The adenosine A
1 receptor
is one member of the
adenosine receptor
The adenosine receptors (or P1 receptors) are a class of purinergic G protein-coupled receptors with adenosine as the endogenous ligand. There are four known types of adenosine receptors in humans: A1, A2A, A2B and A3; each is encoded by a di ...
group of
G protein-coupled
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 p ...
receptors 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 building ...
as
endogenous
Endogenous substances and processes are those that originate from within a living system such as an organism, tissue, or cell.
In contrast, exogenous substances and processes are those that originate from outside of an organism.
For example, es ...
ligand
In coordination chemistry, a ligand is an ion or molecule (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 electr ...
.
Biochemistry
A
1 receptors are implicated in sleep promotion by inhibiting wake-promoting
cholinergic
Cholinergic agents are compounds which mimic the action of acetylcholine and/or butyrylcholine. In general, the word "choline" describes the various quaternary ammonium salts containing the ''N'',''N'',''N''-trimethylethanolammonium cation. F ...
neurons in the
basal forebrain
Part of the human brain, the basal forebrain structures are located in the forebrain to the front of and below the striatum. They include the ventral basal ganglia (including nucleus accumbens and ventral pallidum), nucleus basalis, diagonal band ...
.
A
1 receptors are also present in smooth muscle throughout the vascular system.
The adenosine A
1 receptor has been found to be ubiquitous throughout the entire body.
Signalling
Activation of the adenosine A
1 receptor by an
agonist
An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...
causes binding of G
i1/2/3 or G
o protein. Binding of G
i1/2/3 causes an inhibition of
adenylate 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 ...
and, therefore, a decrease in the
cAMP
Camp may refer to:
Outdoor accommodation and recreation
* Campsite or campground, a recreational outdoor sleeping and eating site
* a temporary settlement for nomads
* Camp, a term used in New England, Northern Ontario and New Brunswick to descri ...
concentration. An increase of the
inositol triphosphate
Inositol trisphosphate or inositol 1,4,5-trisphosphate abbreviated InsP3 or Ins3P or IP3 is an inositol phosphate signaling molecule. It is made by hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2), a phospholipid that is located in the p ...
/
diacylglycerol
A diglyceride, or diacylglycerol (DAG), is a glyceride consisting of two fatty acid chains covalently bonded to a glycerol molecule through ester linkages. Two possible forms exist, 1,2-diacylglycerols and 1,3-diacylglycerols. DAGs can act as s ...
concentration is caused by an activation of
phospholipase C
Phospholipase C (PLC) is a class of membrane-associated enzymes that cleave phospholipids just before the phosphate group (see figure). It is most commonly taken to be synonymous with the human forms of this enzyme, which play an important role ...
, whereas the elevated levels of
arachidonic acid
Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega-6 fatty acid 20:4(ω-6), or 20:4(5,8,11,14). It is structurally related to the saturated arachidic acid found in cupuaçu butter. Its name derives from the New Latin word ''arachi ...
are mediated by
DAG lipase, which cleaves DAG to form arachidonic acid.
Several types of
potassium channels
Potassium channels are the most widely distributed type of ion channel found in virtually all organisms. They form potassium-selective pores that span cell membranes. Potassium channels are found in most cell types and control a wide variety of cel ...
are activated but N-, P-, and Q-type
calcium channels
A calcium channel is an ion channel which shows selective permeability to calcium ions. It is sometimes synonymous with voltage-gated calcium channel, although there are also ligand-gated calcium channels.
Comparison tables
The following tables ex ...
are inhibited.
Mechanism
This receptor has an inhibitory function on most of the tissues in which it rests. In the brain, it slows metabolic activity by a combination of actions. At the neuron's
synapse
In the nervous system, a synapse is a structure that permits a neuron (or nerve cell) to pass an electrical or chemical signal to another neuron or to the target effector cell.
Synapses are essential to the transmission of nervous impulses from ...
, it reduces
synaptic vesicle
In a neuron, synaptic vesicles (or neurotransmitter 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 impulse ...
release.
Ligands
Caffeine
Caffeine is a central nervous system (CNS) stimulant of the methylxanthine class. It is mainly used recreationally as a cognitive enhancer, increasing alertness and attentional performance. Caffeine acts by blocking binding of adenosine t ...
, as well as
theophylline
Theophylline, also known as 1,3-dimethylxanthine, is a phosphodiesterase inhibiting drug used in therapy for respiratory diseases such as chronic obstructive pulmonary disease (COPD) and asthma under a variety of brand names. As a member of the ...
, has been found to antagonize both A
1 and
A2A receptors in the brain.
Agonists
* 2-Chloro-N(6)-cyclopentyladenosine (
CCPA
Catabolite Control Protein A (CcpA) is a master regulator of carbon metabolism in gram-positive bacteria. It is a member of the LacI/ GalR transcription regulator family. In contrast to most LacI/GalR proteins, CcpA is allosterically regulated ...
).
*
N6-Cyclopentyladenosine
''N''6-Cyclopentyladenosine (CPA) is a drug which acts as a selective adenosine A1 receptor agonist. It has mainly cardiovascular effects with only subtle alterations of behavior. CPA is widely used in scientific research into the adenosine rece ...
