D3 receptor interactions: evidence of functional A2A/D3 heteromeric complexes". Molecular Pharmacology 67 (2): 400–7. doi:10.1124/mol.104.003376. PMID 15539641. 
  8. ^ Zezula J, Freissmuth M (Mar 2008). "The A(2A)-adenosine receptor: a GPCR with unique features?". British Journal of Pharmacology. 153 Suppl 1 (S1): S184–90. doi:10.1038/sj.bjp.0707674. PMC 2268059. PMID 18246094. 
  9. ^ Ferré S, Goldberg SR, Lluis C, Franco R (2009). "Looking for the role of cannabinoid receptor heteromers in striatal function". Neuropharmacology. 56 Suppl 1 (Suppl 1): 226–34. doi:10.1016/j.neuropharm.2008.06.076. PMC 2635338. PMID 18691604. 
  10. ^ Marcellino D, Carriba P, Filip M, Borgkvist A, Frankowska M, Bellido I, Tanganelli S, Müller CE, Fisone G, Lluis C, Agnati LF, Franco R, Fuxe K (Apr 2008). "Antagonistic cannabinoid CB1/dopamine D2 receptor interactions in striatal CB1/D2 heteromers. A combined neurochemical and behavioral analysis". Neuropharmacology 54 (5): 815–23. doi:10.1016/j.neuropharm.2007.12.011. PMID 18262573. 
  11. ^ Ferré S, Ciruela F, Quiroz C, Luján R, Popoli P, Cunha RA, Agnati LF, Fuxe K, Woods AS, Lluis C, Franco R (2007). "Adenosine receptor heteromers and their integrative role in striatal function". TheScientificWorldJournal 7: 74–85. doi:10.1100/tsw.2007.211. PMID 17982579. 
  12. ^ Wardas J (2008). "Potential role of adenosine A2A receptors in the treatment of schizophrenia". Frontiers in Bioscience : A Journal and Virtual Library 13 (13): 4071–96. doi:10.2741/2995. PMID 18508501. 
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  27. ^ Weiss SM, Benwell K, Cliffe IA, Gillespie RJ, Knight AR, Lerpiniere J, Misra A, Pratt RM, Revell D, Upton R, Dourish CT (Dec 2003). "Discovery of nonxanthine adenosine A2A receptor antagonists for the treatment of Parkinson's disease". Neurology 61 (11 Suppl 6): S101–6. doi:10.1212/01.WNL.0000095581.20961.7D. PMID 14663021. 
  28. ^ Cristalli G, Lambertucci C, Taffi S, Vittori S, Volpini R (2003). "Medicinal chemistry of adenosine A2A receptor agonists". Current Topics in Medicinal Chemistry 3 (4): 387–401. doi:10.2174/1568026033392282. PMID 12570757. 
  29. ^ Cacciari B, Pastorin G, Spalluto G (2003). "Medicinal chemistry of A2A adenosine receptor antagonists". Current Topics in Medicinal Chemistry 3 (4): 403–11. doi:10.2174/1568026033392183. PMID 12570758. 
  30. ^ Cristalli G, Cacciari B, Dal Ben D, Lambertucci C, Moro S, Spalluto G, Volpini R (Mar 2007). "Highlights on the development of A(2A) adenosine receptor agonists and antagonists". ChemMedChem 2 (3): 260–81. doi:10.1002/cmdc.200600193. PMID 17177231. 
  31. ^ Diniz C, Borges F, Santana L, Uriarte E, Oliveira JM, Gonçalves J, Fresco P (2008). "Ligands and therapeutic perspectives of adenosine A(2A) receptors". Current Pharmaceutical Design 14 (17): 1698–722. doi:10.2174/138161208784746842. PMID 18673194. 
  32. ^ Cristalli G, Lambertucci C, Marucci G, Volpini R, Dal Ben D (2008). "A2A adenosine receptor and its modulators: overview on a druggable GPCR and on structure-activity relationship analysis and binding requirements of agonists and antagonists". Current Pharmaceutical Design 14 (15): 1525–52. doi:10.2174/138161208784480081. PMID 18537675. 
