This protein is a member of the G protein-coupled receptor (GPCR) family which possess seven transmembrane alpha helices, as well as an extracellular N-terminus and an intracellular C-terminus. Furthermore, located in the intracellular side close to the membrane is a small alpha helix, often referred to as helix 8 (H8). 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). Below this primary (orthosteric) binding pocket lies a secondary (allosteric) binding pocket. The crystal-structure of A2A bound to the antagonist ZM241385 (PDB code: 4EIY) showed that a sodium-ion can be found in this location of the protein, thus giving it the name 'sodium-ion binding pocket'.
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, dopamine D2/A2A and D3/A2A, glutamate mGluR5/A2A and cannabinoid CB1/A2A have all been observed, as well as CB1/A2A/D2 heterotrimers, and the functional significance and endogenous role of these hybrid receptors is still only starting to be unravelled.
The receptor's role in immunomodulation in the context of cancer has suggested that it is an important immune checkpoint molecule.
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 A2A receptor binds with the Gs protein at the intracellular site of the receptor. The Gs protein consists of three subunits; Gsα, Gsβ and Gsγ. A crystal structure of the A2A receptor bound with the agonist NECA and a G protein-mimic has been published in 2016 (PDB code: 5g53).
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, and Parkinson's disease.
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.
Adenosine A2A receptor has been shown to interact with Dopamine receptor D2. 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. 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). Interactions with FOXP3 stimulates CD4+ T-cells into regulatory Treg cells further inhibiting immune response.
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. 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. 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. 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.
^Libert F, Parmentier M, Lefort A, Dinsart C, Van Sande J, Maenhaut C, et al. (May 1989). "Selective amplification and cloning of four new members of the G protein-coupled receptor family". Science. 244 (4904): 569–72. doi:10.1126/science.2541503. PMID2541503.
^Libert F, Passage E, Parmentier M, Simons MJ, Vassart G, Mattei MG (September 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. PMID1662665.
^Fuxe K, Ferré S, Canals M, Torvinen M, Terasmaa A, Marcellino D, et al. (2005). "Adenosine A2A and dopamine D2 heteromeric receptor complexes and their function". Journal of Molecular Neuroscience. 26 (2–3): 209–20. doi:10.1385/JMN:26:2-3:209. PMID16012194.
^Torvinen M, Marcellino D, Canals M, Agnati LF, Lluis C, Franco R, Fuxe K (February 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. PMID15539641.
^Marcellino D, Carriba P, Filip M, Borgkvist A, Frankowska M, Bellido I, et al. (April 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. PMID18262573.
^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. doi:10.2174/138161208784480072. PMID18537671.
^Morelli M, Di Paolo T, Wardas J, Calon F, Xiao D, Schwarzschild MA (December 2007). "Role of adenosine A2A receptors in parkinsonian motor impairment and l-DOPA-induced motor complications". Progress in Neurobiology. 83 (5): 293–309. doi:10.1016/j.pneurobio.2007.07.001. PMID17826884.
^Baraldi PG, Cacciari B, Romagnoli R, Spalluto G, Monopoli A, Ongini E, et al. (January 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. doi:10.1021/jm010924c. PMID11754583.
^Baraldi PG, Fruttarolo F, Tabrizi MA, Preti D, Romagnoli R, El-Kashef H, et al. (March 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. doi:10.1021/jm021023m. PMID12646033.
^Weiss SM, Benwell K, Cliffe IA, Gillespie RJ, Knight AR, Lerpiniere J, et al. (December 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. PMID14663021.
^Cristalli G, Cacciari B, Dal Ben D, Lambertucci C, Moro S, Spalluto G, Volpini R (March 2007). "Highlights on the development of A(2A) adenosine receptor agonists and antagonists". ChemMedChem. 2 (3): 260–81. doi:10.1002/cmdc.200600193. PMID17177231.
^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. PMID18537675.
^Gillespie RJ, Adams DR, Bebbington D, Benwell K, Cliffe IA, Dawson CE, et al. (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. PMID18406614.
^Gillespie RJ, Cliffe IA, Dawson CE, Dourish CT, Gaur S, Giles PR, et al. (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. PMID18407496.
^Gillespie RJ, Cliffe IA, Dawson CE, Dourish CT, Gaur S, Jordan AM, et al. (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. PMID18411049.
