P2Y12 receptors in platelets and other hematopoietic and non-hematopoietic cells

Gachet, Christian

doi:10.1007/s11302-012-9303-x

Cited by 125 publications

(108 citation statements)

References 140 publications

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“…P2Y1 couples to Gq and mediates influx of Ca 2ϩ , platelet shape change and transient aggregation, while P2Y12 receptors couple to Gi family members and mediate inhibition of adenyl cyclase activity and augmentation of platelet aggregation. Optimal platelet aggregation requires activation of both ADP receptors (reviewed in Offermanns, 32 Gachet, 33 and Kahner et al 34 ). One consequence of exposure to ADP is the release of arachidonic acid (AA) from platelet membrane phospholipids.…”

Section: Discussionmentioning

confidence: 99%

NPP4 is a procoagulant enzyme on the surface of vascular endothelium

Albright

Chang

Robert

et al. 2012

Blood

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Ap3A is a platelet-dense granule component released into the extracellular space during the second wave of platelet aggregation on activation. Here, we identify an uncharacterized enzyme, nucleotide pyrophosphatase/phosphodiesterase-4 (NPP4), as a potent hydrolase of Ap3A capable of stimulating platelet aggregation and secretion. We demonstrate that NPP4 is present on the surface of vascular endothelium, where it hydrolyzes Ap3A into AMP and ADP, and Ap4A into AMP and ATP. Platelet aggregation assays with citrated platelet-rich plasma reveal that the primary and secondary waves of aggregation and dense granule release are strongly induced by nanomolar NPP4 in a concentration-dependent manner in the presence of Ap3A, while Ap3A alone initiates a primary wave of aggregation followed by rapid disaggregation. NPP2 and an active site NPP4 mutant, neither of which appreciably hydrolyzes Ap3A, have no effect on platelet aggregation and se- IntroductionThe formation of a platelet-rich thrombus stabilized by fibrin crosslinking is the final common pathway for arterial thrombosis, the most common disease process affecting adults in the United States. The first step in thrombus formation consists of platelet adhesion to the exposed subendothelial extracellular matrix at the site of vascular injury. Here, circulating blood platelets bind collagen via their GPVI receptors, and bind von Willebrand factor via GPIb, triggering inside-out activation of other surface integrins and the release of platelet granule contents into the extracellular space. 1 The release of preformed molecules stored in platelet-dense granules such as ADP, serotonin, and ionized calcium, then amplifies the clotting reaction beyond the platelet monolayer bound on the collagen surface to circulating platelets in the immediate vicinity of the damaged endothelium. This amplification is further augmented by the secretion of thromboxane A2. ADP binding to purinergic receptors on the platelet surface (P2Y1 and P2Y12) induces rapid calcium influx and mobilization resulting in platelet shape change, activation, and partial degranulation thus promoting platelet aggregation. On granule release, local ADP concentrations are estimated to exceed 500M, but ADP is quickly metabolized by ectoenzymes on the surface of endothelial cells (such as CD39 2,3 ) and soluble phosphohydrolyases in blood plasma which attenuate the prothrombotic response. [4][5][6][7] To sustain the clotting reaction, a slow and steady source of ADP at the site of the growing thrombus is required. Another preformed chemical released by platelet-dense granules at high concentrations, diadenosine triphosphate (Ap3A), has an ill-defined role in thrombus formation but has been suggested to provide a source of long-lasting ADP at the site of vascular injury.Ap3A is stored within platelet granules at high concentrations (ϳ20-30mM) and is released with ADP and ATP into the blood during thrombin-induced platelet aggregation at concentrations thought to range between 40 and 100M 8 (see supplemental Table ...

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Section: Discussionmentioning

confidence: 99%

NPP4 is a procoagulant enzyme on the surface of vascular endothelium

Albright

Chang

Robert

et al. 2012

Blood

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“…It constitutes the canonical receptor for ADP on blood platelets and is to date the only P2 receptor subtype to be an established target for drugs in clinical use 6 (see below). Long before its molecular cloning, the pharmacological importance of the P2Y 12 receptor in hemostasis and thrombosis was well recognized.…”

Section: Platelet P2y 12 Receptormentioning

confidence: 99%

“…12 On blood platelets, the P2Y 12 receptor is entirely responsible for the role played by ADP in the amplification of aggregation, secretion, and stabilization of platelet aggregates and in enhancement of the procoagulant activity induced by agonists, such as thrombin, collagen, or thromboxane A 2 . 6 The P2Y 12 receptor is coupled to the G αi2 subunit of the heterotrimeric G proteins, which is responsible for the activation of 2 phosphoinositide 3-kinase isoforms (PI 3-K p110β and p110γ) and the inhibition of cAMP-dependent protein kinase and subsequent phosphorylation of various targets. Notably, one of these signaling proteins is vasodilator-stimulated phosphoprotein, an actin regulatory protein, which is used as a marker of the P2Y 12 receptor activation state, especially to monitor the effects of P2Y 12 -targeting antiplatelet drugs.…”

Section: Platelet P2y 12 Receptormentioning

confidence: 99%

“…The first P2 receptor subtype to be identified was cloned from a chick brain complementary DNA library in 1993. Currently, the known P2 receptor family comprises 7 subtypes of P2X receptors (P2X 1 , P2X 2 , P2X 3 , P2X 4 , P2X 5 , P2X 6 , and P2X 7 ) and 8 subtypes of P2Y receptors (P2Y 1 , P2Y 2 , P2Y 4 , P2Y 6 , P2Y 11 , P2Y 12 , P2Y 13 , and P2Y 14 ). 4 These P2 receptor subtypes display some agonist selectivity.…”

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confidence: 99%

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Purinergic Receptors in Thrombosis and Inflammation

