P2 Receptors and Platelet Activation

Abstract

Adenosine diphosphate (ADP) plays a crucial role in hemostasis and thrombosis by activating platelets. In platelets, the classical P2T receptor is now resolved into three P2 receptor subtypes: the P2Y1, the P2Y12, and the P2X1 receptors. Both pharmacological and molecular biological approaches have confirmed the role of the P2Y1 and P2Y12 receptors in the ADP-induced platelet fibrinogen receptor activation. The P2Y1 and the P2X1 receptors independently contribute to platelet shape change. Whereas the P2Y12 receptor mediates the potentiation of dense granule release reaction, both the P2Y1 and P2Y12 receptors play an important role in the ADP-induced phospholipase A2 activation. The signaling events downstream of these receptors leading to the physiological effects remain elusive, and they are yet to be delineated. KEY WORDS: platelets, P2X1 receptor, P2Y1 receptor, P2T receptor, P2Y12 receptor, ADP receptor, platelet aggregation DOMAINS: thrombosis, signaling, hematology INTRODUCTIONPlatelets aggregate at the site of vascular damage to form a hemostatic plug. Abnormal activation of platelets leads to thrombosis, which in turn leads to stroke and myocardial infarction [1]. Adhesion of platelets to subendothelium results in the release, generation, or exposure of agonists that can activate platelets in a positive-feedback loop. Among these agonists are collagen (exposed), thrombin and thromboxane A 2 (generated), and ADP (adenosine diphosphate), epinephrine, and serotonin (released) [2]. ADP was identified as a platelet agonist [3], which is released upon activation of platelets along with ATP (adenosine triphosphate) and serotonin [4]. The importance of ADP in platelet activation is substantiated by bleeding diathesis in patients with deficiencies in storage of ADP, in mechanisms of secretion, or in ADP receptors [5,6,7,8,9]. Kunapuli: Platelet P2 Receptor Subtypes TheScientificWorldJOURNAL (2002) 2, 424-433 425 NOMENCLATURE OF P2 RECEPTORSReceptors for nucleotides, designated P2 receptors, are divided into two main classes: ligandgated ion channels (P2X) and G protein-coupled receptors (P2Y) [10]. Initially, all the physiological and intracellular signaling events triggered by ADP in platelets were attributed to a single cell surface receptor, designated P2T (thrombocyte P2 receptors) [11]. The historic studies and theories on the nature of the P2T receptor have been dealt in recent review articles [12,13,14]. ADP RECEPTOR-COUPLED EFFECTOR SYSTEMS IN PLATELETSADP has several effects on the receptor-coupled effector systems in platelets:• ADP regulates several second messenger systems in platelets by acting on cell surface P2 receptors [12,13,14,15].• ADP causes rapid calcium influx into platelets in the presence of physiological extracellular calcium ion concentrations [16,17].• ADP activates platelet phospholipase C (PLC), resulting in inositol 1,4,5-trisphosphate formation that leads to mobilization of calcium from intracellular stores [18,19,20].• ADP inhibits stimulated platelet adenylyl cyclase throug...

LDL oxidized by hypochlorous acid causes irreversible platelet aggregation when combined with low levels of ADP, thrombin, epinephrine, or macrophage-derived chemokine (CCL22)

“…The released ATP may play an important activating role by way of the P2 ϫ 1 ATP-gated cation channel receptor on platelets. 72,[83][84][85] In addition, the presence of extracellular apyrases (CD39) on endothelial cells will generate ADP from any released ATP and further enhance platelet activation. [86][87][88] The role of PKC in granule secretion and its activation by lipid mediators is well known.…”

C-type lectin like receptor 2 (CLEC-2) signals independently of lipid raft microdomains in platelets

“…Platelets contain two types of agonist receptors; G-protein coupled receptors (GPCRs) and Tyrosine kinase pathway receptors and ligand-gated ion channels which are important for their activation [3–7]. All tyrosine kinase pathway receptors GPVI, FcγRIIA and CLEC-2 are linked to activation of Syk and PLCγ2 [4, 8–12].…”

Plant extracts inhibit ADP-induced platelet activation in humans: their potential therapeutic role as ADP antagonists

“…Nevertheless, when ADP is secreted from its storage pools in platelet dense granules, it amplifies platelet responses induced by other platelet agonists [5,6]. It is well established that ADP activates platelets through three purinoceptor subtypes, namely P2Y 1 , P2Y 12 and P2X 1 [1,7,8]. The P2Y 1 purinergic receptor is coupled to G q , which is involved in PSC and reversible aggregation, due to a transient increase in cytoplasmic Ca…”

“…The P2Y 12 purinergic receptor is coupled to G i which mediates the inhibition of adenylyl cyclase and amplifies the platelet aggregation response [6]. The P2X 1 ligand-gated cation channel is activated by adenosine triphosphate (ATP) and is also involved in PSC [7,9]. The simultaneous activation of both G q and G i pathways by ADP is necessary to elicit normal platelet aggregation [6].…”