Adenosine A2A receptor
Encyclopedia
The adenosine A2A receptor, also known as ADORA2A, is an adenosine receptor
, but also denotes the human gene
encoding it.
(GPCR) family which possess seven transmembrane alpha helices
. The crystallographic structure of the adenosine A2A receptor (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
).
s 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, dopamine D2
/A2A and D3
/A2A, glutamate mGluR5
/A2A and cannabinoid CB1/A2A have all been observed, as well as CB1/A2A/D2 heterotrimers, and the functional significance and endogenous role of these hybrid receptors is still only starting to be unravelled.
family member, is mediated by G protein
s which activate adenylyl cyclase, which induce synthesis of intracellular cAMP
. The encoded protein is abundant in basal ganglia
, vasculature
, T lymphocytes, and platelet
s and it is a major target of caffeine
.
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.
such as aminophylline
, focused mainly on the role of adenosine receptors in the heart, and led to several randomized controlled trial
s using these receptor antagonists to treat bradyasystolic
arrest
.
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
.
with Dopamine receptor D2
.
Adenosine receptor
The adenosine receptors are a class of purinergic receptors, G protein-coupled receptors with adenosine as endogenous ligand.-Pharmacology:...
, but also denotes the human gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
encoding it.
Structure
This protein is a member of the G protein-coupled receptorG protein-coupled receptor
G protein-coupled receptors , also known as seven-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptor, and G protein-linked receptors , comprise a large protein family of transmembrane receptors that sense molecules outside the cell and activate inside signal...
(GPCR) family which possess seven transmembrane alpha helices
Alpha helix
A common motif in the secondary structure of proteins, the alpha helix is a right-handed coiled or spiral conformation, in which every backbone N-H group donates a hydrogen bond to the backbone C=O group of the amino acid four residues earlier...
. The crystallographic structure of the adenosine A2A receptor (see figure to the right) reveals a ligand
Ligand (biochemistry)
In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. In a narrower sense, it is a signal triggering molecule, binding to a site on a target protein.The binding occurs by intermolecular forces, such as ionic bonds, hydrogen...
binding pocket distinct from that of other structurally determined GPCRs (i.e., the beta-2 adrenergic receptor
Beta-2 adrenergic receptor
The beta-2 adrenergic receptor , also known as ADRB2, is a beta-adrenergic receptor, and also denotes the human gene encoding it.-Gene:The gene is intronless...
and rhodopsin
Rhodopsin
Rhodopsin, also known as visual purple, is a biological pigment of the retina that is responsible for both the formation of the photoreceptor cells and the first events in the perception of light. Rhodopsins belong to the G-protein coupled receptor family and are extremely sensitive to light,...
).
Heteromers
The actions of the A2A receptor are complicated by the fact that a variety of functional heteromerHeteromer
-Pharmacology:* Ligand-gated ion channels such as the nicotinic acetylcholine receptor and GABAA receptor are composed of five subunits arranged around a central pore that opens to allow ions to pass through. There are a large number of different subunits available, which can come together in a...
s 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, dopamine D2
Dopamine receptor D2
Dopamine receptor D2, also known as D2R, is a protein that, in humans, is encoded by the DRD2 gene.- Function :This gene encodes the D2 subtype of the dopamine receptor. This G protein-coupled receptor inhibits adenylyl cyclase activity...
/A2A and D3
Dopamine receptor D3
D dopamine receptor is a protein that in humans is encoded by the DRD3 gene.This gene encodes the D3 subtype of the dopamine receptor. The D3 subtype inhibits adenylyl cyclase through inhibitory G-proteins. This receptor is expressed in phylogenetically older regions of the brain, suggesting that...
/A2A, glutamate mGluR5
Metabotropic glutamate receptor 5
Metabotropic glutamate receptor 5 is a protein that in humans is encoded by the GRM5 gene.- Function :The amino acid L-glutamate is the major excitatory neurotransmitter in the central nervous system and activates both ionotropic and metabotropic glutamate receptors...
/A2A and cannabinoid CB1/A2A have all been observed, as well as CB1/A2A/D2 heterotrimers, and the functional significance and endogenous role of these hybrid receptors is still only starting to be unravelled.
Function
The gene encodes a protein which is one of several receptor subtypes for adenosine. The activity of the encoded protein, a G protein-coupled receptorG protein-coupled receptor
G protein-coupled receptors , also known as seven-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptor, and G protein-linked receptors , comprise a large protein family of transmembrane receptors that sense molecules outside the cell and activate inside signal...
family member, is mediated by G protein
G protein
G proteins are a family of proteins involved in transmitting chemical signals outside the cell, and causing changes inside the cell. They communicate signals from many hormones, neurotransmitters, and other signaling factors. G protein-coupled receptors are transmembrane receptors...
s which activate adenylyl cyclase, which induce synthesis of intracellular cAMP
Cyclic adenosine monophosphate
Cyclic adenosine monophosphate is a second messenger important in many biological processes...
. The encoded protein is abundant in basal ganglia
Basal ganglia
The basal ganglia are a group of nuclei of varied origin in the brains of vertebrates that act as a cohesive functional unit. They are situated at the base of the forebrain and are strongly connected with the cerebral cortex, thalamus and other brain areas...