Hechler

Gachet

2015

ATVB

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143

101

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Abstract-Under various pathological conditions, including thrombosis and inflammation, extracellular nucleotide levels may increase because of both active release and passive leakage from damaged or dying cells. Once in the extracellular compartment, nucleotides interact with plasma membrane receptors belonging to the P2 purinergic family, which are expressed by virtually all circulating blood cells and in most blood vessels. In this review, we focus on the specific role of the 3 platelet P2 receptors P2Y 1 , P2Y 12 , and P2X 1 in hemostasis and arterial thrombosis. Beyond platelets, these 3 receptors, along with the P2Y 2 , P2Y 6 , and P2X 7 receptors, constitute the main P2 receptors mediating the proinflammatory effects of nucleotides, which play important roles in various functions of circulating blood cells and cells of the vessel wall. Each of these P2 receptor subtypes specifically contributes to chronic or acute vascular inflammation and related diseases, such as atherosclerosis, restenosis, endotoxemia, and sepsis. The potential for therapeutic targeting of these P2 receptor subtypes is also discussed.

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“…This increases the number of potential effects of ticagrelor [8][9][10][11][12] . Furthermore, the "pleiotropic effects" of ticagrelor may also occur due to different mechanisms other than interaction with the P2Y 12 receptor [13] . ADP plasma levels increase after injury, inflammation, and ischemia-reperfusion [14] .…”

Section: Introductionmentioning

confidence: 99%

Böbrekte İskemi-Reperfüzyon Hasarında Ticagrelor’un Etkisi: Pleiotropik Etki Geçerli Bir Faktör mü?

Bağcıoğlu¹,

Kocaaslan²,

Uslu³

et al. 2017

Kafkas Univ Vet Fak Derg

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Citation of This ArticleBağcıoğlu M, Kocaaslan R, Uslu M, Fındık Güvendi G: The effect of ticagrelor on ischemia-reperfusion injury of kidney: Is the pleiotropic effect a valid factor? Kafkas Univ Vet Fak Derg, 23 (6): 917-924, 2017. DOI: 10.9775/kvfd.2017 AbstractThe goal of this study was to determine the protective effect of ticagrelor against ischemia-reperfusion injury in the kidney of rats via histological examination, biochemical parameters, and immunohistochemical analysis. Thirty male rats were randomized into five groups. The animals received ticagrelor 5 mg/kg, 10 mg/kg and 20 mg/kg or normal saline 0.1 mL/kg (control) orally before the procedure. The shame group only had laparatomy. An ischemia-reperfusion injury was done by clamping the renal hilus. There was less malondealdehyde assay (MDA) in ticagrelor groups than the control group, and this decrease was statistically significant (P=0.001 in all ticagrelor received groups). The glutathione peroxidase (GPx) and glutathione reductase (GR) were elevated in ticagrelor groups at all doses. Similar findings were observed in all treatment groups. The 5 mg ticagrelor treated group had no changes in glomerules and tubules relative to the control group via histology. Dilated tubular structures were similar to the sham group-both at 10 and 20 mg ticagrelor. Caspas-3 and NF-KB activity was similar in ticagrelor treated groups to sham group. Our study showed that ticagrelor is an effective agent to protect kidney from renal ischemia-reperfusion injury. Ticagrelor may protect the tissues by reducing the concentration of reactive oxygen species and inducing the antioxidant system-especially with the pleiotropic effect. Keywords: Kidney, Ischemia, Reperfusion, Injury, TicagrelorBöbrekte İskemi-Reperfüzyon Hasarında Ticagrelor'un Etkisi: Pleiotropik Etki Geçerli Bir Faktör mü? ÖzetBu çalışmada, ticagrelor'un ratların böbreğinde oluşturulan iskemi-reperfüzyon hasarına karşı koruyucu etkisinin histolojik, biyokimyasal ve immünohistokimyasal yöntemler kullanılarak tanımlanması amaçlanmıştır. Bu amaçla, 30 erkek rat rastgele olarak 5 gruba ayırılmıştır. Bu hayvanlara, yapılacak işlemlerden önce ticagrelor 5 mg/kg, 10 mg/kg ve 20 mg/kg dozlarında, kontrol grubuna da 0.1 mL/kg serum fizyolojik oral olarak verilmiştir. Sham grubunda ise sadece laparatomi yapılmıştır. İskemi-reperfüzyon hasarı renal hilusun klemplenmesi yoluyla yapılmıştır. Ticagrelor verilen gruplarda saptanan malondialdehit (MDA) düzeyinin kontrol grubundan daha az olduğu ve bu düşüklüğün istatistiksel olarak anlamlı olduğu tespit edildi (tüm ticagrelor grupları için P=0.001). Glutatyonperoksidaz (GPx) ve glutatyonredüktaz (GR) düzeyleride ticagrelor verilen tüm gruplarda artmış olarak bulundu. Histopatolojik incelemelerde, tedavi verilen tüm gruplarda benzer sonuçlar gözlendi. Ancak 5 mg ticagrelor verilen grupta glomerul ve tübül yapısında kontrol grubu arasında fark olmadığı belirlendi. 10 ve 20 mg ticagrelor verilen gruplarda, sham grubuna benzer özellikte dilate tübüler yapılar olduğu gözlendi. C...

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P2Y12 receptors in platelets and other hematopoietic and non-hematopoietic cells

Cited by 125 publications

References 140 publications

NPP4 is a procoagulant enzyme on the surface of vascular endothelium

NPP4 is a procoagulant enzyme on the surface of vascular endothelium

Purinergic Receptors in Thrombosis and Inflammation

Böbrekte İskemi-Reperfüzyon Hasarında Ticagrelor’un Etkisi: Pleiotropik Etki Geçerli Bir Faktör mü?

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