Signaling Receptors on Platelets and Megakaryocytes

Woulfe, Donna S.; Yang, Jing; Prévost, Nicolas; O’Brien, Peter J.; Fortna, Ryan R.; Tognolini, Massimiliano; Jiang, Hong; Wu, Jie; Brass, Lawrence F.

doi:10.1385/1-59259-783-1:003

Cited by 14 publications

(27 citation statements)

References 143 publications

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“…44 GPCRs are important seven-transmembrane spanning signaling molecules that play crucial roles in the extension of the platelet plug by most soluble platelet agonists. 45,46 GPCRs can activate associated heterotrimeric guanine nucleotide-binding proteins (G proteins), which in turn act on various effectors (adenylyl cyclase, PLC, PI-3K, p115-RhoGEF). In an orchestrated manner, in platelets, agonists acting through GPCRs: i) stimulate PLCβ isoforms via Gqα, causing an increase in cytosolic Ca 2+ and activation of PKC; ii) reorganize the actin cytoskeleton via G12α and G13α promoting the microtubular ring change and the filopodia and lamellopodia formation that drive platelet shape change; iii) suppress cAMP synthesis via Giα family members by inhibiting adenylyl cyclase, which is particularly relevant when intracellular cAMP levels are high due to the action of endothelial cell-derived prostaglandin I2 (PGI2) and nitric oxide (NO).…”

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confidence: 99%

“…There is evidence that Giα-associated Gβγ subunits also activate other signaling pathways such as PI-3Kψ, Src kinases and the Rap1B Ras family protein, which is an important contributor to pathways converging on the activation of αIIbβ3. 46 Studies on mice deficient in specific G-proteins have helped to establish the role of these proteins in platelet activation and thrombus formation. 46 Platelet agonists with a prominent role in the process of extension of the platelet plug are ADP, TxA2, thrombin and epinephrine.…”

Section: +mentioning

confidence: 99%

“…46 Studies on mice deficient in specific G-proteins have helped to establish the role of these proteins in platelet activation and thrombus formation. 46 Platelet agonists with a prominent role in the process of extension of the platelet plug are ADP, TxA2, thrombin and epinephrine.…”

Section: +mentioning

confidence: 99%

“…Within seconds, thrombin increases ten-fold the cytosolic level of Ca 2+ , triggering downstream events as activation of PLA2. 46 The thrombin-induced platelet responses are mediated at least partially by the GP Ib/IX/V complex, [12][13][14][15][16][17][18][19] and mainly by two protease activated receptors (PAR), namely PAR-1 and PAR-4 in humans and PAR-3 and PAR-4 in mice. 61 The GP Ibα subunit of the GP Ib/IX/V complex contains a high affinity binding site for α-thrombin, accounting for as much as 90% of the total protease that can bind to platelets.…”

Section: © F E R R a T A S T O R T I F O U N D A T I O Nmentioning

confidence: 99%

“…In contrast, in P2Y12 −/− mice ADP does not induce aggregation nor inhibits cAMP synthesis, despite the maintenance of other P2Y1-mediated responses, such as shape change or PLC activation. [46][47][48] The platelet responses to other agonists are also severely affected in P2Y12-deficient mice, which have a significantly prolonged bleeding time and are protected from arterial thrombosis in the FeCl3 model. Few patients have been identified with hemorrhagic diathesis associated to P2Y12 congenital defects, whereas so far there has been no report of patients with a P2Y1 deficiency.…”

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Platelet receptors and signaling in the dynamics of thrombus formation

