Identification of P2Y12-dependent and -independent mechanisms of glycoprotein VI–mediated Rap1 activation in platelets

Larson, Mark K.; Chen, Hong; Kahn, Mark L.; Taylor, Anne M.; Fabre, Jean Etienne; Mortensen, Richard M.; Conley, Pamela B.; Parise, Leslie V.

doi:10.1182/blood-2002-05-1533

Cited by 76 publications

(75 citation statements)

References 48 publications

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“…One important intracellular pathway which regulates G i -dependent integrin αIIbβ3 activation is constituted by phosphoinositide 3-kinase (PI 3-K) [56, [67][68][69][70]. PI 3-K isoform p110β regulates integrin activation through a classical lipid kinase-dependent mechanism, involving the small GTPase Rap1 and/or the serine-threonine protein kinase B/Akt (PKB/Akt) [71][72][73][74][75][76], whereas p110γ appears to regulate integrin principally through a non-catalytic signalling mechanism [77,78]. Whether other PI3K class I isoforms such as the p110α or PI3K class II or III isoforms, which are highly expressed in blood platelets, play a role in integrin αIIbβ3 activation remains to be determined.…”

Section: Receptormentioning

confidence: 99%

P2 receptors and platelet function

Hechler

Gachet

2011

Purinergic Signalling

136

127

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Following vessel wall injury, platelets adhere to the exposed subendothelium, become activated and release mediators such as TXA 2 and nucleotides stored at very high concentration in the so-called dense granules. Released nucleotides and other soluble agents act in a positive feedback mechanism to cause further platelet activation and amplify platelet responses induced by agents such as thrombin or collagen. Adenine nucleotides act on platelets through three distinct P2 receptors: two are G proteincoupled ADP receptors, namely the P2Y 1 and P2Y 12 receptor subtypes, while the P2X 1 receptor ligand-gated cation channel is activated by ATP. The P2Y 1 receptor initiates platelet aggregation but is not sufficient for a full platelet aggregation in response to ADP, while the P2Y 12 receptor is responsible for completion of the aggregation to ADP. The latter receptor, the molecular target of the antithrombotic drugs clopidogrel, prasugrel and ticagrelor, is responsible for most of the potentiating effects of ADP when platelets are stimulated by agents such as thrombin, collagen or immune complexes. The P2X 1 receptor is involved in platelet shape change and in activation by collagen under shear conditions. Each of these receptors is coupled to specific signal transduction pathways in response to ADP or ATP and is differentially involved in all the sequential events involved in platelet function and haemostasis. As such, they represent potential targets for antithrombotic drugs.

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Section: Receptormentioning

confidence: 99%

P2 receptors and platelet function

Hechler

Gachet

2011

Purinergic Signalling

136

127

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“…Rap 1b is a small GTPase that is activated in a PI3-kinase ␥-dependent mechanism following G␣ i /G␣ z -coupled receptor stimulation. 24,66 It has been shown to play an important role in fibrinogen receptor activation in megakaryocytes. 23 Recent studies have also shown that platelets from Rap 1b knockout mice have a lesser extent of aggregation induced by ADP, compared with the wild-type mouse platelets.…”

mentioning

confidence: 99%

Role of G protein–gated inwardly rectifying potassium channels in P2Y12 receptor–mediated platelet functional responses

Shankar

Murugappan²,

Kim³

et al. 2004

Blood

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The role of the G i -coupled platelet P2Y 12 receptor in platelet function has been well established. However, the functional effector or effectors contributing directly to ␣IIb␤3 activation in human platelets has not been delineated. As the P2Y 12 receptor has been shown to activate G protein-gated, inwardly rectifying potassium (GIRK) channels, we investigated whether GIRK channels mediate any of the functional responses of the platelet P2Y 12 receptor. Western blot analysis revealed that platelets express GIRK1, GIRK2, and GIRK4. In aspirin-treated and washed human platelets, 2 structurally distinct GIRK inhibitors, SCH23390 (R(؉)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride) and U50488H (trans-(؎)-3,4-dichloro-N-methyl-N-[2-(pyrrolidinyl)cyclohexyl] benzeneacetamide methanesulfonate), inhibited adenosine diphosphate (ADP)-, 2-methylthioADP (2-MeSADP)-, U46619-, and low-dose thrombin-mediated platelet aggregation. However, the GIRK channel inhibitors did not affect platelet aggregation induced by high concentrations of thrombin, AYPGKF, or convulxin. Furthermore, the GIRK channel inhibitors reversed SFLLRN-induced platelet aggregation, inhibited the P2Y 12 -mediated potentiation of dense granule secretion and Akt phosphorylation, and did not affect the agonist-induced G qmediated platelet shape change and intracellular calcium mobilization. Unlike AR-C 69931MX, a P2Y 12 receptor-selective antagonist, the GIRK channel blockers did not affect the ADP-induced adenlylyl cyclase inhibition, indicating that they do not directly antagonize the P2Y 12 receptor. We conclude that GIRK channels are important functional effectors of the P2Y 12 receptor in human platelets. IntroductionPlatelets play an important role in normal hemostasis and abnormal activation of platelets leads to thrombosis. During vascular injury or conditions of high shear, exposure of the collagen-rich subendothelium activates the platelets and results in the formation of a stable thrombus due to the combined action of adenosine diphosphate (ADP) secreted from platelet-dense granules and generated thrombin. 1 Any perturbations in this system can have pathologic cardiovascular implications such as intravascular thrombus formation and vascular occlusion.ADP is an important component of the platelet-dense granules and also an important platelet agonist that stimulates platelets by acting on the G q -coupled P2Y 1 receptor and G i -coupled P2Y 12 receptor. 2,3 Once released, it amplifies the primary responses of other agonists such as collagen and thrombin, leading to enhanced platelet aggregation and stability of the thrombus. 4,5 It is now well established that concomitant signaling through G q -coupled P2Y 1 and G i -coupled P2Y 12 is necessary and sufficient for the integrin GPIIb/IIIa activation. 3 Furthermore, selective G i activation, when coupled with selective G 12/13 stimulation, also results in platelet aggregation. 6,7 Notably, the P2Y 12 -coupled G i signaling is also crucial for potentiating dense...

