Adenosine A1 receptor

The adenosine A1 receptor is one member of the is_associated_with::adenosine receptor group of is_associated_with::G protein-coupled receptors with is_associated_with::adenosine as is_associated_with::endogenous is_associated_with::ligand.

Biochemistry
A1 receptors are implicated in sleep promotion by inhibiting wake-promoting is_associated_with::cholinergic neurons in the is_associated_with::basal forebrain. A1 receptors are also present in smooth muscle throughout the vascular system.

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

Signaling
Activation of the adenosine A1 receptor by an is_associated_with::agonist causes binding of Gi1/2/3 or Go protein. Binding of Gi1/2/3 causes an inhibition of is_associated_with::adenylate cyclase and, therefore, a decrease in the cAMP concentration. An increase of the is_associated_with::inositol triphosphate/is_associated_with::diacylglycerol concentration is caused by an activation of is_associated_with::phospholipase C, whereas the elevated levels of is_associated_with::arachidonic acid are mediated by DAG lipase, which cleaves DAG to form arachidonic acid. Several types of is_associated_with::potassium channels are activated but N-, P-, and Q-type is_associated_with::calcium channels 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, it reduces is_associated_with::synaptic vesicle release.

Ligands
is_associated_with::Caffeine, as well as is_associated_with::theophylline, has been found to antagonize both A1 and A2A receptors in the brain.

Agonists

 * 2-Chloro-N(6)-cyclopentyladenosine (CCPA).
 * is_associated_with::N6-Cyclopentyladenosine
 * N(6)-cyclohexyladenosine

PAMs

 * 2‑Amino-3-(4′-chlorobenzoyl)-4-substituted-5-arylethynyl thiophene # 4e

Antagonists

 * Non-selective
 * is_associated_with::Caffeine
 * is_associated_with::Theophylline
 * is_associated_with::CGS-15943


 * Selective
 * 8-Cyclopentyl-1,3-dimethylxanthine (CPX / 8-cyclopentyltheophylline)
 * is_associated_with::8-Cyclopentyl-1,3-dipropylxanthine (DPCPX)
 * 8-Phenyl-1,3-dipropylxanthine
 * is_associated_with::Bamifylline
 * BG-9719
 * BG-9928
 * FK-453
 * FK-838
 * is_associated_with::Rolofylline (KW-3902)
 * N-0861

In heart
The A1 and A2A receptors of endogenous adenosine are believed to play a role in regulating is_associated_with::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 is_associated_with::heart rate. This makes adenosine a useful medication for treating and diagnosing is_associated_with::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 is_associated_with::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 is_associated_with::hypoperfusion caused by is_associated_with::hypotension, is_associated_with::heart attack or is_associated_with::cardiac arrest caused by nonperfusing is_associated_with::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 is_associated_with::neonatal medicine;

Because a reduction in A1 expression appears to prevent hypoxia-induced is_associated_with::ventriculomegaly and loss of white matter, the 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 is_associated_with::periventricular leukomalacia (PVL) as related to neonatal caffeine use. Caffeine may reduce cerebral blood flow in premature infants, it is presumed by blocking vascular A2 ARs. Thus, it may prove more advantageous to use selective A1 antagonists to help reduce adenosine-induced brain injury.