The adenosine receptors (or P1 receptors) are a class of purinergic receptors, G-protein coupled receptors with adenosine as endogenous ligand.

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 A_2A play roles in the heart, regulating myocardial oxygen consumption and coronary blood flow.

Comparison of subtypes

Adenosine receptors

Receptor	Gene	Mechanism	Effects	Agonists	Antagonists
A1		Gi/o --> cAMP↑/↓ Inhibition ↓ vesicle release ↓ NMDA receptor activity	decrease heart rate	CCPA	caffeine theophylline DPCPX CPT CPX
A2A		Gs --> cAMP↑	coronary artery vasodilatation	CGS21680 ATL-146e	caffeine theophylline KW6002 SCH-58261
A2b		Gs --> cAMP↑			theophylline
A3		Gi/o -->	cardioprotective in cardiac ischemia inhibition of neutrophil degranulation	Cl-IB-MECA MRS3558	theophylline MRS1191 MRS1523 MRE3008F20

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 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).

In the heart

The A₁, together with A_2A 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.

A_2A adenosine receptor

As with the A₁, the A_2A receptors are believed to play a role in regulating myocardial oxygen consumption and coronary blood flow.

Mechanism

The activity of A_2A 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.

Function

The A_2A 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

Specific antagonists include KW6002 and SCH-58261, while specific agonists include CGS21680 and ATL-146e.

A_2B 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.

References

External links

• IUPHAR GPCR Database - Adenosine Receptors