Adenosine A2A receptor

ADORA2A
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2YDO, 2YDV, 3EML, 3PWH, 3QAK, 3REY, 3RFM, 3UZA, 3UZC, 3VG9, 3VGA, 4EIY, 4UG2, 4UHR, 5IU4, 5IU7, 5IUA, 5IU8, 5IUB
Identifiers
Aliases	ADORA2A, adenosine A2a receptor, A2aR, ADORA2, RDC8
External IDs	OMIM: 102776; MGI: 99402; HomoloGene: 20166; GeneCards: ADORA2A; OMA:ADORA2A - orthologs
Gene location (Human) Chr. Chromosome 22 (human)[1] Band 22q11.23 Start 24,417,879 bp[1] End 24,442,357 bp[1]
Gene location (Mouse) Chr. Chromosome 10 (mouse)[2] Band 10|10 C1 Start 75,152,711 bp[2] End 75,170,618 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in putamen caudate nucleus nucleus accumbens blood bone marrow right lobe of liver lymph node apex of heart granulocyte bone marrow cells Top expressed in olfactory tubercle superior frontal gyrus perirhinal cortex Ileal epithelium globus pallidus nucleus accumbens entorhinal cortex embryo thymus primary visual cortex More reference expression data BioGPS More reference expression data
Gene ontology Molecular function G protein-coupled adenosine receptor activity G protein-coupled receptor activity signal transducer activity protein binding identical protein binding enzyme binding alpha-actinin binding type 5 metabotropic glutamate receptor binding protein heterodimerization activity Cellular component integral component of membrane membrane plasma membrane integral component of plasma membrane intermediate filament endomembrane system postsynaptic density axon dendrite axolemma asymmetric synapse presynaptic membrane soma postsynaptic membrane presynaptic active zone integral component of postsynaptic membrane integral component of presynaptic membrane glutamatergic synapse Golgi membrane Biological process cAMP biosynthetic process G protein-coupled adenosine receptor signaling pathway sensory perception adenylate cyclase-modulating G protein-coupled receptor signaling pathway cell-cell signaling blood coagulation blood circulation cellular defense response central nervous system development phagocytosis inflammatory response signal transduction apoptotic process synaptic transmission, dopaminergic response to amphetamine regulation of transcription, DNA-templated negative regulation of protein kinase activity protein kinase C-activating G protein-coupled receptor signaling pathway synaptic transmission, cholinergic locomotory behavior negative regulation of cell population proliferation positive regulation of glutamate secretion positive regulation of acetylcholine secretion, neurotransmission regulation of norepinephrine secretion response to caffeine positive regulation of synaptic transmission, GABAergic synaptic transmission, glutamatergic positive regulation of urine volume positive regulation of renal sodium excretion negative regulation of locomotion vasodilation eating behavior negative regulation of vascular permeability negative regulation of cysteine-type endopeptidase activity involved in apoptotic process response to alkaloid negative regulation of neuron apoptotic process positive regulation of circadian sleep/wake cycle, sleep negative regulation of alpha-beta T cell activation astrocyte activation neuron projection morphogenesis positive regulation of protein secretion negative regulation of inflammatory response regulation of mitochondrial membrane potential membrane depolarization regulation of calcium ion transport positive regulation of synaptic transmission, glutamatergic excitatory postsynaptic potential inhibitory postsynaptic potential prepulse inhibition positive regulation of apoptotic signaling pathway G protein-coupled receptor signaling pathway adenylate cyclase-activating G protein-coupled receptor signaling pathway positive regulation of long-term synaptic potentiation regulation of synaptic vesicle exocytosis Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 135 11540 Ensembl ENSG00000128271 ENSMUSG00000020178 UniProt P29274 Q60613 RefSeq (mRNA) NM_000675 NM_001278497 NM_001278498 NM_001278499 NM_001278500 NM_009630 NM_001331095 NM_001331096 RefSeq (protein) NP_000666 NP_001265426 NP_001265427 NP_001265428 NP_001265429 NP_001318024 NP_001318025 NP_033760 Location (UCSC) Chr 22: 24.42 – 24.44 Mb Chr 10: 75.15 – 75.17 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

