Adenosine A2A receptor
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| Location (UCSC) | Chr 22: 24.42 – 24.44 Mb | Chr 10: 75.15 – 75.17 Mb | |||||||
| PubMed search | [3] | [4] | |||||||
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The adenosine A2A receptor, also known as ADORA2A, is an adenosine receptor, and also denotes the human gene encoding it.[5][6]
Structure
This protein is a member of the
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'.[8]
Heteromers
The actions of the A2A receptor are complicated by the fact that a variety of functional
CB1/A2A[14] have all been observed, as well as CB1/A2A/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 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).[20]
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.[21]
Physiological role
A1 and A2A receptors are believed to regulate myocardial oxygen demand and to increase coronary circulation by vasodilation. In addition, A2A receptor can suppress immune cells, thereby protecting tissue from inflammation.[22]
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.[23][24][25][26][27][28][29]
Ligands
A number of selective A2A 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 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.[39][40][41][42]
Agonists
- Adenosine
- ATL-146e[43]
- Binodenoson[43]
- Cannabidiol[44]
- CGS-21680[43]
- DPMA (N6-(2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethyl)adenosine)[43]
- Limonene [citation needed]
- LUF-5833[45][46]
- NECA (5′-(N-ethylcarboxamido)adenosine)[43]
- Regadenoson
- UK-432,097
- YT-146 (2-octynyladenosine)[47]
- Zeatin riboside
Antagonists
- ATL-444[48]
- Caffeine
- Istradefylline (KW-6002)[49]
- Lu AA41063
- Lu AA47070
- MSX-2
- MSX-3[50]
- Preladenant (SCH-420,814)[51]
- MSX-3
- SCH-58261[52]
- SCH-412,348
- SCH-442,416
- ST-1535[53]
- Theophylline
- VER-6623
- VER-6947
- VER-7835
- Vipadenant (BIIB-014)
- ZM-241,385
Inverse agonists
- KW-6356[54]
Interactions
Adenosine A2A receptor has been shown to interact with Dopamine receptor D2.[55] 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
transforming growth factor-beta (TGF-β) and inhibitory receptors (i.e., PD-1).[57] Interactions with FOXP3 stimulates CD4+ T-cells into regulatory Treg cells further inhibiting immune response.[58]
Blockade of A2AR has been attempted to various ends, namely
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.[60]
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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- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000020178 – Ensembl, May 2017
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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): 1344–1364. 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. 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): 62–66. 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): 243–247. 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): 434–438. 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): 225–227. 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. 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): 569–572. 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): 13987–13997. 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) (Pt 3): 877–885. 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): 332–333. 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): 335–341. PMID 8088373.
- Iwamoto T, Umemura S, Toya Y, Uchibori T, Kogi K, Takagi N, et al. (March 1994). "Identification of adenosine A2 receptor-cAMP system in human aortic endothelial cells". Biochemical and Biophysical Research Communications. 199 (2): 905–910. PMID 8135838.
- Salmon JE, Brogle N, Brownlie C, Edberg JC, Kimberly RP, Chen BX, et al. (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): 2775–2785. 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): 362–368. S2CID 12017755.
- Le F, Townsend-Nicholson A, Baker E, 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): 512–521. 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): 674–678. 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): 614–624. 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): 1132–1138. PMID 10326835.
External links
- Human ADORA2A genome location and ADORA2A gene details page in the UCSC Genome Browser.