In humans, there are four adenosine receptors. Each is encoded by a separate gene and has different functions, although also overlapping. For instance, both A1 receptors and A2a play roles in the heart, regulating myocardial oxygen consumption and coronary blood flow.
Comparison of subtypes
|A1||ADORA1||Gi/o --> cAMP↑/↓
|A2a||ADORA2A||Gs --> cAMP↑||
|A2b||ADORA2B||Gs --> cAMP↑||
A1 adenosine receptor
The adenosine A1 receptor has been found to be ubiquitous throughout the entire body.
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. Presynaptically, it reduces synaptic vesicle release while post synaptically it has been found to stabilize the magnesium on the NMDA receptor.
Antagonism and agonism
Caffeine, along with theophylline have been found to antagonize both A1 and A2a receptors in the brain. Specific antagonists 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).
The A1, together with A2a receptors, of endogenous adenosine are believed to 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 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.
In neonatal medicine
Adenosine antagonists are widely used in neonatal medicine;
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.
However, we are unaware of clinical studies that have examined the incidence of periventricular leukomalacia (PVL) as related to neonatal caffeine use. Caffeine may reduce cerebral blood flow in premature infants, possibly by blocking vascular A2 ARs. Thus, it may prove more advantageous to use selective A1 antagonists to help reduce adenosine-induced brain injury.
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.
The activity of A2A adenosine receptor, a G-protein coupled receptor family member, is mediated by G proteins which activate adenylyl cyclase. It is abundant in basal ganglia, vasculature and platelets 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.
Agonists and antagonists
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.
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.
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- Unless else specified in boxes, then ref is:senselab
- "Entrez Gene: ADORA2A adenosine A2a receptor".
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