Disease relevance of ADORA2A

• The results indicate that the acute treatment with adenosine A2A receptor antagonists may have a limited value in treatment of global ischemia [1].
• Cerebral ischemia in gerbils: effects of acute and chronic treatment with adenosine A2A receptor agonist and antagonist [1].
• A neuroprotective effect of adenosine A2A receptor antagonists was also shown in animal models of Parkinson's disease (MPTP, 6-OHDA, methamphetamine) [2].
• These results suggest that selective adenosine A2A receptor antagonists represent a new class of antiparkinsonian agents that improve disability without producing hyperactivity and without inducing dyskinesia [3].
• Adenosine A2A receptor activation reduces proinflammatory events and decreases cell death following intracerebral hemorrhage [4].

Psychiatry related information on ADORA2A

• We have undertaken an analysis of several DNA sequence variations in the adenosine 2A receptor (ADORA2A) in a large sample of panic disorder pedigrees [5].
• Analyses carried out by broadening the panic disorder phenotype to include agoraphobia continued to support linkage to ADORA2A [5].
• Adenosine A2A receptor dysfunction correlates with age at onset anticipation in blood platelets of subjects with Huntington's disease [6].
• Administration of the adenosine A2A receptor agonist 2-[p-[2-(2-aminoethylamino) carbonylethyl] phenethyl amino]-5'-N-ethylcarboxamidoadenosine (APEC) dose dependently suppressed basal locomotor activity [7].
• Evidence suggests that the adenosine A2a receptor (A2aAR) may be implicated in the pathogenesis of mood disorders [8].

High impact information on ADORA2A

• Adenosine A2A receptor activation reduces hepatic ischemia reperfusion injury by inhibiting CD1d-dependent NKT cell activation [9].
• Adenosine A2A receptor antagonists as new agents for the treatment of Parkinson's disease [10].
• The novel adenosine A2A receptor antagonist KW-6002 has been examined for antiparkinsonian activity in MPTP-treated primates [3].
• In vivo effects were studied in a bleomycin-induced dermal fibrosis model using adenosine A2A receptor-deficient wild-type littermate mice, C57BL/6 mice, and mice treated with adenosine A2A receptor antagonist [11].
• RESULTS: Adenosine A2A receptor occupancy promoted collagen production by primary human dermal fibroblasts, which was blocked by adenosine A2A, but not A1 or A2B, receptor antagonism [11].

Chemical compound and disease context of ADORA2A

• The adenosine A2a receptor (A2aAR) is thought to be implicated in the pathogenesis of panic disorder because caffeine, a potent antagonist for A2aAR, can precipitate panic attacks, and because disruption of the A2aAR gene increased anxiety-behaviors in mice [12].
• Modulation of orphan nuclear receptor NURR1 expression by methotrexate in human inflammatory joint disease involves adenosine A2A receptor-mediated responses [13].
• Given the implications with respect to the pathogenesis of dopaminergic dysfunction in schizophrenia and Parkinson's disease (PD), as well as the reciprocal antagonistic interactions between adenosine A2a receptor (A2aAR) and the dopamine D2 receptors, A2aAR may be a candidate gene conferring susceptibility to PD or schizophrenia [14].
• Blockade of the adenosine A2A receptor potentiates the effects of levodopa in experimental animals and may offer a novel nondopaminergic target for drug therapy in Parkinson's disease (PD) [15].
• Kyowa Hakko is developing KW-6002, an adenosine A2A receptor antagonist, for the potential treatment of Parkinson's disease (PD) [183211] [16].

Biological context of ADORA2A

• Our findings provide evidence for a susceptibility locus for panic disorder, and possibly including agoraphobia, either within the ADORA2A gene or in a nearby region of chromosome 22, and serves as the first successful candidate gene replication study in panic disorder [5].
• Association tests were not significant for any of the five ADORA2A SNPs [5].
• Pairwise estimations of linkage disequilibrium between the SNPs showed strong patterns of linkage disequilibrium across the ADORA2A locus [5].
• Individuals from 70 panic disorder pedigrees, and 83 child-parent 'trios', were genotyped at five single-nucleotide polymorphisms (SNPs) in and near the ADORA2A gene and were analyzed for genetic linkage and association [5].
• Two overlapping cosmids containing the hA2aR gene were isolated from a chromosome 22 library and characterized [17].

