Adenosine A2A receptor explained

The adenosine A_2A receptor, also known as ADORA2A, is an adenosine receptor, and also denotes the human gene encoding it.^{[1] [2]}

Structure

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 A_2A receptor reveals a ligand binding pocket distinct from that of other structurally determined GPCRs (i.e., the beta-2 adrenergic receptor and rhodopsin).^[3] Below this primary (orthosteric) binding pocket lies a secondary (allosteric) binding pocket. The crystal-structure of A_2A 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'.^[4]

Heteromers

The actions of the A_2A receptor are complicated by the fact that a variety of functional heteromers composed of a mixture of A_2A 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/A_2A,^{[5] [6]} dopamine D₂/A_2A^[7] and D₃/A_2A,^[8] glutamate mGluR₅/A_2A^[9] and cannabinoid CB₁/A_2A^[10] have all been observed, as well as CB₁/A_2A/D₂ heterotrimers,^[11] and the functional significance and endogenous role of these hybrid receptors is still only starting to be unravelled.^{[12] [13] [14]}

The receptor's role in immunomodulation in the context of cancer has suggested that it is an important immune checkpoint molecule.^[15]

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 A_2A receptor binds with the G_s protein at the intracellular site of the receptor. The G_s protein consists of three subunits; G_sα, G_sβ and G_sγ. A crystal structure of the A_2A receptor bound with the agonist NECA and a G protein-mimic has been published in 2016 (PDB code: 5g53).^[16]

The encoded protein (the A_2A 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

A₁ and A_2A receptors are believed to regulate myocardial oxygen demand and to increase coronary circulation by vasodilation. In addition, A_2A receptor can suppress immune cells, thereby protecting tissue from inflammation.^[18]

The A_2A 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.^{[19] [20] [21] [22] [23] [24] [25]}

Ligands

A number of selective A_2A ligands have been developed,^[26] with several possible therapeutic applications.^[27]

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.^{[28] [29] [30] [31] [32] [33] [34]}

However the development of more highly selective A_2A ligands has led towards other applications, with the most significant focus of research currently being the potential therapeutic role for A_2A antagonists in the treatment of Parkinson's disease.^{[35] [36] [37] [38]}

Agonists

• ATL-146e^[39]
• YT-146/2-octynyladenosine^[40]
• CGS-21680^[39]
• DPMA (N6-(2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethyl)adenosine)^[39]
• Regadenoson
• UK-432,097
  • Limonene LUF-5833 ^{[41] [42]}
• Zeatin riboside
• NECA (5′-(N-Ethylcarboxamido)adenosine)^[39]
• binodenoson^[39]
• Cannabidiol^[43]

Antagonists

• ATL-444^[44]
• Istradefylline (KW-6002)^[45]
• MSX-3^[46]
• Preladenant (SCH-420,814)^[47]
• SCH-58261^[48]
• SCH-412,348
• SCH-442,416
• ST-1535^[49]
• Caffeine
• VER-6623
• VER-6947
• VER-7835
• Vipadenant (BIIB-014)
• ZM-241,385

Interactions

Adenosine A2A receptor has been shown to interact with Dopamine receptor D2.^[50] 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, it 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.^[51] Abundant extracellular adenosine can then bind to the A2A receptor resulting in a G_s-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).^[52] Interactions with FOXP3 stimulates CD4+ T-cells into regulatory T_reg cells further inhibiting immune response.^[53]

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. The A2AR antogonist CPI-444 has shown this in combination with anti-PD-L1 or anti-CTLA-4 treatment as it eliminated tumors in up to 90% of treated mice, including restoration of immune responses in models that incompletely responded to anti-PD-L1 or anti-CTLA-4 monotherapy. Further, tumor growth was fully inhibited when mice with cleared tumors were later rechallenged, indicating that CPI-444 induced systemic antitumor immune memory. ^[54] 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.^[55] 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.

