ADP Receptors and Clinical Bleeding Disorders

Abstract

Abstract-ADP plays a key role in hemostasis and thrombosis. Despite its early identification in 1961 as the first known aggregating agent, the molecular basis of ADP-induced platelet activation is only beginning to be understood. The present review proposes a model of 3 purinergic receptors contributing separately to the complex process of ADP-induced platelet aggregation: the P2X 1 ionotropic receptor, responsible for rapid influx of ionized calcium into the cytosol; the P2Y 1 metabotropic receptor, responsible for mobilization of ionized calcium from internal stores, which initiates aggregation; and an as-yet-unidentified P2Y receptor coupled to G ␣i2 , which is essential for the full aggregation response to ADP. It is probable that this as-yet-unidentified receptor is the molecular target of the ADP-selective antiaggregating drugs ticlopidine and clopidogrel. In addition, it is probably defective in patients with a bleeding diathesis that is characterized by selective impairment of platelet responses to ADP. Key Words: adenosine diphosphate Ⅲ purino receptors Ⅲ platelets Ⅲ bleeding disorders Ⅲ thrombosis A DP, the first known low-molecular-weight, plateletaggregating agent, was initially identified after observations that a small molecule derived from red blood cells stimulated platelet adhesion to glass and induced platelet aggregation. 1,2 Adenine nucleotides, which originate from platelet dense granules and damaged cells, especially red blood cells and endothelial cells, interact with P2 receptors to regulate a broad range of physiological processes. P2 receptors are widely distributed in many different cell types. These receptors are divided into 2 main groups: the G proteincoupled, or "metabotropic," superfamily termed P2Y and the ligand-gated ion channel, or "ionotropic," superfamily termed P2X. 3 Seven subtypes of P2X and 11 subtypes of P2Y receptor have been identified to date.Several lines of evidence indicate that ADP plays a key role in the formation of the hemostatic plug and in the pathogenesis of arterial thrombi: (1) ADP is contained at high concentrations in the platelet dense granules and is released when platelets are stimulated by other agents, such as thrombin or collagen, thus reinforcing platelet aggregation 4 ; (2) inhibitors of ADP-induced platelet aggregation are effective antithrombotic drugs 5,6 ; and (3) patients with defects of ADP receptors or those lacking ADP in platelet granules have a bleeding diathesis. 4,7 ADP-Induced Platelet ActivationAddition of exogenous ADP to washed human platelets results in shape change, reversible aggregation at physiological concentrations of ionized calcium in the external medium, and finally, desensitization. In a minority of individuals, the close platelet-to-platelet contact brought about by the aggregation process triggers the formation of trace amounts of thromboxane A 2 , which stimulates platelet secretion and reinforces aggregation. 8 This effect is greatly enhanced 9 and can be observed in most individuals 8 when the concentration of ion...

The platelet P2Y receptors as targets for new antithrombotic drugs

“…The combined action of two platelet ADP receptors, P2Y 1 (coupled to Gq and PLCb) and P2Y 12 (negatively coupled to adenylyl cyclase through Gi), is necessary for the full platelet aggregation response to ADP [9]. The relative role of these receptors in platelet function has been elucidated by studies of patients with congenital P2Y 12 deficiency [9,10], knock-out mice [11][12][13] and selective antagonists [9,14].…”

“…The relative role of these receptors in platelet function has been elucidated by studies of patients with congenital P2Y 12 deficiency [9,10], knock-out mice [11][12][13] and selective antagonists [9,14]. The interaction of ADP with P2Y 1 leads to calcium mobilization, platelet shape change and rapidly reversible aggregation, while its interaction with P2Y 12 leads to the formation of large and stable platelet aggregates, and amplifies platelet secretion [9].In the last few years, search for selective, direct antagonists of P2Y 1 and P2Y 12 has been very active. Several ATP-derived antagonists of P2Y 12 have been synthesized by Astra-Zeneca, the last of which, AR-C69931MX, proved to have good antithrombotic effects in several animal models of thrombosis [15].…”

Molecular defects of the platelet P2 receptors

“…it amplifies the platelet responses induced by other platelet agonists [1,8,9], stabilizes platelet aggregates [10][11][12] and inhibits the antiplatelet effects of prostacyclin [13].…”

“…The interaction of ADP with its G q -coupled, P2Y 1 receptor mediates a transient rise in cytoplasmic Ca 2+ , platelet shape change and rapidly reversible aggregation, while its interaction with the G i -coupled, P2Y 12 receptor mediates inhibition of adenylyl cyclase, phosphatidylinositol 3-kinase activation and the amplification of the platelet aggregation response [1]. About 20-30% of the plateletbinding sites for ADP are associated with P2Y 1 , while the remaining 70% are associated with P2Y 12 [1,14].…”

“…About 20-30% of the plateletbinding sites for ADP are associated with P2Y 1 , while the remaining 70% are associated with P2Y 12 [1,14]. Concomitant activation of both the G q and G i pathways by ADP is necessary to elicit normal aggregation [1,10].…”