Anatomical context of ADORA2A

• Expression in the basal ganglia is consistent with a role for the hA2aR in motor control [17].
• By northern blot analysis, high expression of the hA2aR gene was identified in the caudate nucleus with low levels of expression in other brain regions [17].
• Stably transfected cell lines bound a variety of adenosine agonists and antagonists with affinities characteristic of a brain adenosine A2a receptor [18].
• Theophylline induces neutrophil apoptosis through adenosine A2A receptor antagonism [19].
• This study was designed to determine whether theophylline would augment granulocyte apoptosis via a mechanism of adenosine A2A receptor antagonism [19].

Associations of ADORA2A with chemical compounds

• Characterization and chromosomal localization of the human A2a adenosine receptor gene: ADORA2A [20].
• Adenosine A2A receptor and dopamine D3 receptor interactions: evidence of functional A2A/D3 heteromeric complexes [21].
• Neither 5'-N-ethylcarboxamidoadenosine (NECA), a mixed adenosine A1 and A2 receptor agonist, nor CGS 21680, a selective adenosine A2A receptor agonist, affected nucleoside release [22].
• The selective adenosine A2A receptor antagonist, 4-[2-[7-amino-2-(2-furyl)(1,2,4)-triazin-5-ylamino]-ethyl]ph enol (ZM241385) (50 nM), increased the release of glutamate (three- to four-fold) and of aspartate (nearly two-fold) upon iodoacetic acid-induced glycolysis inhibition, in the presence or in the absence of Ca2+ [23].
• Chlorofuryl-triazolo-quinazolinamine (CGS-15943; 1 micromol/L), an adenosine A1 and A2 receptor antagonist, and aminofuryltriazolotriazinyl-aminoethylphenol (ZM-241385; 1 micromol/L), a selective adenosine A2a receptor antagonist, inhibited the effect of CGS-21680 [24].

Physical interactions of ADORA2A

• Biochemical identification of the dopamine D2 receptor domains interacting with the adenosine A2A receptor [25].
• 4. It is concluded that in human lymphocyte membranes [3H]-SCH 58261 directly labels binding sites showing the characteristic properties of the adenosine A2A-receptor [26].

Co-localisations of ADORA2A

• These results demonstrate that there is a high expression of adenosine A2A receptor mRNA in the primate striatum that is extensively co-localized with dopamine D2 receptor and preproenkephalin A mRNAs [27].

Regulatory relationships of ADORA2A

• Virtually all adenosine A2A receptor mRNA-containing neurons co-expressed dopamine D2 receptor mRNA, whereas only very few adenosine A2A receptor mRNA containing neurons co-expressed dopamine D1 receptor or substance P mRNAs [27].
• Adenosine A2A receptor stimulation increases angiogenesis by down-regulating production of the antiangiogenic matrix protein thrombospondin 1 [28].

Other interactions of ADORA2A

• Adenosine A2a receptor/dopamine D2 receptor hetero-oligomerization: a hypothesis that may explain behavioral sensitization to psychostimulants and schizophrenia [29].
• The cDNA of an unidentified recently cloned G protein-coupled receptor, RDC8, has been expressed in Y1 adrenal cells, in dog thyrocytes in primary culture and in Xenopus oocytes [30].
• Arachidonic acid activates phospholipase D in human neutrophils; essential role of endogenous leukotriene B4 and inhibition by adenosine A2A receptor engagement [31].
• These results indicate that the angiogenic effects of adenosine A2A receptor activation are, at least in part, caused by the suppression of TSP1 secretion [28].
• 1. The present study describes for the first time the characterization of the adenosine A2A receptor in human lymphocyte membranes with the new potent and selective antagonist radioligand, [3H]-5-amino-7-(2-phenylethyl)-2-(2-furyl)-pyrazolo [4,3-e]-1,2,4 triazolo [1,5-c] pyrimidine, ([3H]-SCH 58261) [26].

Analytical, diagnostic and therapeutic context of ADORA2A

• Human genomic Southern blot analysis demonstrates the presence of a single gene encoding the hA2aR located on chromosome 22 [17].
• Southern blot and sequence analyses demonstrate that the hA2aR gene spans approximately 9-10 kb with a single intron interrupting the coding sequence between the regions encoding transmembrane domains III and IV [17].
• The cellular expression of adenosine A2A receptor mRNA in the adult monkey and human striatum was examined by using single and double in situ hybridization with ribonucleotide probes [27].
• Site-directed mutagenesis of the human adenosine A2A receptor. Critical involvement of Glu13 in agonist recognition [32].
• This pharmacology is consistent with the literature for A2AR and suggests that Sf9 cells co-expressing A2AR, beta1, gamma2, and XLGalphaolf could serve as a heterologous expression system for A2AR drug screening [33].

References