^Sullivan GW (November 2003). "Adenosine A2A receptor agonists as anti-inflammatory agents". Current Opinion in Investigational Drugs. 4 (11): 1313–9. PMID14758770.
^Lappas CM, Sullivan GW, Linden J (July 2005). "Adenosine A2A agonists in development for the treatment of inflammation". Expert Opinion on Investigational Drugs. 14 (7): 797–806. doi:10.1517/13543722.214.171.1247. PMID16022569.
^Kaster MP, Rosa AO, Rosso MM, Goulart EC, Santos AR, Rodrigues AL (January 2004). "Adenosine administration produces an antidepressant-like effect in mice: evidence for the involvement of A1 and A2A receptors". Neuroscience Letters. 355 (1–2): 21–4. doi:10.1016/j.neulet.2003.10.040. PMID14729225.
^Lobato KR, Binfaré RW, Budni J, Rosa AO, Santos AR, Rodrigues AL (May 2008). "Involvement of the adenosine A1 and A2A receptors in the antidepressant-like effect of zinc in the forced swimming test". Progress in Neuro-Psychopharmacology & Biological Psychiatry. 32 (4): 994–9. doi:10.1016/j.pnpbp.2008.01.012. PMID18289757.
^Burton JH, Mass M, Menegazzi JJ, Yealy DM (August 1997). "Aminophylline as an adjunct to standard advanced cardiac life support in prolonged cardiac arrest". Annals of Emergency Medicine. 30 (2): 154–8. doi:10.1016/S0196-0644(97)70134-3. PMID9250637.
^Khoury MY, Moukarbel GV, Obeid MY, Alam SE (May 2001). "Effect of aminophylline on complete atrioventricular block with ventricular asystole following blunt chest trauma". Injury. 32 (4): 335–8. doi:10.1016/S0020-1383(00)00222-9. PMID11325371.
^Perouansky M, Shamir M, Hershkowitz E, Donchin Y (July 1998). "Successful resuscitation using aminophylline in refractory cardiac arrest with asystole". Resuscitation. 38 (1): 39–41. doi:10.1016/S0300-9572(98)00079-3. PMID9783508.
^Viskin S, Belhassen B, Roth A, Reicher M, Averbuch M, Sheps D, et al. (February 1993). "Aminophylline for bradyasystolic cardiac arrest refractory to atropine and epinephrine". Annals of Internal Medicine. 118 (4): 279–81. doi:10.7326/0003-4819-118-4-199302150-00006. PMID8420445.
^Mori A, Shindou T (December 2003). "Modulation of GABAergic transmission in the striatopallidal system by adenosine A2A receptors: a potential mechanism for the antiparkinsonian effects of A2A antagonists". Neurology. 61 (11 Suppl 6): S44–8. doi:10.1212/01.WNL.0000095211.71092.A0. PMID14663009.
^Pinna A, Wardas J, Simola N, Morelli M (November 2005). "New therapies for the treatment of Parkinson's disease: adenosine A2A receptor antagonists". Life Sciences. 77 (26): 3259–67. doi:10.1016/j.lfs.2005.04.029. PMID15979104.
^Kelsey JE, Langelier NA, Oriel BS, Reedy C (January 2009). "The effects of systemic, intrastriatal, and intrapallidal injections of caffeine and systemic injections of A2A and A1 antagonists on forepaw stepping in the unilateral 6-OHDA-lesioned rat". Psychopharmacology. 201 (4): 529–39. doi:10.1007/s00213-008-1319-0. PMID18791705.
^Kase H, Aoyama S, Ichimura M, Ikeda K, Ishii A, Kanda T, et al. (December 2003). "Progress in pursuit of therapeutic A2A antagonists: the adenosine A2A receptor selective antagonist KW6002: research and development toward a novel nondopaminergic therapy for Parkinson's disease". Neurology. 61 (11 Suppl 6): S97–100. doi:10.1212/01.WNL.0000095219.22086.31. PMID14663020.
^Hodgson RA, Bertorelli R, Varty GB, Lachowicz JE, Forlani A, Fredduzzi S, et al. (July 2009). "Characterization of the potent and highly selective A2A receptor antagonists preladenant and SCH 412348 [7-[2-[4-2,4-difluorophenyl]-1-piperazinyl]ethyl]-2-(2-furanyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine] in rodent models of movement disorders and depression". The Journal of Pharmacology and Experimental Therapeutics. 330 (1): 294–303. doi:10.1124/jpet.108.149617. PMID19332567.
