Details for: ADORA2A

Gene ID: 135

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: ADORA2A

Ensembl ID: ENSG00000128271

Description: adenosine A2a receptor

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • double-positive, alpha-beta thymocyte CL0000809
    CSI 8.96
    rCSI 9.13%
    PRS 99.23
  • indirect pathway medium spiny neuron CL4023029
    CSI 1.16
    rCSI 27.96%
    PRS 93.13
  • platelet CL0000233
    CSI 0.97
    rCSI 4.01%
    PRS 95.82

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary [ADORA2A](/details-gene/135) encodes the adenosine A2a receptor, a G protein-coupled receptor (GPCR) that mediates the physiological effects of adenosine. Functionally, it is integral to the '[G alpha (s) signalling events](https://reactome.org/content/detail/R-HSA-418555)' pathway, leading to the activation of adenylate cyclase. Expression data indicates that **Overall**, [ADORA2A](/details-gene/135) is a highly significant gene in the immune system, particularly in developing T cells, with its highest significance observed in [double-positive, alpha-beta thymocyte](/details-cell/CL0000809). It also shows notable significance in the central nervous system within [indirect pathway medium spiny neuron](/details-cell/CL4023029)s and in hematopoietic lineages such as [platelet](/details-cell/CL0000233)s. Its clinical relevance is noted in OMIM entry '[102776](https://omim.org/entry/102776)'. ## Cellular Roles and Expression Landscape The expression profile of [ADORA2A](/details-gene/135) highlights its specialized roles in immunology and neurobiology. **Overall**, the gene's most profound significance is within the T cell lineage, demonstrated by a very high Cell Significance Index (CSI) of 8.96 in [double-positive, alpha-beta thymocyte](/details-cell/CL0000809)s. This strongly suggests a critical function during T cell development in the thymus, a role supported by its annotation in processes like '[Negative regulation of alpha-beta t cell activation (GO:0046636)](https://www.ebi.ac.uk/QuickGO/term/GO:0046636)' and '[Apoptotic process (GO:0006915)](https://www.ebi.ac.uk/QuickGO/term/GO:0006915)'. In the central nervous system, [ADORA2A](/details-gene/135) is a significant gene in [indirect pathway medium spiny neuron](/details-cell/CL4023029)s (CSI: 1.16). These neurons are key components of the basal ganglia circuits that control motor function, and the presence of [ADORA2A](/details-gene/135) is consistent with its established role in modulating dopaminergic signaling. Additionally, [ADORA2A](/details-gene/135) shows significance in [platelet](/details-cell/CL0000233)s (CSI: 0.97), where it is involved in regulating platelet aggregation and hemostasis, aligning with its function in '[Blood coagulation (GO:0007596)](https://www.ebi.ac.uk/QuickGO/term/GO:0007596)'. ## Pathways and Molecular Function [ADORA2A](/details-gene/135) functions as a canonical GPCR, primarily associated with the '[Adenosine p1 receptors](https://reactome.org/content/detail/R-HSA-417973)' pathway. Upon binding adenosine, it activates the '[G alpha (s) signalling events](https://reactome.org/content/detail/R-HSA-418555)' pathway, increasing intracellular cAMP levels. This mechanism is central to its diverse physiological roles. In the immune context, this signaling cascade is largely immunosuppressive. The gene's involvement in the '[Negative regulation of inflammatory response (GO:0050728)](https://www.ebi.ac.uk/QuickGO/term/GO:0050728)' and '[Negative regulation of alpha-beta t cell activation (GO:0046636)](https://www.ebi.ac.uk/QuickGO/term/GO:0046636)' is crucial for preventing excessive