P2 receptors and platelet function

Abstract

Following vessel wall injury, platelets adhere to the exposed subendothelium, become activated and release mediators such as TXA 2 and nucleotides stored at very high concentration in the so-called dense granules. Released nucleotides and other soluble agents act in a positive feedback mechanism to cause further platelet activation and amplify platelet responses induced by agents such as thrombin or collagen. Adenine nucleotides act on platelets through three distinct P2 receptors: two are G proteincoupled ADP receptors, namely the P2Y 1 and P2Y 12 receptor subtypes, while the P2X 1 receptor ligand-gated cation channel is activated by ATP. The P2Y 1 receptor initiates platelet aggregation but is not sufficient for a full platelet aggregation in response to ADP, while the P2Y 12 receptor is responsible for completion of the aggregation to ADP. The latter receptor, the molecular target of the antithrombotic drugs clopidogrel, prasugrel and ticagrelor, is responsible for most of the potentiating effects of ADP when platelets are stimulated by agents such as thrombin, collagen or immune complexes. The P2X 1 receptor is involved in platelet shape change and in activation by collagen under shear conditions. Each of these receptors is coupled to specific signal transduction pathways in response to ADP or ATP and is differentially involved in all the sequential events involved in platelet function and haemostasis. As such, they represent potential targets for antithrombotic drugs.

Ca2+Influx through P2X1 Receptors Amplifies P2Y1 Receptor-Evoked Ca2+Signaling and ADP-Evoked Platelet Aggregation

“…It is well established that ADP-evoked P2Y1 and P2Y12 receptor signals interact to enhance downstream functional responses in the platelet (Hechler and Gachet, 2011). We now demonstrate that costimulation of ATP-gated P2X1 receptors and ADP-stimulated P2Y receptors also potentiates platelet aggregation.…”

“…(Vial et al, 2002), but the impact of this interaction on functional responses has not been determined. It is established that the coupling of P2Y1 receptors to aggregation requires coactivation of P2Y12-stimulated pathways (Kahner et al, 2006;Hechler and Gachet, 2011) and that P2X1 receptors do not directly potentiate P2Y12-evoked aggregation . Therefore, to explore the consequence of P2X1:P2Y1 interactions on platelet function, we compared responses to the selective P2X1 agonist a,b-meATP, the physiologic P2Y1 and P2Y12 agonist ADP, and both agonists combined.…”

“…Individual cells normally express more than one P2 receptor subtype, and interactions between their signaling pathways have the potential to regulate cellular responses. For example, platelets express only P2X1, P2Y1, and P2Y12 receptors (Kahner et al, 2006;Hechler and Gachet, 2011;Mahaut-Smith et al, 2011). ATP-gated P2X1 receptors generate significant transient increases in intracellular Ca 21 leading to shape change but not aggregation responses (Oury et al, 2001;Rolf et al, 2001;Rolf and Mahaut-Smith, 2002;Hechler et al, 2003).…”

New Fundamentals in Hemostasis

“…The second platelet ADP receptor, P2Y 1 , coupling to G q , has a prominent role in initial platelet responses, in contrast to P2Y 12 which is more active in later stages (117). The TP receptor for autocrine produced thromboxane A 2 (suppressed by the drug aspirin) and the 5-HT 2A receptor for serotonin also couple to G q , the latter of which has limited signaling capacity (211).…”

Comparison of P2Y12 receptor inhibition by clopidogrel and prasugrel in patients undergoing percutaneous coronary intervention

“…There is ample evidence that response to clopidogrel is also influenced by pharmacokinetic variables such as intestinal absorption and metabolic activation in the liver, both of which, in turn, are affected by genetic polymorphisms 21 . As P2Y12 receptor plays a pivotal role in platelet aggregation, poor platelet response to clopidogrel may be overcome by the use of more potent P2Y12 antagonists or higher doses of clopidogrel 22 .…”