Blood Platelet Adenosine Receptors as Potential Targets for Anti-Platelet Therapy

Abstract

Adenosine receptors are a subfamily of highly-conserved G-protein coupled receptors. They are found in the membranes of various human cells and play many physiological functions. Blood platelets express two (A2A and A2B) of the four known adenosine receptor subtypes (A1, A2A, A2B, and A3). Agonization of these receptors results in an enhanced intracellular cAMP and the inhibition of platelet activation and aggregation. Therefore, adenosine receptors A2A and A2B could be targets for anti-platelet therapy, especially under circumstances when classic therapy based on antagonizing the purinergic receptor P2Y12 is insufficient or problematic. Apart from adenosine, there is a group of synthetic, selective, longer-lasting agonists of A2A and A2B receptors reported in the literature. This group includes agonists with good selectivity for A2A or A2B receptors, as well as non-selective compounds that activate more than one type of adenosine receptor. Chemically, most A2A and A2B adenosine receptor agonists are adenosine analogues, with either adenine or ribose substituted by single or multiple foreign substituents. However, a group of non-adenosine derivative agonists has also been described. This review aims to systematically describe known agonists of A2A and A2B receptors and review the available literature data on their effects on platelet function.

Adenosine Receptor Agonists Increase the Inhibition of Platelet Function by P2Y12 Antagonists in a cAMP- and Calcium-Dependent Manner

“…AR subtypes A 2A and A 2B are expressed in platelets, while A 1 , and A 3 are not [ 9 , 11 ]. Platelet AR activation decreases platelet activation and aggregation, mediated by an increase in intracellular cAMP (cyclic adenosine monophosphate) levels [ 12 , 13 ]. Adenosine is a natural AR agonist; however, as it is an extremely short-lasting one (less than 10 s in physiological conditions), there is a great need for synthetic, long-lasting agonists [ 13 , 14 ].…”

P2Y12 Inhibition beyond Thrombosis: Effects on Inflammation

“…Therefore, adenosine acts as a regulator of immune cells that aims at preserving host integrity and promotes the resolution of inflammation. Moreover, adenosine is a potent inhibitor of platelet aggregation and adenosine receptor agonists have been shown to potentiate antiplatelet effects of P2Y 12 antagonists [87,133,134]. Thus, adenosine might have a beneficial effect in the management of severe inflammatory disorders including sepsis.…”

Adenosine and the Cardiovascular System: The Good and the Bad

“…A 3 Rs are implicated more specifically in ischemia/reperfusion protection, but all receptor subtypes seem to be implicated in ischemia myocardium protection [7]. Finally, A 2A and A 2B receptors are expressed on platelets, where their activation leads to antiplatelet properties via calcium flux inhibition [28].…”