Adenosine A2A receptor

ADORA2A
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesADORA2A, adenosine A2a receptor, A2aR, ADORA2, RDC8
External IDsMGI: 99402 HomoloGene: 20166 GeneCards: ADORA2A
RNA expression pattern
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez

135

11540

Ensembl

ENSG00000128271

ENSMUSG00000020178

UniProt

P29274

Q60613

RefSeq (mRNA)

NM_000675
NM_001278497
NM_001278498
NM_001278499
NM_001278500

NM_009630
NM_001331095
NM_001331096

RefSeq (protein)

NP_000666
NP_001265426
NP_001265427
NP_001265428
NP_001265429

NP_001318024
NP_001318025
NP_033760

Location (UCSC)Chr 22: 24.42 – 24.44 MbChr 10: 75.32 – 75.33 Mb
PubMed search[1][2]
Wikidata
View/Edit HumanView/Edit Mouse

The adenosine A2A receptor, also known as ADORA2A, is an adenosine receptor, and also denotes the human gene encoding it.[3][4]

Structure

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).[5]

Heteromers

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. Heteromers consisting of adenosine A1/A2A,[6][7] dopamine D2/A2A[8] and D3/A2A,[9] glutamate mGluR5/A2A[10] and cannabinoid CB1/A2A[11] have all been observed, as well as CB1/A2A/D2 heterotrimers,[12] and the functional significance and endogenous role of these hybrid receptors is still only starting to be unravelled.[13][14][15]

The receptor's role in immunomodulation in the context of cancer has suggested that it is an important immune checkpoint molecule.[16]

Function

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 (the A2A receptor) 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.[17]

Physiological role

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.[18]

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.[19][20][21][22][23][24][25]

Ligands

A number of selective A2A ligands have been developed,[26][27][28][29][30][31][32][33][34][35][36][37] with several possible therapeutic applications.[38][39][40][41][42][43]

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.[44][45][46][47][48][49][50]

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.[51][52][53][54]

Agonists

Antagonists

Interactions

Adenosine A2A receptor has been shown to interact with Dopamine receptor D2.[63] As a result, Adenosine receptor A2A decreases activity in the Dopamine D2 receptors.

In cancer immunotherapy

The adenosine A2A receptor has also been shown to play a regulatory role in the adaptive immune system. In this role, A2AR functions similarly to programmed cell death-1 (PD-1) and cytotoxic t-lymphocyte associated protein-4 (CTLA-4) receptors, namely to suppress immunologic response and prevent associated tissue damage. Extracellular adenosine gathers in response to cellular stress and breakdown through interactions with hypoxia induced HIF-1α.[64] Abundant extracellular adenosine can then bind to the A2A receptor resulting in a Gs-protein coupled response, resulting in the accumulation of intracellular cAMP, which functions primarily through protein kinase A to upregulate inhibitory cytokines such as transforming growth factor-beta (TGF-β) and inhibitory receptors (i.e., PD-1).[65] Interactions with FOXP3 stimulates CD4+ T-cells into regulatory Treg cells further inhibiting immune response.[66]

Blockade of A2AR has been attempted to various ends, namely cancer immunotherapy. While several A2A receptor antagonists have progressed to clinical trials for the treatment of Parkinson’s disease, A2AR blockade in the context of cancer is less characterized. Mice treated with A2AR antagonists, such as ZM241385 (listed above) or caffeine, show significantly delayed tumor growth due to T-cells resistant to inhibition.[64] This is further highlighted by A2AR knockout mice who show increased tumor rejection. Multiple checkpoint pathway inhibition has been shown to have an additive effect, as shown by an increase in response with blockade to PD-1 and CTLA-4 via monoclonal antibodies as compared to the blockade of a single pathway. Researchers believe that A2AR blockade could increase the efficacy of such treatments even further.[65] Finally, inhibition of A2AR, either through pharmacologic or genetic targeting, in chimeric antigen receptor (CAR) T-cells reveals promising results. Blockade of A2AR in this setting has shown to increase tumor clearance through CAR T-cell therapy in mice.[67] Targeting of the A2A receptor is an attractive option for the treatment of a variety of cancers, especially with the therapeutic success of the blockade of other checkpoint pathways such as PD-1 and CTLA-4.

