The adenosine A2A receptor, also known as ADORA2A, is an
adenosine receptor
The adenosine receptors (or P1 receptors) are a class of Purinergic receptor, purinergic G protein-coupled receptors with adenosine as the endogenous ligand (biochemistry), ligand. There are four known types of adenosine receptors in humans: Aden ...
, and also denotes the human
gene
In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
encoding it.
Structure
This protein is a member of the
G protein-coupled receptor
G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily related ...
(GPCR) family which possess seven transmembrane
alpha helices
An alpha helix (or α-helix) is a sequence of amino acids in a protein that are twisted into a coil (a helix).
The alpha helix is the most common structural arrangement in the secondary structure of proteins. It is also the most extreme type of l ...
, 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 A2A receptor reveals a
ligand
In coordination chemistry, a ligand is an ion or molecule with a functional group that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's el ...
binding pocket distinct from that of other structurally determined GPCRs (i.e., the
beta-2 adrenergic receptor
The beta-2 adrenergic receptor (β2 adrenoreceptor), also known as ADRB2, is a cell membrane-spanning beta-adrenergic receptor that binds epinephrine (adrenaline), a hormone and neurotransmitter whose signaling, via adenylate cyclase stimulati ...
and
rhodopsin
Rhodopsin, also known as visual purple, is a protein encoded by the ''RHO'' gene and a G-protein-coupled receptor (GPCR). It is a light-sensitive receptor protein that triggers visual phototransduction in rod cells. Rhodopsin mediates dim ...
).; Below this primary ( orthosteric) binding pocket lies a secondary ( allosteric) binding pocket. The crystal-structure of A2A 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'.
Heteromers
The actions of the A2A receptor are complicated by the fact that a variety of functional heteromers 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. Heteromers 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.
The receptor's role in immunomodulation in the context of cancer has suggested that it is an important
immune checkpoint
Immune checkpoints are regulators of the immune system. These pathways are crucial for self-tolerance, which prevents the immune system from attacking cells indiscriminately. However, some cancers can protect themselves from attack by stimulat ...
molecule.
Function
The gene encodes a protein which is one of several receptor subtypes for
adenosine
Adenosine (symbol A) is an organic compound that occurs widely in nature in the form of diverse derivatives. The molecule consists of an adenine attached to a ribose via a β-N9- glycosidic bond. Adenosine is one of the four nucleoside build ...
. The activity of the encoded protein, a
G protein-coupled receptor
G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily related ...
family member, is mediated by
G protein
G proteins, also known as guanine nucleotide-binding proteins, are a Protein family, family of proteins that act as molecular switches inside cells, and are involved in transmitting signals from a variety of stimuli outside a cell (biology), ...
s which activate
adenylyl cyclase
Adenylate cyclase (EC 4.6.1.1, also commonly known as adenyl cyclase and adenylyl cyclase, abbreviated AC) is an enzyme with systematic name ATP diphosphate-lyase (cyclizing; 3′,5′-cyclic-AMP-forming). It catalyzes the following reaction:
:A ...
, which induce synthesis of intracellular cAMP. The A2A receptor binds with the Gs protein at the intracellular site of the receptor. The Gs protein consists of three subunits; Gsα, Gsβ and Gsγ. A crystal structure of the A2A receptor bound with the agonist NECA and a G protein-mimic has been published in 2016 ( PDB code: 5g53).
The encoded protein (the A2A receptor) is abundant in
basal ganglia
The basal ganglia (BG) or basal nuclei are a group of subcortical Nucleus (neuroanatomy), nuclei found in the brains of vertebrates. In humans and other primates, differences exist, primarily in the division of the globus pallidus into externa ...
,
vasculature
In vertebrates, the circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the body. It includes the cardiovascular system, or vascular system, that consists of the heart an ...
platelet
Platelets or thrombocytes () are a part of blood whose function (along with the coagulation#Coagulation factors, coagulation factors) is to react to bleeding from blood vessel injury by clumping to form a thrombus, blood clot. Platelets have no ...
s and it is a major target of
caffeine
Caffeine is a central nervous system (CNS) stimulant of the methylxanthine chemical classification, class and is the most commonly consumed Psychoactive drug, psychoactive substance globally. It is mainly used for its eugeroic (wakefulness pr ...
, which is a competitive antagonist of this protein.