The adenosine A_2A receptor, also known as ADORA2A, is an adenosine receptor, and also denotes the human gene encoding it.^[5][6]

This protein is a member of the G protein-coupled receptor (GPCR) family which possess seven transmembrane alpha helices, as well as an extracellular N-terminus and an intracellular C-terminus. Furthermore, located in the intracellular side close to the membrane is a small alpha helix, often referred to as helix 8 (H8). The crystallographic structure of the adenosine A_2A receptor reveals a ligand binding pocket distinct from that of other structurally determined GPCRs (i.e., the beta-2 adrenergic receptor and rhodopsin).^[7] Below this primary (orthosteric) binding pocket lies a secondary (allosteric) binding pocket. The crystal-structure of A_2A 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]

The actions of the A_2A receptor are complicated by the fact that a variety of functional heteromers composed of a mixture of A_2A 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. Heteromers consisting of adenosine A₁/A_2A,^[9][10] dopamine D₂/A_2A^[11] and D₃/A_2A,^[12] glutamate mGluR₅/A_2A^[13] and cannabinoid CB₁/A_2A^[14] have all been observed, as well as CB₁/A_2A/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]

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 A_2A receptor binds with the G_s protein at the intracellular site of the receptor. The G_s protein consists of three subunits; G_sα, G_sβ and G_sγ. A crystal structure of the A_2A receptor bound with the agonist NECA and a G protein-mimic has been published in 2016 (PDB code: 5g53).^[20]

The encoded protein (the A_2A 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]

A₁ and A_2A receptors are believed to regulate myocardial oxygen demand and to increase coronary circulation by vasodilation. In addition, A_2A receptor can suppress immune cells, thereby protecting tissue from inflammation.^[22]

The A_2A 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]}

A number of selective A_2A 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 A_2A ligands has led towards other applications, with the most significant focus of research currently being the potential therapeutic role for A_2A antagonists in the treatment of Parkinson's disease.^{[39][40][41][42]}

Adenosine A2A receptor has been shown to interact with Dopamine receptor D2.^[54] As a result, Adenosine receptor A2A decreases activity in the Dopamine D2 receptors.

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 programmed cell death-1 (PD-1) and cytotoxic t-lymphocyte associated protein-4 (CTLA-4) receptors, namely to suppress immunologic response and prevent associated tissue damage. Extracellular adenosine gathers in response to cellular stress and breakdown through interactions with hypoxia induced HIF-1α.^[55] Abundant extracellular adenosine can then bind to the A2A receptor resulting in a G_s-protein coupled response, resulting in the accumulation of intracellular cAMP, which functions primarily through protein kinase A to upregulate inhibitory cytokines such as transforming growth factor-beta (TGF-β) and inhibitory receptors (i.e., PD-1).^[56] Interactions with FOXP3 stimulates CD4+ T-cells into regulatory T_reg cells further inhibiting immune response.^[57]

Blockade of A2AR has been attempted to various ends, namely cancer immunotherapy. While several A2A receptor antagonists have progressed to clinical trials for the treatment of Parkinson's disease, A2AR blockade in the context of cancer is less characterized. Mice treated with A2AR antagonists, such as ZM241385 (listed above) or caffeine, show significantly delayed tumor growth due to T-cells resistant to inhibition.^[55] This is further highlighted by A2AR knockout mice who show increased tumor rejection. Multiple checkpoint pathway inhibition has been shown to have an additive effect, as shown by an increase in response with blockade to PD-1 and CTLA-4 via monoclonal antibodies as compared to the blockade of a single pathway. The A2AR antogonist CPI-444 has shown this in combination with anti-PD-L1 or anti-CTLA-4 treatment as it eliminated tumors in up to 90% of treated mice, including restoration of immune responses in models that incompletely responded to anti-PD-L1 or anti-CTLA-4 monotherapy. Further, tumor growth was fully inhibited when mice with cleared tumors were later rechallenged, indicating that CPI-444 induced systemic antitumor immune memory. ^[58] Researchers believe that A2AR blockade could increase the efficacy of such treatments even further.^[56] Finally, inhibition of A2AR, either through pharmacologic or genetic targeting, in 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.^[59] 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.

• Human ADORA2A genome location and ADORA2A gene details page in the UCSC Genome Browser.