References

  1. ↑ "Human PubMed Reference:".
  2. ↑ "Mouse PubMed Reference:".
  3. ↑ 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. 244 (4904): 569–72. PMID 2541503. doi:10.1126/science.2541503.
  4. ↑ 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. PMID 1662665. doi:10.1016/0888-7543(91)90125-X.
  5. ↑ 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. 322 (5905): 1211–7. PMC 2586971 Freely accessible. PMID 18832607. doi:10.1126/science.1164772.
  6. ↑ 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. 26 (7): 2080–7. PMID 16481441. doi:10.1523/JNEUROSCI.3574-05.2006.
  7. ↑ 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. 13 (13): 2391–9. PMID 17981720. doi:10.2741/2852.
  8. ↑ 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. PMID 16012194. doi:10.1385/JMN:26:2-3:209.
  9. ↑ 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. PMID 15539641. doi:10.1124/mol.104.003376.
  10. ↑ 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. PMC 2268059 Freely accessible. PMID 18246094. doi:10.1038/sj.bjp.0707674.
  11. ↑ 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. PMC 2635338 Freely accessible. PMID 18691604. doi:10.1016/j.neuropharm.2008.06.076.
  12. ↑ 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. PMID 18262573. doi:10.1016/j.neuropharm.2007.12.011.
  13. ↑ 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. PMID 17982579. doi:10.1100/tsw.2007.211.
  14. ↑ Wardas J (2008). "Potential role of adenosine A2A receptors in the treatment of schizophrenia". Frontiers in Bioscience. 13 (13): 4071–96. PMID 18508501. doi:10.2741/2995.
  15. ↑ Simola N, Morelli M, Pinna A (2008). "Adenosine A2A receptor antagonists and Parkinson's disease: state of the art and future directions". Current Pharmaceutical Design. 14 (15): 1475–89. PMID 18537671. doi:10.2174/138161208784480072.
  16. ↑ Cekic C, Linden J (Dec 2014). "Adenosine A2A receptors intrinsically regulate CD8+ T cells in the tumor microenvironment". Cancer Research. 74 (24): 7239–49. PMC 4459794 Freely accessible. PMID 25341542. doi:10.1158/0008-5472.CAN-13-3581.
  17. ↑ "Entrez Gene: ADORA2A adenosine A2A receptor".
  18. ↑ Ohta A, Sitkovsky M (2001). "Role of G-protein-coupled adenosine receptors in downregulation of inflammation and protection from tissue damage". Nature. 414 (6866): 916–20. PMID 11780065. doi:10.1038/414916a.
  19. ↑ Hack SP, Christie MJ (2003). "Adaptations in adenosine signaling in drug dependence: therapeutic implications". Critical Reviews in Neurobiology. 15 (3–4): 235–74. PMID 15248812. doi:10.1615/CritRevNeurobiol.v15.i34.30.
  20. ↑ Morelli M, Di Paolo T, Wardas J, Calon F, Xiao D, Schwarzschild MA (Dec 2007). "Role of adenosine A2A receptors in parkinsonian motor impairment and l-DOPA-induced motor complications". Progress in Neurobiology. 83 (5): 293–309. PMID 17826884. doi:10.1016/j.pneurobio.2007.07.001.
  21. ↑ Schiffmann SN, Fisone G, Moresco R, Cunha RA, Ferré S (Dec 2007). "Adenosine A2A receptors and basal ganglia physiology". Progress in Neurobiology. 83 (5): 277–92. PMC 2148496 Freely accessible. PMID 17646043. doi:10.1016/j.pneurobio.2007.05.001.
  22. ↑ Ferré S, Diamond I, Goldberg SR, Yao L, Hourani SM, Huang ZL, Urade Y, Kitchen I (Dec 2007). "Adenosine A2A receptors in ventral striatum, hypothalamus and nociceptive circuitry implications for drug addiction, sleep and pain". Progress in Neurobiology. 83 (5): 332–47. PMC 2141681 Freely accessible. PMID 17532111. doi:10.1016/j.pneurobio.2007.04.002.
