Adenosine receptors are ubiquitous regulators of many cellular signaling pathways; involved in a diverse array of physiological and pathophysiological mechanisms, they are present on every cell. This makes adenosine receptors vital targets in drug discovery for novel therapeutic applications. Throughout this blog post, we will look in more detail at adenosine receptors and their sub-types.
Basic Structure and Function of Adenosine Receptors
Adenosine receptors are part of the G protein-coupled receptor family of transmembrane proteins. They play a fundamental role in physiological processes relating to arousal, cardiac contraction, locomotion, vascular tone, adipocyte content, diuresis, and immunity. Adenosine receptors predominantly mediate the physiological actions of adenosine, which appears to play a neuromodulator role in nervous tissue and acts as a “retaliatory metabolite” in non-nervous tissue.1
Adenosine receptors have a seven transmembrane α-helical structure which displays an extracellular amino-terminus and an intracellular carboxy-terminus. The N-terminal amino-terminus has N-glycosylation sites, while the carboxy-terminus comprises serine and threonine residues.2
Adenosine Receptor Sub-types
Four sub-sets of adenosine receptors have been identified to date, including A1, A2A, A2B, and A3. A1 and A3 adenosine receptors are coupled to Gi/o proteins and inhibit cyclic AMP production, decreasing protein kinase A. Adenosine receptors A2A and A2B, on the other hand, increase cyclic AMP, which activates protein kinase A through phosphorylation.2
A1 Adenosine Receptors
A1 adenosine receptors are heavily expressed within the CNS, particularly in the neocortex, cerebellum, and hippocampus, where they regulate the expression of serotonin, glutamate, acetylcholine, and GABA.2 They are also found in cardiac muscle and inhibit certain Ca2+ channels from regulating heart rate.3 A1 adenosine receptors are therapeutic targets for numerous cardiovascular disorders like supraventricular tachyarrhythmia and atrioventricular node block and can be used as bradyarrhythmias for transplanted hearts.4
A2A, A2B Adenosine Receptors
A2 adenosine receptors are found in pre and postsynaptic nerve terminals, mast cells, pulmonary smooth muscle, and leukocytes. A2A adenosine receptors are expressed in numerous neurons, where they are responsible for GABA, acetylcholine, and glutamate modulation, potentially influencing motor functions. A2A adenosine receptors in the periphery and the CNS are being targeted in the development of anti-inflammatory drugs, and their antagonists have been studied for neurodegenerative diseases like Parkinson’s disease.4
A2B adenosine receptors are mostly expressed in the gastrointestinal tract, bladder, lung, and mast cells. Although structurally similar to A2A, A2B adenosine receptors have very different functions. The low affinity of A2B adenosine receptors indicates that they are only activated with increases in extracellular adenosine. A2B adenosine receptors are major targets for anti-inflammatory drugs for many different tissues. They also play a key role in the anti-tumor immune response, which kills tumor cells and therefore have therapeutic applications in oncology.5
A3 Adenosine Receptors
A3 adenosine receptors are broadly distributed, located in the heart, brain cortex, kidneys, lungs, and testis, as well as in eosinophils, neutrophils, and mast cells.4 A3 adenosine receptors are central mediators of cardioprotective functions and inhibit neutrophil degranulation. As A3 adenosine receptors couple to mitogen-activated protein kinases, they may play a vital role in cell growth, survival, differentiation, and death.3 A3 adenosine receptors are targeted for asthma because they stimulate phospholipase D and, subsequently, the release of inflammatory mediators like histamine.4
Challenges of Adenosine Receptors as Drug Targets
Despite being central to disease treatment research, few clinically approved drugs have been discovered targeting adenosine receptors because of insufficient efficacy or toxic side effects. This is due to the vastly different, complex roles they play within the body. It is, therefore, difficult to demonstrate the effects of potential treatments on specific systems at the level that is required for clinically safe and effective treatment.6 To combat these issues, new ligand technologies have enabled the production of much more specific agonists and antagonists of adenosine receptors, resulting in more clinical trials for new drugs.
To further the development of effective, non-toxic drugs there are a number of things to consider: global and local examination of adenosine receptors in human disease models; cautious partitioning of the drug action site via administration in animals with cell-specific receptor deletions; close assessment of the effects of a drug throughout a particular disease course; and careful monitoring of individual differences.6
Adenosine receptors are central to drug discovery for a wide variety of diseases, and advances in ligand discovery and drug assessments are improving their clinical use. The correct targeting of adenosine receptors can benefit the treatment of numerous inflammatory and autoimmune disorders, chronic pain, arrhythmia, along with some metabolic disorders.
- Alexander, S.P.H. 2007. Adenosine Receptors. 2nd Edition. xPharm: The Comprehensive Pharmacology Reference. Pages 1-3.
- Sheth, S., Brito, R., Mukherjea, D., Rybak, L.P. and Ramkumar, V. 2014. Adenosine receptors: expression, function, and regulation. International journal of molecular sciences. 15(2), pp.2024-2052.
- Jacobson, K.A. and Gao, Z.G. 2006. Adenosine receptors as therapeutic targets. Nature reviews Drug discovery. 5(3), pp.247-264.
- Sachdeva, S. and Gupta, M. 2013. Adenosine and its receptors as therapeutic targets: an overview. Saudi Pharmaceutical Journal. 21(3), pp.245-253.
- Van Galen, P.J., Stiles, G.L., Michaels, G. and Jacobson, K.A. 1992. Adenosine A1 and A2 receptors: structure–function relationships. Medicinal research reviews. 12(5), pp.423-471.
- Chen, J.F., Eltzschig, H.K. and Fredholm, B.B. 2013. Adenosine receptors as drug targets—what are the challenges? Nature reviews Drug discovery. 12(4), pp.265-286.