Adenosine Receptors
Nucleotides and their Derivatives

Author: Umberto Audisio
Date: 19/02/2012


Umberto Audisio, Enrico Brunetti.

Adenosine receptors as potential therapeutic targets.

P1 purinergic receptors are a group of G protein-coupled receptors, whose preferential ligand is extracellular adenosine. Four subtypes of adenosine receptors have been identified in humans: A1, A2A, A2B and A3.
Besides a wide variety of synthetic molecules identified as more or less specific agonists and antagonists, there are at least two naturally occurring molecules which have such properties: inosine is a partial agonist for A1 and A3 receptors, while caffeine (and its derivative theophylline) is a non-selective antagonist (with lower affinity for the A3 subtype).
Current evidence does not give any good reason to classify the receptors according to their affinity.

International Union of Basic and Clinical Pharmacology. LXXXI. Nomenclature and classification of adenosine receptors--an update. 2011

International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors. 2001


Adenosine receptors are classical GPCRs, with structure similarities with rhodopsin. The peptide has 7 alpha-helices spanning the plasma membrane, presents asparagine-linked glycosylation and sites for palmitoylation near the carboxyl terminus.
A1 and A3 receptors are coupled to Gi/o and A2a A2b receptors to Gs.
It has been shown that adenosine receptors can form homo- or hetero- oligomers and even couple with other GCPRs (P2 receptors and dopamine receptors), even though the consequences of this pairing are not clear.


According to their preferential G-protein coupling, A1 and A3 receptors show similar effects: they mediate inhibition of adenylyl cyclase and activate several types of K+-channels while inactivating Ca2+-channels.
A2A and A2B, on the other hand, stimulate the formation of cAMP and mobilize intracellular Ca2+.
All receptor subtypes seem to activate the MAPK pathway, even though their activity varies in different cell subsets, according to their protein expression profile.
Even if A1/A3 and A2A/A2B receptors respectively show similar effects, their signaling is probably modulated by different desensitization kinetics: A1 and A2A seem to desensitize quite rapidly, while A3 and A2B show slower down-modulation.


As the response to adenosine strictly depends on the level of expression of its receptors, physiological adenosine can activate receptors where they are adbundant, but not where they are sparse. The density of receptors shifts the dose response curves, but it does not alterate the maximal response.

So, knowing the receptor distribution can bring important advantages in order to understand the physiological and pathological actions of these pathways, the effects of caffeine consumption and to give important insights for pharmacological approaches.

Tabella distribuzione

Roles of the adenosinergic pathway.

Adenosine is involved in a wide variety of physiological and patophysiological processes. These involve different levels of ligand availability and receptor subtype expression.

A1: decreased renal blood flow, tubuloglomerular feedback, inhibition of lipolysis, inhibition of neurotransmitter and insulin/glucagon release, reduced heart rate, sleep, bone resorption, analgesia (acupuncture?), preconditioning.

A2A: wakefulness, locomotion, neurodegeneration, immunosuppression, vasodilatation, inhibition of platelet aggregation, angiogenesis.

A2B :preconditioning, pain,vascular integrity.

A3: increased mast cell activation, airway contraction, inflammatory pain, white cell chemotaxis.

All these processes are eligible targets for drug development (agonists, antagonists and allosteric modulators, both selective and unselective): there are have been serious attempts to develop A2A receptor antagonists to prevent neurodegeneration in Parkinson’s and Alzheimer’s diseases, and agonists for immunesuppression.
There are some issues with the development of drugs targeting adenosine receptors because of their pleiotropic functions and their almost ubiquitous distribution, so that obtaining a specific effect avoiding side effects could prove quite difficult.
Finally it is important to consider that the majority of humans is exposed to caffeine on a daily basis, so that any ulterior interference with the adenosine signaling pathway should take into account the basal, and to date only partially understood, antagonistic effects of this compound. .

Clinical trials list:
- supraventriculat tacyarrhythmia (approved)
- regulation of VEGF and cytokine release
- cardioprotection (pre- and post- conditioning)
- neuropathic pain

Dipiridamole (extracellular adenosine-increasing drug)
- coronary vasodilation
- Schizophrenia

A1 partial agonists (to prevent heart block):
- Peripheral neuropathic pain
- Diabetic hypertriglyceridemia
- Atrial fibrillation

Adenosine receptors as drug targets. 2010

Actions of caffeine in the brain with special reference to factors that contribute to its widespread use. 1999

Novel investigational adenosine A2A receptor antagonists for Parkinson's disease. 2009

Adenosine receptors and cancer. 2011

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