Adenosine receptor
Encyclopedia
The adenosine receptors (or P1 receptors) are a class of purinergic receptors, G protein-coupled receptor
s with adenosine as endogenous
ligand
.
s such as dopamine
and glutamate, 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 being used in hospitals as treatment for severe tachycardia
(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
effect through action on A1 and A2A receptors in the brain. Xanthine
derivatives such as caffeine
and theophylline
act as non-selective antagonists at A1 and A2A receptors in both heart and brain and so have the opposite effect to adenosine, producing a stimulant
effect and rapid heart rate. These compounds also act as phosphodiesterase inhibitor
s, which produces additional anti-inflammatory
effects, and makes them medically useful for the treatment of conditions such as asthma
, 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.
release while post synaptically it has been found to stabilize the magnesium on the NMDA receptor
.
include 8-Cyclopentyl-1,3-dipropylxanthine (DPCPX), and Cyclopentyltheophylline (CPT) or 8-cyclopentyl-1,3-dipropylxanthine (CPX), while specific agonists include 2-chloro-N(6)-cyclopentyladenosine (CCPA
).
cell function, resulting in a decrease in heart rate
. This makes adenosine a useful medication for treating and diagnosing tachyarrhythmias, 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 protective mechanisms. However, in altered cardiac function, such as hypoperfusion caused by hypotension
, heart attack or cardiac arrest
caused by nonperfusing bradycardias, 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.
Because a reduction in A1 expression appears to prevent hypoxia-induced ventriculomegaly
and loss of white matter and therefore raise 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.
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.
(KW-6002) and SCH-58261, while specific agonists include CGS-21680 and ATL-146e.
G 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...
s with adenosine as endogenous
Endogenous
Endogenous substances are those that originate from within an organism, tissue, or cell. Endogenous retroviruses are caused by ancient infections of germ cells in humans, mammals and other vertebrates...
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...
.
Pharmacology
In humans, there are four adenosine receptors. Each is encoded by a separate gene and 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 neurotransmitterNeurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
s such as dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
and glutamate, 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 being used in hospitals as treatment for severe tachycardia
Tachycardia
Tachycardia comes from the Greek words tachys and kardia . Tachycardia typically refers to a heart rate that exceeds the normal range for a resting heart rate...
(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
Sedative
A sedative or tranquilizer is a substance that induces sedation by reducing irritability or excitement....
effect through action on A1 and A2A receptors in the brain. Xanthine
Xanthine
Xanthine , is a purine base found in most human body tissues and fluids and in other organisms. A number of stimulants are derived from xanthine, including caffeine and theobromine....
derivatives such as 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...
and theophylline
Theophylline
Theophylline, also known as dimethylxanthine, is a methylxanthine drug used in therapy for respiratory diseases such as COPD and asthma under a variety of brand names. Because of its numerous side-effects, the drug is now rarely administered for clinical use. As a member of the xanthine family, it...
act as non-selective antagonists at A1 and A2A receptors in both heart and brain and so have the opposite effect to adenosine, producing a stimulant
Stimulant
Stimulants are psychoactive drugs which induce temporary improvements in either mental or physical function or both. Examples of these kinds of effects may include enhanced alertness, wakefulness, and locomotion, among others...
effect and rapid heart rate. These compounds also act as phosphodiesterase inhibitor
Phosphodiesterase inhibitor
A phosphodiesterase inhibitor is a drug that blocks one or more of the five subtypes of the enzyme phosphodiesterase , therefore preventing the inactivation of the intracellular second messengers cyclic adenosine monophosphate and cyclic guanosine monophosphate by the respective PDE...
s, which produces additional anti-inflammatory
Anti-inflammatory
Anti-inflammatory refers to the property of a substance or treatment that reduces inflammation. Anti-inflammatory drugs make up about half of analgesics, remedying pain by reducing inflammation as opposed to opioids, which affect the central nervous system....
effects, and makes them medically useful for the treatment of conditions such as asthma
Asthma
Asthma is the common chronic inflammatory disease of the airways characterized by variable and recurring symptoms, reversible airflow obstruction, and bronchospasm. Symptoms include wheezing, coughing, chest tightness, and shortness of breath...