^Rose S, Jackson MJ, Smith LA, Stockwell K, Johnson L, Carminati P, Jenner P (September 2006). "The novel adenosine A2a receptor antagonist ST1535 potentiates the effects of a threshold dose of L-DOPA in MPTP treated common marmosets". European Journal of Pharmacology. 546 (1–3): 82–7. doi:10.1016/j.ejphar.2006.07.017. PMID16925991.
^Kamiya T, Saitoh O, Yoshioka K, Nakata H (June 2003). "Oligomerization of adenosine A2A and dopamine D2 receptors in living cells". Biochemical and Biophysical Research Communications. 306 (2): 544–9. doi:10.1016/S0006-291X(03)00991-4. PMID12804599.
^ abSitkovsky MV, Kjaergaard J, Lukashev D, Ohta A (October 2008). "Hypoxia-adenosinergic immunosuppression: tumor protection by T regulatory cells and cancerous tissue hypoxia". Clinical Cancer Research. 14 (19): 5947–52. doi:10.1158/1078-0432.CCR-08-0229. PMID18829471.
Furlong TJ, Pierce KD, Selbie LA, Shine J (September 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. PMID1331670.
Makujina SR, Sabouni MH, Bhatia S, Douglas FL, Mustafa SJ (October 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. PMID1426003.
Karlsten R, Gordh T, Post C (June 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. PMID1438021.
Libert F, Passage E, Parmentier M, Simons MJ, Vassart G, Mattei MG (September 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. PMID1662665.
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. PMID1835521.
Libert F, Parmentier M, Lefort A, Dinsart C, Van Sande J, Maenhaut C, et al. (May 1989). "Selective amplification and cloning of four new members of the G protein-coupled receptor family". Science. 244 (4904): 569–72. doi:10.1126/science.2541503. PMID2541503.
MacCollin M, Peterfreund R, MacDonald M, Fink JS, Gusella J (March 1994). "Mapping of a human A2a adenosine receptor (ADORA2) to chromosome 22". Genomics. 20 (2): 332–3. doi:10.1006/geno.1994.1181. PMID8020991.
Nonaka H, Ichimura M, Takeda M, Nonaka Y, Shimada J, Suzuki F, et al. (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. doi:10.1016/0922-4106(94)90159-7. PMID8088373.
Iwamoto T, Umemura S, Toya Y, Uchibori T, Kogi K, Takagi N, Ishii M (March 1994). "Identification of adenosine A2 receptor-cAMP system in human aortic endothelial cells". Biochemical and Biophysical Research Communications. 199 (2): 905–10. doi:10.1006/bbrc.1994.1314. PMID8135838.
Salmon JE, Brogle N, Brownlie C, Edberg JC, Kimberly RP, Chen BX, Erlanger BF (September 1993). "Human mononuclear phagocytes express adenosine A1 receptors. A novel mechanism for differential regulation of Fc gamma receptor function". Journal of Immunology. 151 (5): 2775–85. PMID8360491.
Le F, Townsend-Nicholson A, Baker E, Sutherland GR, Schofield PR (June 1996). "Characterization and chromosomal localization of the human A2a adenosine receptor gene: ADORA2A". Biochemical and Biophysical Research Communications. 223 (2): 461–7. doi:10.1006/bbrc.1996.0916. PMID8670304.
Jiang Q, Van Rhee AM, Kim J, Yehle S, Wess J, Jacobson KA (September 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. PMID8794889.
Ledent C, Vaugeois JM, Schiffmann SN, Pedrazzini T, El Yacoubi M, Vanderhaeghen JJ, et al. (August 1997). "Aggressiveness, hypoalgesia and high blood pressure in mice lacking the adenosine A2a receptor". Nature. 388 (6643): 674–8. doi:10.1038/41771. PMID9262401.
Koshiba M, Rosin DL, Hayashi N, Linden J, Sitkovsky MV (March 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. PMID10051547.
Borgland SL, Castañón M, Spevak W, Parkinson FE (December 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. doi:10.1139/cjpp-76-12-1132. PMID10326835.