Physiological role
A1 and A2A receptors are believed to regulate myocardial oxygen demand and to increase
coronary circulation
Coronary circulation is the Circulatory system#Coronary vessels, circulation of blood in the arteries and veins that supply the cardiac muscle, heart muscle (myocardium).
Coronary arteries supply oxygen saturation (medicine), oxygenated blood to ...
by
vasodilation
Vasodilation, also known as vasorelaxation, is the widening of blood vessels. It results from relaxation of smooth muscle cells within the vessel walls, in particular in the large veins, large arteries, and smaller arterioles. Blood vessel wa ...
. In addition, A2A receptor can suppress immune cells, thereby protecting tissue from
inflammation
Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin ''calor'', '' ...
.
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, and Parkinson's disease.
Ligands
A number of selective A2A ligands have been developed,
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Older research on adenosine receptor function, and non-selective adenosine receptor
antagonists
An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.aminophylline, focused mainly on the role of adenosine receptors in the heart, and led to several
randomized controlled trial
A randomized controlled trial (or randomized control trial; RCT) is a form of scientific experiment used to control factors not under direct experimental control. Examples of RCTs are clinical trials that compare the effects of drugs, surgical ...
s using these receptor antagonists to treat bradyasystolic
arrest
An arrest is the act of apprehending and taking a person into custody (legal protection or control), usually because the person has been suspected of or observed committing a crime. After being taken into custody, the person can be question ...
.
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 (PD), or simply Parkinson's, is a neurodegenerative disease primarily of the central nervous system, affecting both motor system, motor and non-motor systems. Symptoms typically develop gradually and non-motor issues become ...
.
Agonists
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Adenosine
Adenosine (symbol A) is an organic compound that occurs widely in nature in the form of diverse derivatives. The molecule consists of an adenine attached to a ribose via a β-N9- glycosidic bond. Adenosine is one of the four nucleoside build ...
Cannabidiol
Cannabidiol (CBD) is a phytocannabinoid, one of 113 identified cannabinoids in ''Cannabis'', along with tetrahydrocannabinol (THC), and accounts for up to 40% of the plant's extract. Medically, it is an anticonvulsant used to treat multiple f ...
Limonene
Limonene () is a colorless liquid aliphatic hydrocarbon classified as a cyclic monoterpene, and is the major component in the essential oil of citrus fruit peels. The (+)-isomer, occurring more commonly in nature as the fragrance of oranges, ...
Caffeine
Caffeine is a central nervous system (CNS) stimulant of the methylxanthine chemical classification, class and is the most commonly consumed Psychoactive drug, psychoactive substance globally. It is mainly used for its eugeroic (wakefulness pr ...
Theophylline
Theophylline, also known as 1,3-dimethylxanthine, is a drug that inhibits phosphodiesterase and blocks adenosine receptors. It is used to treat chronic obstructive pulmonary disease (COPD) and asthma. Its pharmacology is similar to other met ...
Adenosine A2A receptor has been shown to interact with Dopamine receptor D2. As a result, Adenosine receptor A2A decreases activity in the Dopamine D2 receptors.
In cancer immunotherapy
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
Cytotoxic T-lymphocyte associated protein 4, (CTLA-4) also known as CD152 ( cluster of differentiation 152), is a protein receptor that functions as an immune checkpoint and downregulates immune responses. CTLA-4 is constitutively expressed in ...
) 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. Abundant extracellular adenosine can then bind to the A2A receptor resulting in a Gs-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). Interactions with FOXP3 stimulates CD4+ T-cells into regulatory Treg cells further inhibiting immune response.
Blockade of A2AR has been attempted to various ends, namely
cancer immunotherapy
Cancer immunotherapy (immuno-oncotherapy) is the stimulation of the immune system to treat cancer, improving the immune system's natural ability to fight the disease. It is an application of the basic research, fundamental research of cancer im ...
. While several A2A receptor antagonists have progressed to clinical trials for the treatment of
Parkinson's disease
Parkinson's disease (PD), or simply Parkinson's, is a neurodegenerative disease primarily of the central nervous system, affecting both motor system, motor and non-motor systems. Symptoms typically develop gradually and non-motor issues become ...
, 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. 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
A monoclonal antibody (mAb, more rarely called moAb) is an antibody produced from a Lineage (evolution), cell lineage made by cloning a unique white blood cell. All subsequent antibodies derived this way trace back to a unique parent cell.
Mon ...
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. Researchers believe that A2AR blockade could increase the efficacy of such treatments even further. 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. 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.