immune reactions and maintaining homeostasis. In the nervous system, [ADORA2A](/details-gene/135) is localized to neuronal structures such as the '[Postsynaptic membrane (GO:0045211)](https://www.ebi.ac.uk/QuickGO/term/GO:0045211)' and '[Glutamatergic synapse (GO:0098978)](https://www.ebi.ac.uk/QuickGO/term/GO:0098978)'. It plays a key role in modulating neurotransmitter release and neuronal excitability, as reflected by its association with '[Synaptic transmission, dopaminergic (GO:0001963)](https://www.ebi.ac.uk/QuickGO/term/GO:0001963)' and '[Positive regulation of synaptic transmission, glutamatergic (GO:0051968)](https://www.ebi.ac.uk/QuickGO/term/GO:0051968)'. Structurally, the receptor's function is modulated by interactions with other proteins, as evidenced by its binding activities with calmodulin ([GO:0005516](https://www.ebi.ac.uk/QuickGO/term/GO:0005516)) and alpha-actinin ([GO:0051393](https://www.ebi.ac.uk/QuickGO/term/GO:0051393)), and its structure has been resolved by X-ray crystallography ([Link](https://doi.org/10.1126/science.1164772)). ## Research Directions The specific expression patterns and well-defined signaling functions of [ADORA2A](/details-gene/135) suggest several avenues for future research. **Proposed Hypotheses:** 1. Given its exceptionally high significance in [double-positive, alpha-beta thymocyte](/details-cell/CL0000809)s and its role in regulating T cell activation and apoptosis, it is hypothesized that [ADORA2A](/details-gene/135) signaling acts as a critical rheostat during thymic negative selection. Specifically, high levels of adenosine in the thymic microenvironment may engage [ADORA2A](/details-gene/135) on strongly self-reactive thymocytes to trigger apoptosis, thereby preventing their maturation and egress. 2. Considering its expression in [indirect pathway medium spiny neuron](/details-cell/CL4023029)s and its functional opposition to dopamine D2 receptors, we hypothesize that selective antagonism of [ADORA2A](/details-gene/135) can restore motor control in animal models of Parkinson's disease by disinhibiting the indirect pathway and enhancing dopamine-like effects. **Experimental Approach:** To test the first hypothesis regarding the role of [ADORA2A](/details-gene/135) in thymic selection, a T cell-specific conditional knockout mouse model (e.g., *Adora2afl/fl;Lck-Cre*) could be generated. Thymocytes from these mice would be analyzed by flow cytometry to assess alterations in the proportions of developmental stages and the rate of apoptosis in response to T cell receptor stimulation. Furthermore, these mice should be monitored for the spontaneous development of autoimmune disease, which would indicate a failure of central tolerance. **Therapeutic Potential:** [ADORA2A](/details-gene/135) is a well-established and highly druggable therapeutic target. - **Inhibition:** In oncology, blocking [ADORA2A](/details-gene/135) on tumor-infiltrating lymphocytes is a promising strategy to counteract the immunosuppressive effects of adenosine in the tumor microenvironment, thereby enhancing anti-tumor immunity. This makes [ADORA2A](/details-gene/135) inhibitors prime candidates for combination therapies with checkpoint inhibitors. - **Activation:** Conversely, [ADORA2A](/details-gene/135) **agonists** could be beneficial for treating inflammatory conditions where dampening immune responses is desired. In neurodegenerative diseases like Parkinson's, **antagonists** are being investigated to alleviate motor symptoms by modulating basal ganglia circuitry. The challenge remains in achieving tissue-specific effects to minimize off-target side effects.