, vasculature
Circulatory system
The circulatory system is an organ system that passes nutrients , gases, hormones, blood cells, etc...
, T lymphocytes, and platelet
Platelet
Platelets, or thrombocytes , are small,irregularly shaped clear cell fragments , 2–3 µm in diameter, which are derived from fragmentation of precursor megakaryocytes. The average lifespan of a platelet is normally just 5 to 9 days...
s and it is a major target of caffeine
Caffeine
Caffeine is a bitter, white crystalline xanthine alkaloid that acts as a stimulant drug. Caffeine is found in varying quantities in the seeds, leaves, and fruit of some plants, where it acts as a natural pesticide that paralyzes and kills certain insects feeding on the plants...
.
Physiological role
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.The A2A receptor is responsible for regulating myocardial blood flow by vasodilating
Vasodilation
Vasodilation refers to the widening of blood vessels resulting from relaxation of smooth muscle cells within the vessel walls, particularly in the large arteries, smaller arterioles and large veins. The process is essentially the opposite of vasoconstriction, or the narrowing of blood vessels. When...
the coronary arteries
Coronary circulation
Coronary circulation is the circulation of blood in the blood vessels of the heart muscle . The vessels that deliver oxygen-rich blood to the myocardium are known as 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.
Ligands
A number of selective A2A ligands have been developed, with several possible therapeutic applications. Older research on adenosine receptor function, and non-selective adenosine receptor antagonistsReceptor antagonist
A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...
such as aminophylline
Aminophylline
Aminophylline is a bronchodilator. It is a compound of the bronchodilator theophylline with ethylenediamine in 2:1 ratio. The ethylenediamine improves solubility, and the aminophylline is usually found as a dihydrate-Properties:...
, focused mainly on the role of adenosine receptors in the heart, and led to several randomized controlled trial
Randomized controlled trial
A randomized controlled trial is a type of scientific experiment - a form of clinical trial - most commonly used in testing the safety and efficacy or effectiveness of healthcare services or health technologies A randomized controlled trial (RCT) is a type of scientific experiment - a form of...
s using these receptor antagonists to treat bradyasystolic
Bradycardia
Bradycardia , in the context of adult medicine, is the resting heart rate of under 60 beats per minute, though it is seldom symptomatic until the rate drops below 50 beat/min. It may cause cardiac arrest in some patients, because those with bradycardia may not be pumping enough oxygen to their heart...
arrest
Cardiac arrest
Cardiac arrest, is the cessation of normal circulation of the blood due to failure of the heart to contract effectively...
.
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
Parkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...
.
Agonists
- ATL-146e
- YT-146 (2-(1-octynyl)adenosine)
- CGS-21680
- DPMA (N6-(2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethyl)adenosine)
- RegadenosonRegadenosonRegadenoson is an A2A adenosine receptor agonist that is a coronary vasodilator. It produces maximal hyperemia quickly and maintains it for an optimal duration that is practical for radionuclide myocardial perfusion imaging....
- UK-432,097UK-432,097UK-432,097 is a drug developed by Pfizer for the treatment of chronic obstructive pulmonary disease, which acts as a potent and selective agonist of the adenosine A2A receptor. It was discontinued from clinical trials following poor efficacy results, but its high selectivity has made it useful for...
Antagonists
- IstradefyllineIstradefyllineIstradefylline is an antagonist at the A2A receptor. It has been found to be useful in the treatment of Parkinson's disease. Istradefylline reduces dyskinesia resulting from long-term treatment with classical antiparkinson drugs such as levodopa. Istradefylline is an analog of caffeine....
(KW-6002) - MSX-3
- PreladenantPreladenantPreladenant is a drug developed by Schering-Plough which acts as a potent and selective antagonist at the adenosine A2A receptor. It is being researched as a potential treatment for Parkinson's disease. Positive results were reported in Phase II clinical trials in humans....
(SCH-420,814) - SCH-58261SCH-58261SCH-58261 is a drug which acts as a potent and selective antagonist for the adenosine receptor A2A, with more than 50x selectivity for A2A over other adenosine receptors...
- SCH-412,348
- SCH-442,416SCH-442,416SCH-442,416 is a highly selective adenosine A2a subtype receptor antagonist. It is widely used in its 11C radiolabelled form to map the distribution of A2a receptors in the brain, where they are mainly found in the striatum, nucleus accumbens, and olfactory tubercle...
- ST-1535
- Caffeine
- VER-6623
- VER-6947
- VER-7835
- Vipadenant (BIIB-014)
- ZM-241,385ZM-241,385ZM-241,385 is a high affinity antagonist ligand selective for the adenosine A2A receptor.In animal models, ZM-241,385 has been shown to protect against beta amyloid neurotoxicity and therefore may be useful as a treatment for Alzheimer's disease...
Interactions
Adenosine A2A receptor has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with Dopamine receptor D2
Dopamine receptor D2
Dopamine receptor D2, also known as D2R, is a protein that, in humans, is encoded by the DRD2 gene.- Function :This gene encodes the D2 subtype of the dopamine receptor. This G protein-coupled receptor inhibits adenylyl cyclase activity...
.