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The adenosine receptors (or P1 receptors) are a class of
purinergic Purinergic receptors, also known as purinoceptors, are a family of plasma membrane molecules that are found in almost all mammalian tissues. Within the field of purinergic signalling, these receptors have been implicated in learning and memory, ...
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 ...
s with
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 ...
as the
endogenous Endogeny, in biology, refers to the property of originating or developing from within an organism, tissue, or cell. For example, ''endogenous substances'', and ''endogenous processes'' are those that originate within a living system (e.g. an ...
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 ...
. There are four known types of adenosine receptors in humans: A1, A2A, A2B and A3; each is encoded by a different
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 ...
. The adenosine receptors are commonly known for their antagonists
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 ...
, and
theobromine Theobromine, also known as xantheose, is the principal alkaloid of ''Theobroma cacao'' (cacao plant). Theobromine is slightly water-soluble (330 mg/L) with a bitter taste. In industry, theobromine is used as an additive and precursor to ...
, whose action on the receptors produces the stimulating effects of
coffee Coffee is a beverage brewed from roasted, ground coffee beans. Darkly colored, bitter, and slightly acidic, coffee has a stimulating effect on humans, primarily due to its caffeine content, but decaffeinated coffee is also commercially a ...
,
tea Tea is an aromatic beverage prepared by pouring hot or boiling water over cured or fresh leaves of '' Camellia sinensis'', an evergreen shrub native to East Asia which probably originated in the borderlands of south-western China and nor ...
and
chocolate Chocolate is a food made from roasted and ground cocoa beans that can be a liquid, solid, or paste, either by itself or to flavoring, flavor other foods. Cocoa beans are the processed seeds of the cacao tree (''Theobroma cacao''); unprocesse ...
.


Pharmacology

Each type of adenosine receptor has different functions, although with some overlap. For instance, both A1 receptors and A2A play roles in the heart, regulating myocardial oxygen consumption and coronary blood flow, while the A2A receptor also has broader anti-inflammatory effects throughout the body. These two receptors also have important roles in the brain, regulating the release of other
neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a Chemical synapse, synapse. The cell receiving the signal, or target cell, may be another neuron, but could also be a gland or muscle cell. Neurotra ...
s such as
dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. It is an amine synthesized ...
and
glutamate Glutamic acid (symbol Glu or E; known as glutamate in its anionic form) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a Essential amino acid, non-essential nutrient for humans, meaning that ...
, while the A2B and A3 receptors are located mainly peripherally and are involved in processes such as inflammation and immune responses. Most older compounds acting on adenosine receptors are nonselective, with the endogenous agonist
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 ...
being used in hospitals as treatment for severe
tachycardia Tachycardia, also called tachyarrhythmia, is a heart rate that exceeds the normal resting rate. In general, a resting heart rate over 100 beats per minute is accepted as tachycardia in adults. Heart rates above the resting rate may be normal ...
(rapid heart beat), and acting directly to slow the heart through action on all four adenosine receptors in heart tissue, as well as producing a
sedative A sedative or tranquilliser is a substance that induces sedation by reducing irritability or Psychomotor agitation, excitement. They are central nervous system (CNS) Depressant, depressants and interact with brain activity, causing its decelera ...
effect through action on A1 and A2A receptors in the brain.
Xanthine Xanthine ( or , from Ancient Greek for its yellowish-white appearance; archaically xanthic acid; systematic name 3,7-dihydropurine-2,6-dione) is a purine base found in most human body tissues and fluids, as well as in other organisms. Several ...
derivatives such as
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 ...
and
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 ...
act as non-selective
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.stimulant Stimulants (also known as central nervous system stimulants, or psychostimulants, or colloquially as uppers) are a class of drugs that increase alertness. They are used for various purposes, such as enhancing attention, motivation, cognition, ...
effect and rapid heart rate. These compounds also act as
phosphodiesterase inhibitor A phosphodiesterase inhibitor is a drug that blocks one or more of the five subtypes of the enzyme phosphodiesterase (PDE), thereby preventing the inactivation of the intracellular second messengers, cyclic adenosine monophosphate (cAMP) and cycl ...
s, which produces additional
anti-inflammatory Anti-inflammatory is the property of a substance or treatment that reduces inflammation, fever or swelling. Anti-inflammatory drugs, also called anti-inflammatories, make up about half of analgesics. These drugs reduce pain by inhibiting mechan ...
effects, and makes them medically useful for the treatment of conditions such as
asthma Asthma is a common long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wh ...
, but less suitable for use in scientific research. Newer adenosine receptor agonists and antagonists are much more potent and subtype-selective, and have allowed extensive research into the effects of blocking or stimulating the individual adenosine receptor subtypes, which is now resulting in a new generation of more selective drugs with many potential medical uses. Some of these compounds are still derived from adenosine or from the xanthine family, but researchers in this area have also discovered many selective adenosine receptor ligands that are entirely structurally distinct, giving a wide range of possible directions for future research.