Genular Protein ID: 4080930424

Symbol: AA2AR_HUMAN

Name: Adenosine receptor A2a

UniProtKB Accession Codes:

P29274 B2R7E0

Database IDs:

ABCD 1 AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BindingDB 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CDD 1 CTD 1 ChEBI 4 ChEMBL 1 DMDM 1 DNASU 1 DisGeNET 1 DisProt 1 DrugBank 21 DrugCentral 1 EMBL 11 EMDB 3 Ensembl 4 EvolutionaryTrace 1 ExpressionAtlas 1 GO 68 Gene3D 1 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 GlyCosmos 1 GlyGen 1 GuidetoPHARMACOLOGY 1 HGNC 1 HPA 1 InParanoid 1 IntAct 1 InterPro 4 KEGG 1 MANE-Select 1 MIM 1 MINT 1 MalaCards 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 Orphanet 1 OrthoDB 1 PANTHER 2 PDB 77 PDBsum 77 PIR 1 PRINTS 3 PRO 1 PROSITE 2 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 1 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 1 RNAct 1 Reactome 4 RefSeq 5 SIGNOR 1 SMART 1 SMR 1 STRING 1 SUPFAM 1 SignaLink 1 TCDB 1 TreeFam 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 neXtProt 1

Citations:

PubMed ID: 1331670

Title: Molecular characterization of a human brain adenosine A2 receptor.

PubMed ID: 1331670

DOI: 10.1016/0169-328x(92)90152-2

PubMed ID: 8670304

Title: Characterization and chromosomal localization of the human A2a adenosine receptor gene: ADORA2A.

PubMed ID: 8670304

DOI: 10.1006/bbrc.1996.0916

PubMed ID: 15461802

Title: A genome annotation-driven approach to cloning the human ORFeome.

PubMed ID: 15461802

DOI: 10.1186/gb-2004-5-10-r84

PubMed ID: 14702039

Title: Complete sequencing and characterization of 21,243 full-length human cDNAs.

PubMed ID: 14702039

DOI: 10.1038/ng1285

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

PubMed ID: 17689978

Title: The neuronal Ca(2+) -binding protein 2 (NECAB2) interacts with the adenosine A(2A) receptor and modulates the cell surface expression and function of the receptor.

PubMed ID: 17689978

DOI: 10.1016/j.mcn.2007.05.007

PubMed ID: 20836733

Title: The dopamine D(4) receptor, the ultimate disordered protein.

PubMed ID: 20836733

DOI: 10.3109/10799893.2010.513842

PubMed ID: 7775460

Title: Site-directed mutagenesis identifies residues involved in ligand recognition in the human A2a adenosine receptor.

PubMed ID: 7775460

DOI: 10.1074/jbc.270.23.13987

PubMed ID: 16339847

Title: The ubiquitin-specific protease Usp4 regulates the cell surface level of the A2A receptor.

PubMed ID: 16339847

DOI: 10.1124/mol.105.015818

PubMed ID: 18832607

Title: The 2.6 angstrom crystal structure of a human A2A adenosine receptor bound to an antagonist.

PubMed ID: 18832607

DOI: 10.1126/science.1164772

PubMed ID: 21593763

Title: Agonist-bound adenosine A2A receptor structures reveal common features of GPCR activation.

PubMed ID: 21593763

DOI: 10.1038/nature10136

PubMed ID: 10391209

Title: Characterization of single-nucleotide polymorphisms in coding regions of human genes.

PubMed ID: 10391209

DOI: 10.1038/10290

Sequence Information:

  • Length: 412
  • Mass: 44707
  • Checksum: 9438E9D64A6BE61B
  • Sequence:
    • MPIMGSSVYI TVELAIAVLA ILGNVLVCWA VWLNSNLQNV TNYFVVSLAA ADIAVGVLAI 
PFAITISTGF CAACHGCLFI ACFVLVLTQS SIFSLLAIAI DRYIAIRIPL RYNGLVTGTR 
AKGIIAICWV LSFAIGLTPM LGWNNCGQPK EGKNHSQGCG EGQVACLFED VVPMNYMVYF 
NFFACVLVPL LLMLGVYLRI FLAARRQLKQ MESQPLPGER ARSTLQKEVH AAKSLAIIVG 
LFALCWLPLH IINCFTFFCP DCSHAPLWLM YLAIVLSHTN SVVNPFIYAY RIREFRQTFR 
KIIRSHVLRQ QEPFKAAGTS ARVLAAHGSD GEQVSLRLNG HPPGVWANGS APHPERRPNG 
YALGLVSGGS AQESQGNTGL PDVELLSHEL KGVCPEPPGL DDPLAQDGAG VS

