ADORA2A

Official Full Name

adenosine A2a receptor

Organism

Homo sapiens

GeneID

135

Background

This gene encodes a member of the guanine nucleotide-binding protein (G protein)-coupled receptor (GPCR) superfamily, which is subdivided into classes and subtypes. The receptors are seven-pass transmembrane proteins that respond to extracellular cues and activate intracellular signal transduction pathways. This protein, an adenosine receptor of A2A subtype, uses adenosine as the preferred endogenous agonist and preferentially interacts with the G(s) and G(olf) family of G proteins to increase intracellular cAMP levels. It plays an important role in many biological functions, such as cardiac rhythm and circulation, cerebral and renal blood flow, immune function, pain regulation, and sleep. It has been implicated in pathophysiological conditions such as inflammatory diseases and neurodegenerative disorders. Alternative splicing results in multiple transcript variants. A read-through transcript composed of the upstream SPECC1L (sperm antigen with calponin homology and coiled-coil domains 1-like) and ADORA2A (adenosine A2a receptor) gene sequence has been identified, but it is thought to be non-coding. [provided by RefSeq, Jun 2013]

Synonyms

A2aR; RDC8; ADORA2;

Bio Chemical Class

GPCR rhodopsin

Protein Sequence

MPIMGSSVYITVELAIAVLAILGNVLVCWAVWLNSNLQNVTNYFVVSLAAADIAVGVLAIPFAITISTGFCAACHGCLFIACFVLVLTQSSIFSLLAIAIDRYIAIRIPLRYNGLVTGTRAKGIIAICWVLSFAIGLTPMLGWNNCGQPKEGKNHSQGCGEGQVACLFEDVVPMNYMVYFNFFACVLVPLLLMLGVYLRIFLAARRQLKQMESQPLPGERARSTLQKEVHAAKSLAIIVGLFALCWLPLHIINCFTFFCPDCSHAPLWLMYLAIVLSHTNSVVNPFIYAYRIREFRQTFRKIIRSHVLRQQEPFKAAGTSARVLAAHGSDGEQVSLRLNGHPPGVWANGSAPHPERRPNGYALGLVSGGSAQESQGNTGLPDVELLSHELKGVCPEPPGLDDPLAQDGAGVS

Open

Disease

Alzheimer disease, Arterial occlusive disease, Choreiform disorder, Chronic obstructive pulmonary disease, Colorectal cancer, Coronary atherosclerosis, Diabetic foot ulcer, General pain disorder, Glaucoma, Heart failure, Hyper-lipoproteinaemia, Hypertension, Lung cancer, Multiple sclerosis, Orthostatic hypotension, Pain, Parkinsonism, Prostate cancer, Radionuclide imaging, Schizophrenia, Solid tumour/cancer, Unspecific substance use disorder, Vasomotor/allergic rhinitis

Approved Drug

3 +

Clinical Trial Drug

21 +

Discontinued Drug

8 +

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Detailed Information

Crucially important in cellular communication, the ADORA2A gene encodes a member of the guanine nucleotide-binding protein (G protein)-coupled receptor (GPCR). A key participant in this family, the A2A subtype receptor mostly controls reactions to the endogenous signaling chemical adenosine. With a seven-pass transmembrane structure, this receptor may send signals from the external environment into the cell and turn on several intracellular pathways controlling many physiological functions.

Figure 1 describes the characteristics and signaling pathways of adenosine receptors, highlighting their affinity for adenosine and their effects on adenylyl cyclase and phospholipase C. Figure 1. Overview of Adenosine Receptor Characteristics. (Garcia-Garcia L, et al., 2021)

Structural Characteristics

Adenosine receptor group comprises ADORA2A among A1, A2B, and A3 receptors. Mostly expressed in many tissues, including the central nervous system (CNS), it is especially found in the striatum and nucleus accumbens and in immunological organs like the spleen and thymus. As a binding site for regulatory proteins, the receptor's structural design has a somewhat longer C-terminal tail than that of other subtypes. The signaling features of the receptor depend on this tail, which also affects its transduction capacity and expression.