Further reading

• Russo EB . Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects . British Journal of Pharmacology . 163 . 7 . 1344–64 . August 2011 . 21749363 . 3165946 . 10.1111/j.1476-5381.2011.01238.x .
• Ongini E, Adami M, Ferri C, Bertorelli R . Adenosine A2A receptors and neuroprotection . Annals of the New York Academy of Sciences . 825 . 1 Neuroprotecti . 30–48 . October 1997 . 9369973 . 10.1111/j.1749-6632.1997.tb48412.x . 1997NYASA.825...30O . 20814890 .
• Furlong TJ, Pierce KD, Selbie LA, Shine J . Molecular characterization of a human brain adenosine A2 receptor . Brain Research. Molecular Brain Research . 15 . 1–2 . 62–6 . September 1992 . 1331670 . 10.1016/0169-328X(92)90152-2 .
• Makujina SR, Sabouni MH, Bhatia S, Douglas FL, Mustafa SJ . Vasodilatory effects of adenosine A2 receptor agonists CGS 21680 and CGS 22492 in human vasculature . European Journal of Pharmacology . 221 . 2–3 . 243–7 . October 1992 . 1426003 . 10.1016/0014-2999(92)90708-C .
• Karlsten R, Gordh T, Post C . 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 . June 1992 . 1438021 . 10.1111/j.1600-0773.1992.tb00503.x .
• Libert F, Passage E, Parmentier M, Simons MJ, Vassart G, Mattei MG . Chromosomal mapping of A1 and A2 adenosine receptors, VIP receptor, and a new subtype of serotonin receptor . Genomics . 11 . 1 . 225–7 . September 1991 . 1662665 . 10.1016/0888-7543(91)90125-X .
• Martinez-Mir MI, Probst A, Palacios JM . Adenosine A2 receptors: selective localization in the human basal ganglia and alterations with disease . Neuroscience . 42 . 3 . 697–706 . 1992 . 1835521 . 10.1016/0306-4522(91)90038-P . 23693441 .
• Libert F, Parmentier M, Lefort A, Dinsart C, Van Sande J, Maenhaut C, Simons MJ, Dumont JE, Vassart G . 6 . Selective amplification and cloning of four new members of the G protein-coupled receptor family . Science . 244 . 4904 . 569–72 . May 1989 . 2541503 . 10.1126/science.2541503 . 1989Sci...244..569L .
• Kim J, Wess J, van Rhee AM, Schöneberg T, Jacobson KA . Site-directed mutagenesis identifies residues involved in ligand recognition in the human A2a adenosine receptor . The Journal of Biological Chemistry . 270 . 23 . 13987–97 . June 1995 . 7775460 . 3427751 . 10.1074/jbc.270.23.13987 . free .
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• Salmon JE, Brogle N, Brownlie C, Edberg JC, Kimberly RP, Chen BX, Erlanger BF . 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 . September 1993 . 10.4049/jimmunol.151.5.2775 . 8360491 . 30807862 . free .
• Peterfreund RA, MacCollin M, Gusella J, Fink JS . Characterization and expression of the human A2a adenosine receptor gene . Journal of Neurochemistry . 66 . 1 . 362–8 . January 1996 . 8522976 . 10.1046/j.1471-4159.1996.66010362.x . 12017755 .
• Le F, Townsend-Nicholson A, Baker E, Sutherland GR, Schofield PR . Grant Robert Sutherland . Characterization and chromosomal localization of the human A2a adenosine receptor gene: ADORA2A . Biochemical and Biophysical Research Communications . 223 . 2 . 461–7 . June 1996 . 8670304 . 10.1006/bbrc.1996.0916 .
• Jiang Q, Van Rhee AM, Kim J, Yehle S, Wess J, Jacobson KA . 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 . September 1996 . 8794889 . 3418326 .
• Ledent C, Vaugeois JM, Schiffmann SN, Pedrazzini T, El Yacoubi M, Vanderhaeghen JJ, Costentin J, Heath JK, Vassart G, Parmentier M . 6 . Aggressiveness, hypoalgesia and high blood pressure in mice lacking the adenosine A2a receptor . Nature . 388 . 6643 . 674–8 . August 1997 . 9262401 . 10.1038/41771 . 1997Natur.388..674L . 2662174 . free .
• Koshiba M, Rosin DL, Hayashi N, Linden J, Sitkovsky MV . 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 . March 1999 . 10051547 .
• Borgland SL, Castañón M, Spevak W, Parkinson FE . 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 . December 1998 . 10326835 . 10.1139/cjpp-76-12-1132 .

Notes and References

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2. Libert F, Passage E, Parmentier M, Simons MJ, Vassart G, Mattei MG . Chromosomal mapping of A1 and A2 adenosine receptors, VIP receptor, and a new subtype of serotonin receptor . Genomics . 11 . 1 . 225–7 . September 1991 . 1662665 . 10.1016/0888-7543(91)90125-X .

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