Genular Protein ID: 2512058737

Symbol: A8K1F6_HUMAN

Name: N/A

UniProtKB Accession Codes:

A8K1F6

Database IDs:

ARBA 11 AlphaFoldDB 1 BioGRID-ORCS 1 CDD 1 CTD 1 DNASU 1 DisGeNET 1 EMBL 2 GO 3 Gene3D 1 InterPro 4 NCBI Taxonomy 1 OrthoDB 1 PANTHER 2 PRINTS 3 PROSITE 3 Pfam 1 RefSeq 2 RuleBase 1 SAM 1 SMART 1 SUPFAM 1

Sequence Information:

  • Length: 412
  • Mass: 44647
  • Checksum: 94255F04DDE1C75E
  • Sequence:
    • MPIMGSSVYI TVELAIAVLA ILGNVLVCWA VWLNSNLQNV TNYFVVSLAA ADIAVGVLAI 
PFAITISTGF CAACHGCLFI ACFVLVLTQS SIFSLLAIAI DRYIAIRIPL RYNGLVTGTR 
AKGIIAICWV LSFAIGLTPM LGWNNCGQPK EGKNHSQGCG EGQVACLFED VVPMNYMVYF 
NFFACVLVPL LLMLGVYLRI FLAARRQLKQ MESQPLPGER ARSTLQKEVH AAKSLAIIVG 
LFALCWLPLH IINCFTSFCP DCSHAPLWLM YLAIVLSHTN SVVNPFIYAY RIREFRQTFR 
KIIRSHVLRQ QEPFKAAGTS ARVLAAHGSD GEQVSLRLNG HPPGVWANGS APHPERRPNG 
YALGLVSGGS AQESQGNTGL PDVELLSHEL KGVCPEPPGL DDPLAQDGAG VS

Genular Protein ID: 3403555348

Symbol: B3KVQ4_HUMAN

Name: N/A

UniProtKB Accession Codes:

B3KVQ4

Database IDs:

ARBA 11 AlphaFoldDB 1 BioGRID-ORCS 1 CDD 1 CTD 1 DNASU 1 DisGeNET 1 EMBL 2 GO 3 Gene3D 1 InterPro 4 KEGG 1 NCBI Taxonomy 1 PANTHER 2 PRINTS 3 PROSITE 3 Pfam 1 PharmGKB 1 RefSeq 1 RuleBase 1 SAM 1 SMART 1 SMR 1 SUPFAM 1

Citations:

PubMed ID: 14702039

Title: Complete sequencing and characterization of 21,243 full-length human cDNAs.

PubMed ID: 14702039

DOI: 10.1038/ng1285

Sequence Information:

  • Length: 412
  • Mass: 44721
  • Checksum: 712F5F0900CEACB2
  • Sequence:
    • MPIMGSSVYI TVELAIAVLA ILGNVLVCWA VWLNSNLQNV TNYFLVSLAA ADIAVGVLAI 
PFAITISTGF CAACHGCLFI ACFVLVLTQS SIFSLLAIAI DRYIAIRIPL RYNGLVTGTR 
AKGIIAICWV LSFAIGLTPM LGWNNCGQPK EGKNHSQGCG EGQVACLFED VVPMNYMVYF 
NFFACVLVPL LLMLGVYLRI FLAARRQLKQ MESQPLPGER ARSTLQKEVH AAKSLAIIVG 
LFALCWLPLH IINCFTFFCP DCSHAPLWLM YLAIVLSHTN SVVNPFIYAY RIREFRQTFR 
KIIRSHVLRQ QEPFKAAGTS ARVLAAHGSD GEQVSLRLNG HPPGVWANGS APHPERRPNG 
YALGLVSGGS AQESQGNTGL PDVELLSHEL KGVCPEPPGL DDPLAQDGAG VS