The A3 adenosine receptor: an enigmatic player in cell biology.

Adenosine is a primordial signaling molecule present in every cell of the human body that mediates its physiological functions by interacting with 4 subtypes of G-protein-coupled receptors, termed A(1), A(2A), A(2B) and A(3). The A(3) subtype is perhaps the most enigmatic among adenosine receptors since, although several studies have been performed in the years to elucidate its physiological function, it still presents in several cases a double nature in different pathophysiological conditions. The 2 personalities of A(3) often come into direct conflict, e.g., in ischemia, inflammation and cancer, rendering this receptor as a single entity behaving in 2 different ways. This review focuses on the most relevant aspects of A(3) adenosine subtype activation and summarizes the pharmacological evidence as the basis of the dichotomy of this receptor in different therapeutic fields. Although much is still to be learned about the function of the A(3) receptor and in spite of its duality, at the present time it can be speculated that A(3) receptor selective ligands might show utility in the treatment of ischemic conditions, glaucoma, asthma, arthritis, cancer and other disorders in which inflammation is a feature. The biggest and most intriguing challenge for the future is therefore to understand whether and where selective A(3) agonists or antagonists are the best choice.