The ADORA2A receptor interacts mostly with G(s) and G(olf) proteins when triggered by adenosine. A rise in intracellular cyclic AMP (cAMP) levels and the activation of adenylyl cyclase follow from this interaction. The resulting cAMP stimulates the activation of protein kinase A (PKA), therefore regulating the activity of many downstream targets, including ion channels, phosphodiesterases, and transcription factors such as cAMP-responsive element-binding protein (CREB). Fascinatingly, ADORA2A may also activate the mitogen-activated protein kinase (MAPK) signaling cascade, therefore broadening its functional repertoire in certain circumstances via G-protein-independent routes.

Physiological Roles

Many essential biological processes are carried out in great part by ADORA2A. In cardiac function, it controls coronary blood flow and affects heart rhythm, therefore offering a protective action during ischemia episodes. ADORA2A alters blood flow dynamics in the central nervous system, therefore influencing neurovascular coupling and general brain condition. It also plays a part in the immunological response, wherein receptor activation reduces the activity and multiplication of immune cells, therefore implying a function in controlling inflammatory reactions. Furthermore, it modulates pain by providing possible paths for pain management techniques and influences neurotransmitter release, therefore profoundly changing sleep patterns.

Given its broad participation in biological processes, changes in ADORA2A signaling have been linked to several disorders. Because of its involvement in dopamine control, aberrant ADORA2A signaling may aggravate symptoms in neurodegenerative diseases like Parkinson's and Alzheimer's disease. Investigated for their neuroprotective effects, A2A antagonists show promise in restoring dopaminergic activity and thereby reducing Parkinson's disease motor symptoms. Furthermore, a focus for creating anti-inflammatory treatments is dysregulation of A2A receptor activation, as it is associated with inflammatory diseases. The broad-spectrum anti-inflammatory action of A2A agonists suggests their possible application in treating asthma and chronic obstructive pulmonary disease (COPD). The dual function of ADORA2A in stimulating both angiogenesis and immunosuppression hampers cancer therapy targeting. Although A2A receptor activation might improve medication delivery to tumors by vasodilation, its immunosuppressive properties may help tumor survival, therefore enabling the possible use of A2A antagonists in overcoming these obstacles.

Therapeutic Applications

ADORA2A regulation has therapeutic relevance in many different medical disciplines. A2A receptor antagonists are under investigation in Parkinson's disease to help with motor skills and lessen dependency on L-DOPA medication. Using A2A antagonists, improving dopaminergic signaling might provide fresh approaches for addressing cognitive deficiencies linked with neurodegenerative illnesses in cognitive disorders. Furthermore, considering their involvement in pain pathways, A2A receptor modulators might provide fresh analgesic choices, especially in chronic pain disorders. A2A receptor activation suggests potential application in treating ischemic heart diseases as it stimulates coronary vasodilation in the cardiovascular system.

A2A receptor ligands have been investigated and various molecules with medicinal uses have resulted. Strong A2A agonists, including ATL146e and ATL313, which are under investigation for their therapeutic potential in inflammatory disorders and cancer, have come from structural changes of adenosine. Novel approaches for efficiently administering A2A receptor agonists include innovations in medication formulation, including pro-drugs with enhanced bioavailability. Furthermore, serving as fundamental building blocks for creating selective A2A antagonists are alkylxanthines such as caffeine and theophylline. For example, KW-6002 reflects continuous attempts to investigate A2A regulation in movement disorders even when clinical studies offer difficulties.

Research is clarifying the intricate functions of A2A receptors; therefore, there is an increasing possibility for creative therapies based on promising developments in the management of cancer therapy, inflammatory disorders, and neurological illnesses. ADORA2A signaling's dynamic interaction with many biological systems emphasizes its importance as a therapeutic target in contemporary medicine.

References:

Federico S, Spalluto G. Therapeutic potential of A2 and A3 adenosine receptor: a review of novel patented ligands. Expert Opin Ther Pat. 2012;22(4):369-390.
Salvatore CA, Jacobson MA, Taylor HE, et al. Molecular cloning and characterization of the human A3 adenosine receptor. Proc Natl Acad Sci USA. 1993;90(21):10365-10369.
Strickland LN, Faraoni EY, Ruan W, et al. The resurgence of the Adora2b receptor as an immunotherapeutic target in pancreatic cancer. Front Immunol. 2023;14:1163585.
Garcia-Garcia L, Olle L, Martin M, Roca-Ferrer J, et al. Adenosine Signaling in Mast Cells and Allergic Diseases. Int J Mol Sci. 2021 May 14;22(10):5203.

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