Rivera¹,

Lozano²,

et al. 2009

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Hemostasis and pathological thrombus formation are dynamic processes that require a co-ordinated series of events involving platelet membrane receptors, bidirectional intracellular signals, and release of platelet proteins and inflammatory substances. This review aims to summarize current knowledge in the key steps in the dynamics of thrombus formation, with special emphasis on the crucial participation of platelet receptors and signaling in this process. Initial tethering and firm adhesion of platelets to the exposed subendothelium is mediated by glycoprotein (GP) Ib/IX/V complex and collagen receptors, GP VI and α2β1 integrin, in the platelet surface, and by VWF and fibrillar collagen in the vascular site. Interactions between these elements are largely influenced by flow and trigger signaling events that reinforce adhesion and promote platelet activation. Thereafter, soluble agonists, ADP, thrombin, TxA2, produced/released at the site of vascular injury act in autocrine and paracrine mode to amplify platelet activation and to recruit circulating platelets to the developing thrombus. Specific interactions of these agonists with their G-protein coupled receptors generate inside-out signaling leading to conformational activation of integrins, in particular αIIbβ3, increasing their ligand affinity. Binding of αIIbβ3 to its ligands, mainly fibrinogen, supports processes such as clot retraction and platelet aggregation. Stabilization of thrombi is supported by the late wave of signaling events promoted by close contact between aggregated platelets. The best known contact-dependent signaling is outside-in signaling through αIIbβ3, but new ones are being clarified such as those mediated by interaction of Eph receptors with ephrins, or by Sema 4D and Gas-6 binding to their receptors. Finally, newly identified mechanisms appear to control thrombus growth, including back-shifting of activated integrins and actuation of compensatory molecules such as ESAM or PECAM-1. The expanding knowledge of thrombotic disease is expected to translate into the development of new drugs to help management and prevention of thrombosis.Key words: platelet, receptors, thrombus formation.Citation: Rivera J, Lozano ML, Navarro-Núñez L, Vicente V. Platelet receptors and signaling in the dynamics of thrombus formation. Haematologica 2009; 94:700-711. doi:10.3324/haematol.2008 This is an open-access paper. ABSTRACT Platelet receptors and signaling in the dynamics of thrombus formationJosé Rivera, María Luisa Lozano, Leyre Navarro-Núñez, and Vicente Vicente Unit of Hematology and Clinical Oncology, Centro Regional de Hemodonación, University of Murcia, Spain © F e r r a t a S t o r t i F o u n d a t i o nand metastasis, or immunological host defense. 1Internally, platelets contain a cytoskeleton, a dense tubular system, few mitochondrias, glycogen granules, dense (δ) and α storage granules and peroxisomes. The α-granules retain relevant proteins for the hemostatic function of platelets, such as von Willebrand factor (VWF), fibrinogen, P-selectin,...

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confidence: 99%

Section: +mentioning

confidence: 99%

Section: +mentioning

confidence: 99%

Section: © F E R R a T A S T O R T I F O U N D A T I O Nmentioning

confidence: 99%

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confidence: 99%

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Platelet receptors and signaling in the dynamics of thrombus formation

Rivera¹,

Lozano²,

et al. 2009

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The P2X1 receptor and platelet function

Mahaut‐Smith

Jones

Evans

2011

Purinergic Signalling

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Extracellular nucleotides are ubiquitous signalling molecules, acting via the P2 class of surface receptors. Platelets express three P2 receptor subtypes, ADP-dependent P2Y1 and P2Y12 G-protein-coupled receptors and the ATP-gated P2X1 non-selective cation channel. Platelet P2X1 receptors can generate significant increases in intracellular Ca2+, leading to shape change, movement of secretory granules and low levels of αIIbβ3 integrin activation. P2X1 can also synergise with several other receptors to amplify signalling and functional events in the platelet. In particular, activation of P2X1 receptors by ATP released from dense granules amplifies the aggregation responses to low levels of the major agonists, collagen and thrombin. In vivo studies using transgenic murine models show that P2X1 receptors amplify localised thrombosis following damage of small arteries and arterioles and also contribute to thromboembolism induced by intravenous co-injection of collagen and adrenaline. In vitro, under flow conditions, P2X1 receptors contribute more to aggregate formation on collagen-coated surfaces as the shear rate is increased, which may explain their greater contribution to localised thrombosis in arterioles compared to venules within in vivo models. Since shear increases substantially near sites of stenosis, anti-P2X1 therapy represents a potential means of reducing thrombotic events at atherosclerotic plaques.

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Limitations of current therapies to prevent thrombosis: a need for novel strategies

Fabre

Gurney²

2010

Mol. BioSyst.

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Bleeding limits the benefit of current anti-platelet drugs for preventing heart attacks and stroke. Aspirin and clopidogrel, the two most widely prescribed anti-platelet drugs, are metabolized to active compounds that covalently and irreversibly modify their respective therapeutic targets (COX1 and P2Y12). The enduring effects of aspirin and clopidogrel are of concern in patients receiving anti-platelet therapy who require emergency surgery as this places them at greater risk of haemorrhage. As clopidogrel must be activated by cytochrome P450 metabolism, recent pharmacogenomic studies have revealed that patients lacking a functional allele of CYP2C19 derive no therapeutic benefit from the drug. Prasugrel, a second generation thienopyridine, whose bioconversion is not affected by CYP genetic polymorphism, demonstrates improved clinical benefit, but with increased bleeding risk. Anti-platelet drugs currently in cardiovascular trials that may have reduced bleeding risk include reversible P2Y12 antagonists (cangrelor, ticagrelor, and elinogrel), a PAR1 antagonist (SCH 530 348) and an EP3 antagonist (DG-041). The platelet EP3 receptor for prostaglandin E(2) is an attractive therapeutic target as EP3 antagonists may selectively avert thrombosis over atherosclerotic plaques without affecting bleeding risk.

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Signaling Receptors on Platelets and Megakaryocytes

Cited by 14 publications

References 143 publications

Platelet receptors and signaling in the dynamics of thrombus formation

Platelet receptors and signaling in the dynamics of thrombus formation

The P2X1 receptor and platelet function

Limitations of current therapies to prevent thrombosis: a need for novel strategies

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