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“…In this respect, Larson et al [38] have recently shown that the collagen receptor GPVI-mediated Rap1 activation largely depended on ADP signaling through P2Y 12 , but not through P2Y 1 . In the same context, another study showed that, during thromboxane A 2 mimetic-induced platelet aggregation, signaling through the P2Y 12 receptor by secreted ADP causes positive feedback on platelet secretion through a PI-3 kinase pathway [39].…”

Section: The Platelet P2y 1 and P2y 12 Receptors For Adp Intracellulamentioning

confidence: 99%

The Platelet ATP and ADP Receptors

Oury

Tóth-Zsámboki

Vermylen

et al. 2006

CPD

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Adenine nucleotides, ADP and ATP, are coreleased from dense granules during platelet activation, as well as from endothelial cells and damaged red blood cells following vascular injury. Through autocrine and paracrine mechanisms, these extracellular signaling molecules interact with the platelet P2 receptors to amplify ongoing platelet activation. Two receptors for ADP, the G q -protein-coupled P2Y 1 and G i -protein-coupled P2Y 12 and one receptor for ATP, the P2X 1 ion channel, have been identified on platelets. Due to distinct pharmacological properties and differential regulation, the P2Y and P2X receptors essentially operate on different scales of time and distance and trigger selective intracellular signaling cascades. Recent advances in the understanding of the P2Y receptor physiology have reinforced the concept of these receptors as useful targets for antithrombotic therapy. The function of P2X 1 in platelet activation only recently started to be unraveled. This review focuses on recent findings on the physiology of these platelet ADP and ATP receptors, their distinct downstream intracellular signaling pathways as well as on the available agonists, antagonists and inhibitors that allow their pharmacological discrimination.Key Words: Hemostasis, thrombosis, adenine nucleotides, P2Y 1 , P2Y 12 , P2X 1 , antithrombotic therapy. HISTORY AND CLASSIFICATION OF PURINERGIC RECEPTORSThe first report about the potent actions of an adenine compound, AMP, extracted from heart muscle, was published by Drury and Szent-Györgyi in 1929. Initial investigations focused on effects of adenosine and ATP on the heart and vasculature, or concerned the effects of purines on platelets [1] and on mast cells. Further insights into the physiological role of extracellular purines and pyrimidines were provided via the study of their biological sources [2]. In this respect, the detection of nucleotide release from the heart during hypoxia [3] or from skeletal muscle during contraction indicated that secretion of purine compounds might be coupled to metabolic demand to regulate local blood flow. ATP release from sensory nerves suggested that adenine nucleotides play a role as neurotransmitter or neuromodulator in the central and peripheral nervous system [4].These early publications established that purinergic nucleotides act as extracellular signaling molecules [5]. Nucleotides are now documented to contribute to a diverse range of physiological responses such as smooth muscle contraction, neurotransmission, exocrine and endocrine secretion, immune response, inflammation, platelet aggregation, male reproduction, nociception and modulation of cardiac function [6].Purines and pyrimidines mediate their effects by interacting with distinct cell-surface receptors. Purinergic receptors were first formally recognized by Burnstock in 1978 [7]. They were divided into two classes: at P1-purinoceptors adenosine is the principal natural ligand, while P2-purinoceptors recognize both purine and pyrimidine nucleotides Based on an increasin...

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Identification of P2Y12-dependent and -independent mechanisms of glycoprotein VI–mediated Rap1 activation in platelets

Cited by 76 publications

References 48 publications

P2 receptors and platelet function

P2 receptors and platelet function

Role of G protein–gated inwardly rectifying potassium channels in P2Y12 receptor–mediated platelet functional responses

The Platelet ATP and ADP Receptors

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