ADP and platelets: the end of the beginning

Woulfe, Donna S.; Yang, Jing; Brass, Lawrence F.

doi:10.1172/jci13361

Cited by 125 publications

(92 citation statements)

References 25 publications

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“…P2Y 12 is coupled to inhibition of cAMP production by adenylyl cyclase through G i . Co-activation of P2Y 1 and P2Y 12 receptors is required for normal ADPevoked aggregation [27,28]. It is possible that a fewer number of P2Y 1 receptors may have a similar effect on platelet aggregation to a larger number of P2Y 12 receptors.…”

Section: Discussionmentioning

confidence: 99%

Quantification of ADP and ATP receptor expression in human platelets

Wang

Östberg

Wihlborg

et al. 2003

Journal of Thrombosis and Haemostasis

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Summary. The mechanism of ADP-mediated platelet activation has been difficult to unravel due to the large number of receptors for extracellular nucleotides (P2 receptors). mRNA levels in circulating platelets are very low, but have been shown to be translationally active. By optimizing mRNA extraction and using real time (RT)-PCR we were able to establish a protocol for highly sensitive platelet mRNA quantification in human regular blood samples. In platelets from healthy volunteers, only P2X 1 , P2Y 1 and P2Y 12 were found in significant levels, with the following order of expression: P2Y 12 >> P2X 1 > P2Y 1 . Other P2 receptors (P2Y 2 , P2Y 4 , P2Y 6 , P2Y 11 , P2Y 13 , P2X 4 , P2X 7 ) had very low expression. As a control measurement to exclude contamination, P2 receptors in buffy coat were quantified but had a completely different profile. Incubation in vitro revealed a more rapid degradation rate for P2X 1 receptor mRNA than for P2Y 1 and P2Y 12 , indicating that the level of P2X 1 may be relatively higher in newly released platelets and in megacaryocytes. In conclusion, we have developed the first protocol for quantifying mRNA expression in human platelets limiting the P2 receptor drug development targets to P2Y 12 , P2Y 1 and P2X 1 . Furthermore, the method could be used to study platelet expression for any gene in human materials.Keywords: P2X receptor, P2Y receptor, platelets, real time-PCR, Western blot.Platelets play a crucial role in the maintenance of normal hemostasis and are involved in the development of pathological thrombus formation leading to vascular occlusion which is an important mechanism in myocardial infarction and stroke [1,2]. A large number of endogenous mediators can activate platelets, such as thromboxane A2, adenosine diphosphate (ADP), collagen, von Willebrand factor, thrombin, epinephrine and 5-hydroxitryptamine (5-HT). To get full activation of the platelets, these agonists are dependent on two positive feedback loops: the formation of thromboxane A2 by cyclooxygenase in the platelets and the release of ADP from dense platelet granules. Thromboxane A2 and ADP then activates specific receptors on the extracellular side of the platelet membrane.Therapeutic intervention aimed at the first positive feedback loop by inhibiting cyclooxygenase with aspirin is highly efficient in reducing death and cardiovascular events. However, ADP may be even more important as evidenced by the CAPRIE study, in which the ADP receptor inhibition was more beneficial than aspirin in reducing cardiovascular events [3,4].Recently, progress has been made in the understanding of the mechanisms of ADP mediated platelet aggregation, where at least three receptors are considered to be involved; the P2Y 12 , P2Y 1 , and P2X 1 receptors [5]. The importance of the P2Y 12 receptor is proven by the effects of clopidogrel, which after metabolization in the liver, acts as an irreversible antagonist at P2Y 12 receptors. Knockout of the P2Y 1 receptor in mice has demonstrated its importance for thrombus formation, blee...

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Section: Discussionmentioning

confidence: 99%

Quantification of ADP and ATP receptor expression in human platelets

Wang

Östberg

Wihlborg

et al. 2003

Journal of Thrombosis and Haemostasis

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“…The P2Y 12 receptor is negatively coupled to adenylyl cyclase activity through activation of a G protein, as shown by experiments with a radiolabelled GTP photoaffinity ligand [128], receptor antagonists [129], and genetically engineered mice [89,130]. This G protein was identified as G i2 by Ohlmann et al in 1995 [128].…”

Section: The P2y 12 Receptormentioning

confidence: 99%

Historical perspective on ADP-induced platelet activation

Packham

Rand

2011

Purinergic Signalling

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“…ADP generated from damaged tissue has long been recognized to induce platelet aggregation. 81,82 ADP is also secreted by platelets themselves by degranulation, 83,84 potentially forming a positive feedback loop.…”

Section: Early Inflammatory Eventsmentioning

confidence: 99%

Purinergic Signaling in Early Inflammatory Events of the Foreign Body Response: Modulating Extracellular ATP as an Enabling Technology for Engineered Implants and Tissues

Rhett

Fann²,

Yost³

2014

Tissue Engineering Part B: Reviews

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Purinergic signaling is a ubiquitous and vital aspect of mammalian biology in which purines-mainly adenosine triphosphate (ATP)-are released from cells through loss of membrane integrity (cell death), exocytosis, or transport/diffusion across membrane channels, and exert paracrine or autocrine signaling effects through three subclasses of well-characterized receptors: the P1 adenosine receptors, the P2X ionotropic nucleotide receptors, and the P2Y metabotropic receptors. ATP and its metabolites are released by damaged and stressed cells in injured tissues. The early events of wound healing, hemostasis, and inflammation are highly regulated by these signals through activation of purinergic receptors on platelets and neutrophils. Recent data have demonstrated that ATP signaling is of particular importance to targeting leukocytes to sites of injury. This is particularly relevant to the subject of implanted medical devices, engineered tissues, and grafts as all these technologies elicit a wound healing response with varying degrees of encapsulation, rejection, extrusion, or destruction of the tissue or device. Here, we review the biology of purinergic signaling and focus on ATP release and response mechanisms that pertain to the early inflammatory phase of wound healing. Finally, therapeutic options are explored, including a new class of peptidomimetic drugs based on the ATP-conductive channel connexin43.

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ADP and platelets: the end of the beginning

Cited by 125 publications

References 25 publications

Quantification of ADP and ATP receptor expression in human platelets

Quantification of ADP and ATP receptor expression in human platelets

Historical perspective on ADP-induced platelet activation

Purinergic Signaling in Early Inflammatory Events of the Foreign Body Response: Modulating Extracellular ATP as an Enabling Technology for Engineered Implants and Tissues

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