Adenosine A1 receptor

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The adenosine A₁ receptor^[1] is one member of the adenosine receptor group of G protein-coupled receptors with adenosine as endogenous ligand.

[edit] Biochemistry

A₁ receptors are implicated in sleep promotion by inhibiting wake promoting cholinergic neurons in the basal forebrain.^[2] A₁ receptors are also present in smooth muscle throughout the vascular system.^[3]

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

[edit] Signaling

Activation of the adenosine A₁ receptor by an agonist causes binding of G_i1/2/3 or G_o protein. Binding of G_i1/2/3 causes an inhibition of adenylate cyclase and therefore a decrease in the cAMP concentration. An increase of the inositol triphosphate/diacylglycerol concentration is caused by an activation of phospholipase C while the elevated levels of arachidonic acid are mediated by phospholipase 2A Several types of potassium channels are activated but N-, P- and Q-type calcium channels are inhibited.^[4]

[edit] 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.

[edit] Antagonism and agonism

Caffeine, along with theophylline have been found to antagonize both A₁ and A_2a 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).

[edit] In 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.

[edit] 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.

[edit] References

[edit] External links

• IUPHAR GPCR Database - A₁ receptor
• MeSH Adenosine+A1+Receptor

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