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Individual differences |
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Biological: Behavioural genetics · Evolutionary psychology · Neuroanatomy · Neurochemistry · Neuroendocrinology · Neuroscience · Psychoneuroimmunology · Physiological Psychology · Psychopharmacology (Index, Outline)
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 PDB 3EML (see figure to the right) reveals a ligand binding pocket distinct from that of other structurally determined GPCRs (i.e., the beta-2 adrenergic receptor and rhodopsin).
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. Hetereomers 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 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 is abundant in basal ganglia, vasculature, T lymphocytes, and platelets and it is a major target of caffeine.
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.
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.
A number of selective A2A ligands have been developed, with several possible therapeutic applications. 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.
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.
- YT-146 (2-(1-octynyl)adenosine)
- DPMA (N6-(2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethyl)adenosine)
- Istradefylline (KW-6002)
- Preladenant (SCH-420,814)
- Vipadenant (BIIB-014)
- ↑ 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.
- ↑ 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.
- ↑ Jaakola VP, Griffith MT, Hanson MA, Cherezov V, Chien EY, Lane JR, IJzerman AP, Stevens RC (October 2008). The 2.6 Angstrom Crystal Structure of a Human A2A Adenosine Receptor Bound to an Antagonist. Science 322 (5905): 1211–7.
- ↑ 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 (February 2006). Presynaptic control of striatal glutamatergic neurotransmission by adenosine A1-A2A receptor heteromers. Journal of Neuroscience 26 (7): 2080–7.
- ↑ 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 : a Journal and Virtual Library 13 (13): 2391–9.
- ↑ 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.
- ↑ 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.
- ↑ Zezula J, Freissmuth M (March 2008). The A(2A)-adenosine receptor: a GPCR with unique features?. British Journal of Pharmacology Suppl 1 (S1): S184–90.
- ↑ Ferré S, Goldberg SR, Lluis C, Franco R (2009). Looking for the role of cannabinoid receptor heteromers in striatal function. Neuropharmacology Suppl 1: 226–34.
- ↑ 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 (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.
- ↑ 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.
- ↑ Wardas J (2008). Potential role of adenosine A2A receptors in the treatment of schizophrenia. Frontiers in Bioscience : a Journal and Virtual Library 13 (13): 4071–96.
- ↑ 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.
- ↑ Entrez Gene: ADORA2A adenosine A2A receptor.
- ↑ 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.
- ↑ Hack SP, Christie MJ (2003). Adaptations in adenosine signaling in drug dependence: therapeutic implications. Critical Reviews in Neurobiology 15 (3-4): 235–74.
- ↑ 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.
- ↑ Schiffmann SN, Fisone G, Moresco R, Cunha RA, Ferré S (December 2007). Adenosine A2A receptors and basal ganglia physiology. Progress in Neurobiology 83 (5): 277–92.
- ↑ Ferré S, Diamond I, Goldberg SR, Yao L, Hourani SM, Huang ZL, Urade Y, Kitchen I (December 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.
- ↑ Brown RM, Short JL (November 2008). Adenosine A(2A) receptors and their role in drug addiction. The Journal of Pharmacy and Pharmacology 60 (11): 1409–30.
- ↑ 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.
- ↑ Mingote S, Font L, Farrar AM, Vontell R, Worden LT, Stopper CM, Port RG, Sink KS, Bunce JG, Chrobak JJ, Salamone JD (September 2008). Nucleus accumbens adenosine A2A receptors regulate exertion of effort by acting on the ventral striatopallidal pathway. Journal of Neuroscience 28 (36): 9037–46.
- ↑ Ongini E, Monopoli A, Cacciari B, Baraldi PG (2001). Selective adenosine A2A receptor antagonists. Farmaco (Società Chimica Italiana : 1989) 56 (1-2): 87–90.
- ↑ Baraldi PG, Cacciari B, Romagnoli R, Spalluto G, Monopoli A, Ongini E, Varani K, Borea PA (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.
- ↑ Baraldi PG, Fruttarolo F, Tabrizi MA, Preti D, Romagnoli R, El-Kashef H, Moorman A, Varani K, Gessi S, Merighi S, Borea PA (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.
- ↑ Weiss SM, Benwell K, Cliffe IA, Gillespie RJ, Knight AR, Lerpiniere J, Misra A, Pratt RM, Revell D, Upton R, Dourish CT (December 2003). Discovery of nonxanthine adenosine A2A receptor antagonists for the treatment of Parkinson's disease. Neurology 61 (11 Suppl 6): S101–6.
- ↑ 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.
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- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ Gillespie RJ, Cliffe IA, Dawson CE, Dourish CT, Gaur S, Jordan AM, Knight AR, Lerpiniere J, Misra A, Pratt RM, Roffey J, Stratton GC, Upton R, Weiss SM, Williamson DS (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.
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- ↑ 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.
- ↑ El Yacoubi M, Costentin J, Vaugeois JM (December 2003). Adenosine A2A receptors and depression. Neurology 61 (11 Suppl 6): S82–7.
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- ↑ Khoury MY, Moukarbel GV, Obeid MY, Alam SE (2001). Effect of aminophylline on complete atrioventricular block with ventricular asystole following blunt chest trauma. Injury 32 (4): 335–8.
- ↑ Mader TJ, Bertolet B, Ornato JP, Gutterman JM (2000). Aminophylline in the treatment of atropine-resistant bradyasystole. Resuscitation 47 (2): 105–12.
- ↑ Mader TJ, Smithline HA, Durkin L, Scriver G (2003). A randomized controlled trial of intravenous aminophylline for atropine-resistant out-of-hospital asystolic cardiac arrest. Academic Emergency Medicine 10 (3): 192–7.
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