Subtypes


Comparison


A1 adenosine receptor

The adenosine A1 receptor has been found to be ubiquitous throughout the entire body.


Mechanism

This receptor has an inhibitory function on most of the tissues in which it is expressed. In the brain, it slows metabolic activity by a combination of actions. Presynaptically, it reduces
synaptic vesicle In a neuron, synaptic vesicles (or neurotransmitter vesicles) store various neurotransmitters that are exocytosis, released at the chemical synapse, synapse. The release is regulated by a voltage-dependent calcium channel. Vesicle (biology), Ves ...
release while post synaptically it has been found to stabilize the
magnesium Magnesium is a chemical element; it has Symbol (chemistry), symbol Mg and atomic number 12. It is a shiny gray metal having a low density, low melting point and high chemical reactivity. Like the other alkaline earth metals (group 2 ...
on the
NMDA receptor The ''N''-methyl-D-aspartate receptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and predominantly Ca2+ ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other ...
source?.


Antagonism and agonism

Specific A1
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.8-cyclopentyl-1,3-dipropyl xanthine (DPCPX), and cyclopentyltheophylline (CPT) or 8-cyclopentyl-1,3- dipropylxanthine (CPX), while specific agonists include 2-chloro-N(6)-cyclopentyladenosine ( CCPA). Tecadenoson is an effective A1 adenosine agonist, as is selodenoson.


In the heart

The A1, together with A2A receptors of endogenous adenosine play a role in regulating myocardial oxygen consumption and coronary blood flow. Stimulation of the A1 receptor has a myocardial depressant effect by decreasing the conduction of electrical impulses and suppressing
pacemaker A pacemaker, also known as an artificial cardiac pacemaker, is an implanted medical device that generates electrical pulses delivered by electrodes to one or more of the chambers of the heart. Each pulse causes the targeted chamber(s) to co ...
cell function, resulting in a decrease in
heart rate Heart rate is the frequency of the cardiac cycle, heartbeat measured by the number of contractions of the heart per minute (''beats per minute'', or bpm). The heart rate varies according to the body's Human body, physical needs, including the nee ...
. This makes adenosine a useful medication for treating and diagnosing ''
tachyarrhythmia Tachycardia, also called tachyarrhythmia, is a heart rate that exceeds the Heart rate#Resting heart rate, normal resting rate. In general, a resting heart rate over 100 pulse, beats per minute is accepted as tachycardia in adults. Heart rates a ...
s'', or excessively fast heart rates. This effect on the A1 receptor also explains why there is a brief moment of cardiac standstill when adenosine is administered as a rapid IV push during cardiac resuscitation. The rapid infusion causes a momentary myocardial stunning effect. In normal physiological states, this serves as a protective mechanism. However, in altered cardiac function, such as
hypoperfusion Perfusion is the passage of fluid through the circulatory system or lymphatic system to an organ or a tissue, usually referring to the delivery of blood to a capillary bed in tissue. Perfusion may also refer to fixation via perfusion, used in ...
caused by
hypotension Hypotension, also known as low blood pressure, is a cardiovascular condition characterized by abnormally reduced blood pressure. Blood pressure is the force of blood pushing against the walls of the arteries as the heart pumps out blood and is ...
,
heart attack A myocardial infarction (MI), commonly known as a heart attack, occurs when Ischemia, blood flow decreases or stops in one of the coronary arteries of the heart, causing infarction (tissue death) to the heart muscle. The most common symptom ...
or
cardiac arrest Cardiac arrest (also known as sudden cardiac arrest CA is when the heart suddenly and unexpectedly stops beating. When the heart stops beating, blood cannot properly Circulatory system, circulate around the body and the blood flow to the ...
caused by nonperfusing bradycardias (e.g.,
ventricular fibrillation Ventricular fibrillation (V-fib or VF) is an abnormal heart rhythm in which the Ventricle (heart), ventricles of the heart Fibrillation, quiver. It is due to disorganized electrical conduction system of the heart, electrical activity. Ventricula ...
or
pulseless ventricular tachycardia Ventricular tachycardia (V-tach or VT) is a cardiovascular disorder in which fast heart rate occurs in the ventricles of the heart. Although a few seconds of VT may not result in permanent problems, longer periods are dangerous; and multiple ...
), adenosine has a negative effect on physiological functioning by preventing necessary compensatory increases in heart rate and blood pressure that attempt to maintain cerebral perfusion.


