Adenosine A_2A receptor

The adenosine A_2A receptor, also known as ADORA2A, is an adenosine receptor, and also denotes the human gene encoding it.^[5][6]

ADORA2A
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2YDO, 2YDV, 3EML, 3PWH, 3QAK, 3REY, 3RFM, 3UZA, 3UZC, 3VG9, 3VGA, 4EIY, 4UG2, 4UHR, 5IU4, 5IU7, 5IUA, 5IU8, 5IUB
Identifiers
Aliases	ADORA2A, adenosine A2a receptor, A2aR, ADORA2, RDC8
External IDs	OMIM: 102776 MGI: 99402 HomoloGene: 20166 GeneCards: ADORA2A
Gene location (Human) Chr. Chromosome 22 (human)^[1] Band 22q11.23 Start 24,417,879 bp^[1] End 24,442,357 bp^[1]
Gene location (Mouse) Chr. Chromosome 10 (mouse)^[2] Band 10|10 C1 Start 75,152,711 bp^[2] End 75,170,618 bp^[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in putamen caudate nucleus nucleus accumbens blood bone marrow right lobe of liver lymph node bone marrow cells appendix spleen Top expressed in olfactory tubercle superior frontal gyrus globus pallidus nucleus accumbens entorhinal cortex thymus blood extraocular muscle brown adipose tissue somite More reference expression data BioGPS More reference expression data
Gene ontology Molecular function G protein-coupled adenosine receptor activity G protein-coupled receptor activity signal transducer activity protein binding identical protein binding enzyme binding alpha-actinin binding type 5 metabotropic glutamate receptor binding protein heterodimerization activity Cellular component integral component of membrane membrane plasma membrane integral component of plasma membrane intermediate filament endomembrane system postsynaptic density axon dendrite axolemma asymmetric synapse presynaptic membrane neuronal cell body postsynaptic membrane presynaptic active zone integral component of postsynaptic membrane integral component of presynaptic membrane glutamatergic synapse Golgi membrane Biological process cAMP biosynthetic process G protein-coupled adenosine receptor signaling pathway sensory perception adenylate cyclase-modulating G protein-coupled receptor signaling pathway cell-cell signaling blood coagulation blood circulation cellular defense response central nervous system development phagocytosis inflammatory response signal transduction apoptotic process synaptic transmission, dopaminergic response to amphetamine regulation of transcription, DNA-templated negative regulation of protein kinase activity protein kinase C-activating G protein-coupled receptor signaling pathway synaptic transmission, cholinergic locomotory behavior negative regulation of cell population proliferation positive regulation of glutamate secretion positive regulation of acetylcholine secretion, neurotransmission regulation of norepinephrine secretion response to caffeine positive regulation of synaptic transmission, GABAergic synaptic transmission, glutamatergic positive regulation of urine volume positive regulation of renal sodium excretion negative regulation of locomotion vasodilation eating behavior negative regulation of vascular permeability negative regulation of cysteine-type endopeptidase activity involved in apoptotic process response to alkaloid negative regulation of neuron apoptotic process positive regulation of circadian sleep/wake cycle, sleep negative regulation of alpha-beta T cell activation astrocyte activation neuron projection morphogenesis positive regulation of protein secretion negative regulation of inflammatory response regulation of mitochondrial membrane potential membrane depolarization regulation of calcium ion transport positive regulation of synaptic transmission, glutamatergic excitatory postsynaptic potential inhibitory postsynaptic potential prepulse inhibition positive regulation of apoptotic signaling pathway G protein-coupled receptor signaling pathway adenylate cyclase-activating G protein-coupled receptor signaling pathway positive regulation of long-term synaptic potentiation regulation of synaptic vesicle exocytosis Sources:Amigo / QuickGO
Orthologs Species Human Mouse 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 Mb Chr 10: 75.15 – 75.17 Mb PubMed search ^[3] ^[4]
Wikidata
View/Edit Human View/Edit Mouse

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).^[7] 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'.^[8]