, 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.
Comparison of subtypes
| Receptor | Gene | Mechanism | Effects | Agonists | Antagonists |
|---|---|---|---|---|---|
| A1 | Gi/o Gi alpha subunit Gi alpha subunit is a heterotrimeric G protein subunit that inhibits the production of cAMP from ATP.- Receptors :The following G protein-coupled receptors couple to the Gi subunit:* Acetylcholine M2 & M4 receptors... → cAMP Cyclic adenosine monophosphate Cyclic adenosine monophosphate is a second messenger important in many biological processes... ↑/↓
|
Heart rate Heart rate is the number of heartbeats per unit of time, typically expressed as beats per minute . Heart rate can vary as the body's need to absorb oxygen and excrete carbon dioxide changes, such as during exercise or sleep.... |
N6-Cyclopentyladenosine N6-Cyclopentyladenosine is a drug which acts as a selective adenosine A1 receptor agonist. It has mainly cardiovascular effects with only subtle alterations of behaviour. CPA is widely used in scientific research into the adenosine receptors and has been used to derive a large family of derivatives.... CCPA (biochemistry) In biochemistry, CCPA is 2-chloro-N-cyclopentyladenosine, a specific receptor agonist for the Adenosine A1 receptor.... |
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... Theophylline Theophylline, also known as dimethylxanthine, is a methylxanthine drug used in therapy for respiratory diseases such as COPD and asthma under a variety of brand names. Because of its numerous side-effects, the drug is now rarely administered for clinical use. As a member of the xanthine family, it... 8-Cyclopentyl-1,3-dimethylxanthine 8-Cyclopentyl-1,3-dimethylxanthine is a drug which acts as a potent and selective antagonist for the adenosine receptors, with some selectivity for the A1 receptor subtype, as well as a non-selective phosphodiesterase inhibitor. It has stimulant effects in animals with slightly higher potency than... (CPX) |
|
| A2A Adenosine A2A receptor The adenosine A2A receptor, also known as ADORA2A, is an adenosine receptor, but also denotes the human gene encoding it.-Structure:This protein is a member of the G protein-coupled receptor family which possess seven transmembrane alpha helices... |
Gs Gs alpha subunit The Gs alpha subunit is a heterotrimeric G protein subunit that activates the cAMP-dependent pathway by activating adenylate cyclase.-Receptors:The G protein-coupled receptors that couple to this kind of G-protein include:... → cAMP Cyclic adenosine monophosphate Cyclic adenosine monophosphate is a second messenger important in many biological processes... ↑ |
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... vasodilatation |
Regadenoson Regadenoson 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.... |
|
|
| A2B Adenosine A2b receptor The adenosine A2B receptor, also known as ADORA2B, is a G-protein coupled adenosine receptor, and also denotes the human adenosine A2b receptor gene which encodes it.... |
Gs Gs alpha subunit The Gs alpha subunit is a heterotrimeric G protein subunit that activates the cAMP-dependent pathway by activating adenylate cyclase.-Receptors:The G protein-coupled receptors that couple to this kind of G-protein include:... → cAMP Cyclic adenosine monophosphate Cyclic adenosine monophosphate is a second messenger important in many biological processes... ↑ Also recently discovered A2B has Gq → DAG Diglyceride A diglyceride, or a diacylglycerol , is a glyceride consisting of two fatty acid chains covalently bonded to a glycerol molecule through ester linkages.... and IP3 Inositol triphosphate Inositol trisphosphate or inositol 1,4,5-trisphosphate , together with diacylglycerol , is a secondary messenger molecule used in signal transduction and lipid signaling in biological cells. While DAG stays inside the membrane, IP3 is soluble and diffuses through the cell... → Release calcium → activate calmodulin → activate myosin light chain kinase → phosphrylate myosin light chain → myosin light chain plus actin → bronchoconstriction |
|
BAY 60–6583 BAY 60–6583 is a selective adenosine A2B receptor agonist. It has been shown to provide protection from ischemia in both the heart and kidney of test animals, and has also been shown to be beneficial in treatment of acute lung injury, showing a range of potential applications for selective A2B... |