  33. ^ Gillespie RJ, Adams DR, Bebbington D, Benwell K, Cliffe IA, Dawson CE, Dourish CT, Fletcher A, Gaur S, Giles PR, Jordan AM, Knight AR, Knutsen LJ, Lawrence A, Lerpiniere J, Misra A, Porter RH, Pratt RM, Shepherd R, Upton R, Ward SE, Weiss SM, Williamson DS (May 2008). "Antagonists of the human adenosine A2A receptor. Part 1: Discovery and synthesis of thieno[3,2-d]pyrimidine-4-methanone derivatives". Bioorganic & Medicinal Chemistry Letters 18 (9): 2916–9. doi:10.1016/j.bmcl.2008.03.075. PMID 18406614. 
  34. ^ Gillespie RJ, Cliffe IA, Dawson CE, Dourish CT, Gaur S, Giles PR, Jordan AM, Knight AR, Lawrence A, Lerpiniere J, Misra A, Pratt RM, Todd RS, Upton R, Weiss SM, Williamson DS (May 2008). "Antagonists of the human adenosine A2A receptor. Part 2: Design and synthesis of 4-arylthieno[3,2-d]pyrimidine derivatives". Bioorganic & Medicinal Chemistry Letters 18 (9): 2920–3. doi:10.1016/j.bmcl.2008.03.076. PMID 18407496. 
  35. ^ Gillespie RJ, Cliffe IA, Dawson CE, Dourish CT, Gaur S, Jordan AM, Knight AR, Lerpiniere J, Misra A, Pratt RM, Roffey J, Stratton GC, Upton R, Weiss SM, Williamson DS (May 2008). "Antagonists of the human adenosine A2A receptor. Part 3: Design and synthesis of pyrazolo[3,4-d]pyrimidines, pyrrolo[2,3-d]pyrimidines and 6-arylpurines". Bioorganic & Medicinal Chemistry Letters 18 (9): 2924–9. doi:10.1016/j.bmcl.2008.03.072. PMID 18411049. 
  36. ^ Sullivan GW (Nov 2003). "Adenosine A2A receptor agonists as anti-inflammatory agents". Current Opinion in Investigational Drugs (London, England : 2000) 4 (11): 1313–9. PMID 14758770. 
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Further reading[edit]

  • Ongini E, Adami M, Ferri C, Bertorelli R (Oct 1997). "Adenosine A2A receptors and neuroprotection". Annals of the New York Academy of Sciences 825 (1 Neuroprotecti): 30–48. doi:10.1111/j.1749-6632.1997.tb48412.x. PMID 9369973. 
  • Furlong TJ, Pierce KD, Selbie LA, Shine J (Sep 1992). "Molecular characterization of a human brain adenosine A2 receptor". Brain Research. Molecular Brain Research 15 (1-2): 62–6. doi:10.1016/0169-328X(92)90152-2. PMID 1331670. 
  • Makujina SR, Sabouni MH, Bhatia S, Douglas FL, Mustafa SJ (Oct 1992). "Vasodilatory effects of adenosine A2 receptor agonists CGS 21680 and CGS 22492 in human vasculature". European Journal of Pharmacology 221 (2-3): 243–7. doi:10.1016/0014-2999(92)90708-C. PMID 1426003. 
  • Karlsten R, Gordh T, Post C (Jun 1992). "Local antinociceptive and hyperalgesic effects in the formalin test after peripheral administration of adenosine analogues in mice". Pharmacology & Toxicology 70 (6 Pt 1): 434–8. doi:10.1111/j.1600-0773.1992.tb00503.x. PMID 1438021. 
  • Libert F, Passage E, Parmentier M, Simons MJ, Vassart G, Mattei MG (Sep 1991). "Chromosomal mapping of A1 and A2 adenosine receptors, VIP receptor, and a new subtype of serotonin receptor". Genomics 11 (1): 225–7. doi:10.1016/0888-7543(91)90125-X. PMID 1662665. 
  • Martinez-Mir MI, Probst A, Palacios JM (1992). "Adenosine A2 receptors: selective localization in the human basal ganglia and alterations with disease". Neuroscience 42 (3): 697–706. doi:10.1016/0306-4522(91)90038-P. PMID 1835521. 
  • Libert F, Parmentier M, Lefort A, Dinsart C, Van Sande J, Maenhaut C, Simons MJ, Dumont JE, Vassart G (May 1989). "Selective amplification and cloning of four new members of the G protein-coupled receptor family". Science (New York, N.Y.) 244 (4904): 569–72. doi:10.1126/science.2541503. PMID 2541503. 
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source: https://web.archive.org/web/20151124101723/https://en.wikipedia.org/wiki/Adenosine_A2A_receptor

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