  23. ↑ Brown RM, Short JL (Nov 2008). "Adenosine A(2A) receptors and their role in drug addiction". The Journal of Pharmacy and Pharmacology. 60 (11): 1409–30. PMID 18957161. doi:10.1211/jpp/60.11.0001.
  24. ↑ Cunha RA, Ferré S, Vaugeois JM, Chen JF (2008). "Potential therapeutic interest of adenosine A2A receptors in psychiatric disorders". Current Pharmaceutical Design. 14 (15): 1512–24. PMC 2423946 Freely accessible. PMID 18537674. doi:10.2174/138161208784480090.
  25. ↑ Mingote S, Font L, Farrar AM, Vontell R, Worden LT, Stopper CM, Port RG, Sink KS, Bunce JG, Chrobak JJ, Salamone JD (Sep 2008). "Nucleus accumbens adenosine A2A receptors regulate exertion of effort by acting on the ventral striatopallidal pathway". The Journal of Neuroscience. 28 (36): 9037–46. PMC 2806668 Freely accessible. PMID 18768698. doi:10.1523/JNEUROSCI.1525-08.2008.
  26. ↑ Ongini E, Monopoli A, Cacciari B, Baraldi PG (2001). "Selective adenosine A2A receptor antagonists". Farmaco. 56 (1–2): 87–90. PMID 11347973. doi:10.1016/S0014-827X(01)01024-2.
  27. ↑ Baraldi PG, Cacciari B, Romagnoli R, Spalluto G, Monopoli A, Ongini E, Varani K, Borea PA (Jan 2002). "7-Substituted 5-amino-2-(2-furyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines as A2A adenosine receptor antagonists: a study on the importance of modifications at the side chain on the activity and solubility". Journal of Medicinal Chemistry. 45 (1): 115–26. PMID 11754583. doi:10.1021/jm010924c.
  28. ↑ Baraldi PG, Fruttarolo F, Tabrizi MA, Preti D, Romagnoli R, El-Kashef H, Moorman A, Varani K, Gessi S, Merighi S, Borea PA (Mar 2003). "Design, synthesis, and biological evaluation of C9- and C2-substituted pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines as new A2A and A3 adenosine receptors antagonists". Journal of Medicinal Chemistry. 46 (7): 1229–41. PMID 12646033. doi:10.1021/jm021023m.
  29. ↑ 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. PMID 14663021. doi:10.1212/01.WNL.0000095581.20961.7D.
  30. ↑ 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. PMID 12570757. doi:10.2174/1568026033392282.
  31. ↑ Cacciari B, Pastorin G, Spalluto G (2003). "Medicinal chemistry of A2A adenosine receptor antagonists". Current Topics in Medicinal Chemistry. 3 (4): 403–11. PMID 12570758. doi:10.2174/1568026033392183.
  32. ↑ 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. PMID 17177231. doi:10.1002/cmdc.200600193.
  33. ↑ 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. PMID 18673194. doi:10.2174/138161208784746842.
  34. ↑ 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. PMID 18537675. doi:10.2174/138161208784480081.
  35. ↑ 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. PMID 18406614. doi:10.1016/j.bmcl.2008.03.075.
  36. ↑ 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. PMID 18407496. doi:10.1016/j.bmcl.2008.03.076.
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  59. ↑ Mott AM, Nunes EJ, Collins LE, Port RG, Sink KS, Hockemeyer J, Müller CE, Salamone JD (May 2009). "The adenosine A2A antagonist MSX-3 reverses the effects of the dopamine antagonist haloperidol on effort-related decision making in a T-maze cost/benefit procedure". Psychopharmacology. 204 (1): 103–12. PMC 2875244 Freely accessible. PMID 19132351. doi:10.1007/s00213-008-1441-z.
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Further reading