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,^[9][10] dopamine D₂/A_2A^[11] and D₃/A_2A,^[12] glutamate mGluR₅/A_2A^[13] and cannabinoid CB₁/A_2A^[14] have all been observed, as well as CB₁/A_2A/D₂ heterotrimers,^[15] and the functional significance and endogenous role of these hybrid receptors is still only starting to be unravelled.^[16][17][18]

The receptor's role in immunomodulation in the context of cancer has suggested that it is an important immune checkpoint molecule.^[19]

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).^[20]

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.^[21]

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.^[22]

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.^{[23][24][25][26][27][28][29]}

Ligands

A number of selective A_2A ligands have been developed,^[30] with several possible therapeutic applications.^[31]

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.^{[32][33][34][35][36][37][38]}

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.^{[39][40][41][42]}

Agonists

• ATL-146e^[43]
• YT-146/2-octynyladenosine^[44]
• CGS-21680^[43]
• DPMA (N6-(2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethyl)adenosine)^[43]
• Regadenoson
• UK-432,097
• Limonene ^{[citation needed]}
• LUF-5833 ^{[45] [46]}
• Zeatin riboside
• NECA (5′-(N-Ethylcarboxamido)adenosine)^[43]
• binodenoson^[43]
• Cannabidiol^[47]

Antagonists

• ATL-444^[48]
• Istradefylline (KW-6002)^[49]
• MSX-3^[50]
• Preladenant (SCH-420,814)^[51]
• SCH-58261^[52]
• SCH-412,348
• SCH-442,416
• ST-1535^[53]
• 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.^[54] 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.^[55] 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).^[56] Interactions with FOXP3 stimulates CD4+ T-cells into regulatory T_reg cells further inhibiting immune response.^[57]

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.^[55] 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. ^[58] Researchers believe that A2AR blockade could increase the efficacy of such treatments even further.^[56] 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.^[59] 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

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Further reading

• Russo EB (August 2011). "Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects". British Journal of Pharmacology. 163 (7): 1344–64. doi:10.1111/j.1476-5381.2011.01238.x. PMC 3165946. PMID 21749363.
• Ongini E, Adami M, Ferri C, Bertorelli R (October 1997). "Adenosine A2A receptors and neuroprotection". Annals of the New York Academy of Sciences. 825 (1 Neuroprotecti): 30–48. Bibcode:1997NYASA.825...30O. doi:10.1111/j.1749-6632.1997.tb48412.x. PMID 9369973. S2CID 20814890.
• 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. PMID 1331670.
• 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. PMID 1426003.
• 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. PMID 1438021.
• 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. 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. S2CID 23693441.
• 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. Bibcode:1989Sci...244..569L. doi:10.1126/science.2541503. PMID 2541503.
• Kim J, Wess J, van Rhee AM, Schöneberg T, Jacobson KA (June 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. doi:10.1074/jbc.270.23.13987. PMC 3427751. PMID 7775460.
• Szondy Z (December 1994). "Adenosine stimulates DNA fragmentation in human thymocytes by Ca(2+)-mediated mechanisms". The Biochemical Journal. 304. 304 ( Pt 3) (3): 877–85. doi:10.1042/bj3040877. PMC 1137415. PMID 7818494.
• 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. PMID 8020991.
• 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. PMID 8088373.
• 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. PMID 8135838.
• 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. doi:10.4049/jimmunol.151.5.2775. PMID 8360491. S2CID 30807862.
• Peterfreund RA, MacCollin M, Gusella J, Fink JS (January 1996). "Characterization and expression of the human A2a adenosine receptor gene". Journal of Neurochemistry. 66 (1): 362–8. doi:10.1046/j.1471-4159.1996.66010362.x. PMID 8522976. S2CID 12017755.
• 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. PMID 8670304.
• 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. PMC 3418326. PMID 8794889.
• 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. Bibcode:1997Natur.388..674L. doi:10.1038/41771. PMID 9262401. S2CID 2662174.
• 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. PMID 10051547.
• 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. PMID 10326835.

External links

• Human ADORA2A genome location and ADORA2A gene details page in the UCSC Genome Browser.