* N(6)-cyclohexyladenosine
*
Tecadenoson is an effective A1 adenosine agonist, as is
selodenoson.
* Benzyloxy-cyclopentyladenosine (BnOCPA) is an A1R selective agonist.
PAMs
* 2‑Amino-3-(4′-chlorobenzoyl)-4-substituted-5-arylethynyl thiophene # 4e
Antagonists
;Non-selective
*
Caffeine
Caffeine is a central nervous system (CNS) stimulant of the methylxanthine class. It is mainly used recreationally as a cognitive enhancer, increasing alertness and attentional performance. Caffeine acts by blocking binding of adenosine t ...
*
Theophylline
Theophylline, also known as 1,3-dimethylxanthine, is a phosphodiesterase inhibiting drug used in therapy for respiratory diseases such as chronic obstructive pulmonary disease (COPD) and asthma under a variety of brand names. As a member of the ...
*
CGS-15943
CGS-15943 is a drug which acts as a potent and reasonably selective antagonist for the adenosine receptors A1 and A2A, having a Ki of 3.3nM at A2A and 21nM at A1. It was one of the first adenosine receptor antagonists discovered that is not ...
;Selective
* 8-Cyclopentyl-1,3-dimethylxanthine (CPX / 8-cyclopentyltheophylline)
*
8-Cyclopentyl-1,3-dipropylxanthine
8-Cyclopentyl-1,3-dipropylxanthine (DPCPX, PD-116,948) is a drug which acts as a potent and selective antagonist for the adenosine A1 receptor. It has high selectivity for A1 over other adenosine receptor subtypes, but as with other xanthine de ...
(DPCPX)
* 8-Phenyl-1,3-dipropylxanthine
*
Bamifylline
Bamifylline is a drug of the xanthine chemical class which acts as a selective adenosine A1 receptor antagonist.
See also
* Theophylline
* Caffeine
Caffeine is a central nervous system (CNS) stimulant of the methylxanthine chemical cla ...
* BG-9719
* BG-9928
* FK-453
* FK-838
*
Rolofylline
Rolofylline (KW-3902) is an experimental diuretic which acts as a selective adenosine A1 receptor antagonist. It was discovered at NovaCardia, Inc. which was purchased by Merck & Co., Inc. in 2007.
Development of rolofylline was terminated on ...
(KW-3902)
* N-0861
* ISAM-CV202
In heart
The A
1 and A
2A receptors of endogenous adenosine are believed to play a role in regulating
myocardial
Cardiac muscle (also called heart muscle, myocardium, cardiomyocytes and cardiac myocytes) is one of three types of vertebrate muscle tissues, with the other two being skeletal muscle and smooth muscle. It is an involuntary, striated muscle that ...
oxygen consumption and coronary blood flow. Stimulation of the A
1 receptor has a myocardial depressant effect by decreasing the conduction of electrical impulses and suppressing
pacemaker cell
350px, Image showing the cardiac pacemaker or SA node, the primary pacemaker within the electrical_conduction_system_of_the_heart">SA_node,_the_primary_pacemaker_within_the_electrical_conduction_system_of_the_heart.
The_muscle_contraction.htm ...
function, resulting in a decrease in
heart rate
Heart rate (or pulse rate) is the frequency of the heartbeat measured by the number of contractions (beats) of the heart per minute (bpm). The heart rate can vary according to the body's physical needs, including the need to absorb oxygen and excr ...
. This makes adenosine a useful medication for treating and diagnosing ''
tachyarrhythmia
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 (su ...
s'', or excessively fast heart rates. This effect on the A
1 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
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 is measured as the rate at which blood is deliver ...
caused by
hypotension
Hypotension is low blood pressure. Blood pressure is the force of blood pushing against the walls of the arteries as the heart pumps out blood. Blood pressure is indicated by two numbers, the systolic blood pressure (the top number) and the dias ...
,
heart attack
A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops to the coronary artery of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which may tr ...
or
cardiac arrest
Cardiac arrest is when the heart suddenly and unexpectedly stops beating. It is a medical emergency that, without immediate medical intervention, will result in sudden cardiac death within minutes. Cardiopulmonary resuscitation (CPR) and possib ...
caused by nonperfusing
bradycardia
Bradycardia (also sinus bradycardia) is a slow resting heart rate, commonly under 60 beats per minute (BPM) as determined by an electrocardiogram. It is considered to be a normal heart rate during sleep, in young and healthy or elderly adults, a ...
s, 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 A
1 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, the pharmacological blockade of A
1 may have clinical utility.
Theophylline and caffeine are nonselective adenosine antagonists that are used to stimulate respiration in premature infants.
However, we are unaware of clinical studies that have examined the incidence of
periventricular leukomalacia
Periventricular leukomalacia (PVL) is a form of white-matter brain injury, characterized by the necrosis (more often coagulation) of white matter near the lateral ventricles. It can affect newborns and (less commonly) fetuses; premature infan ...
(PVL) as related to neonatal caffeine use. Caffeine may reduce cerebral blood flow in premature infants, it is presumed by blocking vascular A
2 ARs. Thus, it may prove more advantageous to use selective A
1 antagonists to help reduce adenosine-induced brain injury.
References
External links
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*
{{Adenosinergics
Adenosine receptors