  • 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. PMID 9369973. doi:10.1111/j.1749-6632.1997.tb48412.x. 
  • 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. PMID 1331670. doi:10.1016/0169-328X(92)90152-2. 
  • 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. PMID 1426003. doi:10.1016/0014-2999(92)90708-C. 
  • 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. PMID 1438021. doi:10.1111/j.1600-0773.1992.tb00503.x. 
  • 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. PMID 1662665. doi:10.1016/0888-7543(91)90125-X. 
  • 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. PMID 1835521. doi:10.1016/0306-4522(91)90038-P. 
  • 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. 244 (4904): 569–72. PMID 2541503. doi:10.1126/science.2541503. 
  • Kim J, Wess J, van Rhee AM, Schöneberg T, Jacobson KA (Jun 1995). "Site-directed mutagenesis identifies residues involved in ligand recognition in the human A2a adenosine receptor". The Journal of Biological Chemistry. 270 (23): 13987–97. PMC 3427751 Freely accessible. PMID 7775460. doi:10.1074/jbc.270.23.13987. 
  • Szondy Z (Dec 1994). "Adenosine stimulates DNA fragmentation in human thymocytes by Ca(2+)-mediated mechanisms". The Biochemical Journal. 304. 304 (3): 877–85. PMC 1137415 Freely accessible. PMID 7818494. doi:10.1042/bj3040877. 
  • MacCollin M, Peterfreund R, MacDonald M, Fink JS, Gusella J (Mar 1994). "Mapping of a human A2a adenosine receptor (ADORA2) to chromosome 22". Genomics. 20 (2): 332–3. PMID 8020991. doi:10.1006/geno.1994.1181. 
  • Nonaka H, Ichimura M, Takeda M, Nonaka Y, Shimada J, Suzuki F, Yamaguchi K, Kase H (May 1994). "KF17837 ((E)-8-(3,4-dimethoxystyryl)-1,3-dipropyl-7-methylxanthine), a potent and selective adenosine A2 receptor antagonist". European Journal of Pharmacology. 267 (3): 335–41. PMID 8088373. doi:10.1016/0922-4106(94)90159-7. 
  • Iwamoto T, Umemura S, Toya Y, Uchibori T, Kogi K, Takagi N, Ishii M (Mar 1994). "Identification of adenosine A2 receptor-cAMP system in human aortic endothelial cells". Biochemical and Biophysical Research Communications. 199 (2): 905–10. PMID 8135838. doi:10.1006/bbrc.1994.1314. 
  • Salmon JE, Brogle N, Brownlie C, Edberg JC, Kimberly RP, Chen BX, Erlanger BF (Sep 1993). "Human mononuclear phagocytes express adenosine A1 receptors. A novel mechanism for differential regulation of Fc gamma receptor function". Journal of Immunology (Baltimore, Md. : 1950). 151 (5): 2775–85. PMID 8360491. 
  • Peterfreund RA, MacCollin M, Gusella J, Fink JS (Jan 1996). "Characterization and expression of the human A2a adenosine receptor gene". Journal of Neurochemistry. 66 (1): 362–8. PMID 8522976. doi:10.1046/j.1471-4159.1996.66010362.x. 
  • Le F, Townsend-Nicholson A, Baker E, Sutherland GR, Schofield PR (Jun 1996). "Characterization and chromosomal localization of the human A2a adenosine receptor gene: ADORA2A". Biochemical and Biophysical Research Communications. 223 (2): 461–7. PMID 8670304. doi:10.1006/bbrc.1996.0916. 
  • Jiang Q, Van Rhee AM, Kim J, Yehle S, Wess J, Jacobson KA (Sep 1996). "Hydrophilic side chains in the third and seventh transmembrane helical domains of human A2A adenosine receptors are required for ligand recognition". Molecular Pharmacology. 50 (3): 512–21. PMID 8794889. 
  • Ledent C, Vaugeois JM, Schiffmann SN, Pedrazzini T, El Yacoubi M, Vanderhaeghen JJ, Costentin J, Heath JK, Vassart G, Parmentier M (Aug 1997). "Aggressiveness, hypoalgesia and high blood pressure in mice lacking the adenosine A2a receptor". Nature. 388 (6643): 674–8. PMID 9262401. doi:10.1038/41771. 
  • Koshiba M, Rosin DL, Hayashi N, Linden J, Sitkovsky MV (Mar 1999). "Patterns of A2A extracellular adenosine receptor expression in different functional subsets of human peripheral T cells. Flow cytometry studies with anti-A2A receptor monoclonal antibodies". Molecular Pharmacology. 55 (3): 614–24. PMID 10051547. 
  • Borgland SL, Castañón M, Spevak W, Parkinson FE (Dec 1998). "Effects of propentofylline on adenosine receptor activity in Chinese hamster ovary cell lines transfected with human A1, A2A, or A2B receptors and a luciferase reporter gene". Canadian Journal of Physiology and Pharmacology. 76 (12): 1132–8. PMID 10326835. doi:10.1139/cjpp-76-12-1132. 
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