Adenosine A2A receptor

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Adenosine A2a receptor
A2A receptor bilayer.png
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols ADORA2A ; A2aR; ADORA2; RDC8
External IDs OMIM102776 MGI99402 HomoloGene20166 IUPHAR: A2A ChEMBL: 251 GeneCards: ADORA2A Gene
RNA expression pattern
PBB GE ADORA2A 205013 s at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 135 11540
Ensembl ENSG00000128271 ENSMUSG00000020178
UniProt P29274 Q60613
RefSeq (mRNA) NM_000675 NM_009630
RefSeq (protein) NP_000666 NP_033760
Location (UCSC) Chr 22:
24.81 – 24.84 Mb
Chr 10:
75.32 – 75.33 Mb
PubMed search [1] [2]

The adenosine A2A receptor, also known as ADORA2A, is an adenosine receptor, but also denotes the human gene encoding it.[1][2]

Structure[edit]

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).[3]

Heteromers[edit]

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,[4][5] dopamine D2/A2A[6] and D3/A2A,[7] glutamate mGluR5/A2A[8] and cannabinoid CB1/A2A[9] have all been observed, as well as CB1/A2A/D2 heterotrimers,[10] and the functional significance and endogenous role of these hybrid receptors is still only starting to be unravelled.[11][12][13]

Function[edit]

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, which is a competitive antagonist of this protein.[14]

Physiological role[edit]

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.[15]

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.[16][17][18][19][20][21][22]

Ligands[edit]

A number of selective A2A ligands have been developed,[23][24][25][26][27][28][29][30][31][32][33][34] with several possible therapeutic applications.[35][36][37][38][39][40] 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.[41][42][43][44][45][46][47]

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.[48][49][50][51]

Agonists[edit]

Antagonists[edit]

Interactions[edit]

Adenosine A2A receptor has been shown to interact with Dopamine receptor D2.[60] As a result, Adenosine receptor A2A decreases activity in the Dopamine D2 receptors.

References[edit]

  1. ^ 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 (New York, N.Y.) 244 (4904): 569–72. doi:10.1126/science.2541503. PMID 2541503. 
  2. ^ Libert F, Passage E, Parmentier M, Simons M, Vassart G, Mattei M (Sep 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. 
  3. ^ Jaakola V, Griffith M, Hanson M, Cherezov V, Chien E, Lane J et al. (Nov 2008). "The 2.6 angstrom crystal structure of a human A2A adenosine receptor bound to an antagonist". Science (New York, N.Y.) 322 (5905): 1211–7. doi:10.1126/science.1164772. PMC 2586971. PMID 18832607. 
  4. ^ Ciruela F, Casadó V, Rodrigues R, Luján R, Burgueño J, Canals M et al. (Feb 2006). "Presynaptic control of striatal glutamatergic neurotransmission by adenosine A1-A2A receptor heteromers". The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 26 (7): 2080–7. doi:10.1523/JNEUROSCI.3574-05.2006. PMID 16481441. 
  5. ^ Ferre S, Ciruela F, Borycz J, Solinas M, Quarta D, Antoniou K et al. (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. doi:10.2741/2852. PMID 17981720. 
  6. ^ 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 : MN 26 (2-3): 209–20. doi:10.1385/JMN:26:2-3:209. PMID 16012194. 
  7. ^ Torvinen M, Marcellino D, Canals M, Agnati L, Lluis C, Franco R et al. (Feb 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. PMID 15539641. 
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Further reading[edit]

  • Ongini E, Adami M, Ferri C, Bertorelli R (Oct 1997). "Adenosine A2A receptors and neuroprotection". Annals of the New York Academy of Sciences 825 (1 Neuroprotecti): 30–48. doi:10.1111/j.1749-6632.1997.tb48412.x. PMID 9369973. 
  • Furlong T, Pierce K, Selbie L, Shine J (Sep 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 S, Sabouni M, Bhatia S, Douglas F, Mustafa S (Oct 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 (Jun 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 M, Vassart G, Mattei M (Sep 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 M, Probst A, Palacios J (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. 
  • 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 (New York, N.Y.) 244 (4904): 569–72. doi:10.1126/science.2541503. PMID 2541503. 
  • Kim J, Wess J, van Rhee A, Schöneberg T, Jacobson K (Jun 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 (Dec 1994). "Adenosine stimulates DNA fragmentation in human thymocytes by Ca(2+)-mediated mechanisms". The Biochemical Journal. 304. 304 ( Pt 3): 877–85. PMC 1137415. PMID 7818494. 
  • MacCollin M, Peterfreund R, MacDonald M, Fink J, Gusella J (Mar 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 et al. (Mar 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. 
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