MRS-1706 MRS-1706 is a selective inverse agonist for the adenosine A2B receptor. It inhibits release of interleukins and has an antiinflammatory effect.... |
|
| A3 Adenosine A3 receptor The adenosine A3 receptor, also known as ADORA3, is an adenosine receptor, but also denotes the human gene encoding it.- Function :Adenosine A3 receptors are G protein-coupled receptors that couple to Gi/Gq and are involved in a variety of intracellular signaling pathways and physiological functions... |
Gi/o Gi alpha subunit Gi alpha subunit is a heterotrimeric G protein subunit that inhibits the production of cAMP from ATP.- Receptors :The following G protein-coupled receptors couple to the Gi subunit:* Acetylcholine M2 & M4 receptors... → ↓cAMP |
Degranulation Degranulation is a cellular process that releases antimicrobial cytotoxic molecules from secretory vesicles called granules found inside some cells... |
CP-532,903 CP-532,903 is a selective adenosine A3 subtype receptor agonist. It has antiinflammatory effects and has been shown to reduce superoxide generation in damaged tissues, and protects against tissue damage following myocardial ischemia, mediated via an interaction with ATP-sensitive potassium channels.... |
|
|
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 vesicleSynaptic vesicle
In a neuron, synaptic vesicles store various neurotransmitters that are released at the synapse. The release is regulated by a voltage-dependent calcium channel. Vesicles are essential for propagating nerve impulses between neurons and are constantly recreated by the cell...
release while post synaptically it has been found to stabilize the magnesium on the NMDA receptor
NMDA receptor
The NMDA receptor , a glutamate receptor, is the predominant molecular device for controlling synaptic plasticity and memory function....
.
Antagonism and agonism
Specific A1 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...
include 8-Cyclopentyl-1,3-dipropylxanthine (DPCPX), and Cyclopentyltheophylline (CPT) or 8-cyclopentyl-1,3-dipropylxanthine (CPX), while specific agonists include 2-chloro-N(6)-cyclopentyladenosine (CCPA
CCPA (biochemistry)
In biochemistry, CCPA is 2-chloro-N-cyclopentyladenosine, a specific receptor agonist for the Adenosine A1 receptor....
).
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 pacemakerCardiac pacemaker
right|thumb|350px|Image showing the cardiac pacemaker which is the SA nodeThe contraction of heart muscle in all animals with hearts is initiated by chemical impulses. The rate at which these impulses fire controls the heart rate...
cell function, resulting in a decrease in heart rate
Heart rate
Heart rate is the number of heartbeats per unit of time, typically expressed as beats per minute . Heart rate can vary as the body's need to absorb oxygen and excrete carbon dioxide changes, such as during exercise or sleep....
. This makes adenosine a useful medication for treating and diagnosing tachyarrhythmias, 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 protective mechanisms. However, in altered cardiac function, such as hypoperfusion caused by hypotension
Hypotension
In physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the...
, heart attack or cardiac arrest
Cardiac arrest
Cardiac arrest, is the cessation of normal circulation of the blood due to failure of the heart to contract effectively...
caused by nonperfusing bradycardias, 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;Because a reduction in A1 expression appears to prevent hypoxia-induced ventriculomegaly
Ventriculomegaly
Ventriculomegaly is a brain condition that occurs 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% of pregnancies. When this measurement is between 10 and 15 mm, the...
and loss of white matter and therefore raise 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.
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. 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 vasodilatingVasodilation
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.
Agonists and antagonists
Specific antagonists include istradefyllineIstradefylline
Istradefylline 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) and SCH-58261, while specific agonists include CGS-21680 and ATL-146e.