In neonatal medicine

Adenosine antagonists are widely used in neonatal medicine; A reduction in A1 expression appears to prevent hypoxia-induced
ventriculomegaly Ventriculomegaly is a brain condition that mainly occurs in the fetus when the lateral ventricles become dilated. The most common definition uses a width of the atrium of the lateral ventricle of greater than 10 mm. This occurs in around 1 ...
and loss of white matter, which raises the possibility that pharmacological blockade of A1 may have clinical utility. Theophylline and caffeine are nonselective adenosine antagonists that are used to stimulate respiration in premature infants.


Bone homeostasis

Adenosine receptors play a key role in the homeostasis of bone. The A1 receptor has been shown to stimulate
osteoclast An osteoclast () is a type of bone cell that breaks down bone tissue. This function is critical in the maintenance, repair, and bone remodeling, remodeling of bones of the vertebrate, vertebral skeleton. The osteoclast disassembles and digests th ...
differentiation and function. Studies have found that blockade of the A1 Receptor suppresses the osteoclast function, leading to increased bone density.


A2A adenosine receptor

As with the A1, the A2A receptors are believed to play a role in regulating myocardial oxygen consumption and coronary blood flow.


Mechanism

The activity of A2A adenosine receptor, a G-protein coupled receptor family member, is mediated by G proteins that 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 ...
. It is abundant in basal ganglia, vasculature and platelets and it is a major target of caffeine.


Function

The A2A receptor is responsible for regulating myocardial blood flow by vasodilating the
coronary arteries The coronary arteries are the arteries, arterial blood vessels of coronary circulation, which transport oxygenated blood to the Cardiac muscle, heart muscle. The heart requires a continuous supply of oxygen to function and survive, much like any ...
, which increases blood flow to the
myocardium Cardiac muscle (also called heart muscle or myocardium) is one of three types of vertebrate muscle tissues, the others being skeletal muscle and smooth muscle. It is an involuntary, striated muscle that constitutes the main tissue of the wall o ...
, 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.


Agonists and antagonists

Specific antagonists include istradefylline (KW-6002) and SCH-58261, while specific agonists include CGS-21680 and ATL-146e.


Bone homeostasis

The role of A2A receptor opposes that of A1 in that it inhibits osteoclast differentiation and activates
osteoblast Osteoblasts (from the Greek combining forms for " bone", ὀστέο-, ''osteo-'' and βλαστάνω, ''blastanō'' "germinate") are cells with a single nucleus that synthesize bone. However, in the process of bone formation, osteoblasts fu ...
s. Studies have shown it to be effective in decreasing inflammatory osteolysis in inflamed bone. This role could potentiate new therapeutic treatment in aid of bone regeneration and increasing bone volume.


A2B adenosine receptor

This integral membrane protein stimulates adenylate cyclase activity in the presence of adenosine. This protein also interacts with netrin-1, which is involved in axon elongation.


Bone homeostasis

Similarly to A2A receptor, the A2B receptor promotes osteoblast differentiation. The osteoblast cell is derived from the Mesenchymal Stem Cell (MSC) which can also differentiate into a chondrocyte. The cell signalling involved in the stimulation of the A2B receptor directs the route of differentiation to osteoblast, rather than chondrocyte via the Runx2 gene expression. Potential therapeutic application in aiding bone degenerative diseases, age related changes as well as injury repair.


A3 adenosine receptor

It has been shown in studies to inhibit some specific signal pathways of adenosine. It allows for the inhibition of growth in human melanoma cells. Specific antagonists include ''MRS1191'', ''MRS1523'' and ''MRE3008F20'', while specific agonists include Cl-IB-MECA and MRS3558.


Bone homeostasis

The role of A3 receptor is less defined in this field. Studies have shown that it plays a role in the downregulation of
osteoclast An osteoclast () is a type of bone cell that breaks down bone tissue. This function is critical in the maintenance, repair, and bone remodeling, remodeling of bones of the vertebrate, vertebral skeleton. The osteoclast disassembles and digests th ...
s. Its function in regards to osteoblasts remains ambiguous.


Ligand affinities


Adenosine receptor agonists


Adenosine receptor antagonists


References


External links

* * {{Authority control G protein-coupled receptors