Functional characterization of platelet ADP receptors

Kunapuli, Satya P.

doi:10.1080/09537109876401

Cited by 41 publications

(33 citation statements)

References 62 publications

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“…These results indicate that inhibition of Fc␥RIIA-induced activation of Rap1B by ADP scavengers is not due to the reduced increase of intracellular Ca 2ϩ . Activation of Rap1B Requires a G i -dependent Pathway-ADP binds to two different purinergic receptors on the platelet surface, P2Y1 and P2Y12, which are coupled to G q and G i , respectively (30). To investigate the relative contribution of each one of these receptors on activation of Rap1B induced by clustering of Fc␥RIIA, we performed experiments with selective antagonists.…”

Section: Activation Of Rap1b In Human Platelets Stimulated Bymentioning

confidence: 99%

A Gi-dependent Pathway Is Required for Activation of the Small GTPase Rap1B in Human Platelets

Lova

Paganini

Sinigaglia

et al. 2002

Journal of Biological Chemistry

117

131

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In platelets stimulated by cross-linking of Fc␥RIIA, inhibition of Rap1B activation by ADP scavengers could be overcome by the simultaneous recruitment of the G i -coupled ␣ 2A -adrenergic receptor by epinephrine. By contrast, serotonin, which binds to a G q -coupled receptor, could not restore activation of Rap1B. When tested alone, epinephrine was found to be able to induce GTP binding to Rap1B, whereas serotonin produced only a slight effect. Finally, activation of Rap1B induced by stimulation of the G qcoupled thromboxane A 2 receptor by U46619 was completely inhibited by ADP scavengers under conditions in which intracellular Ca 2؉ mobilization was unaffected. Inhibition of U46619-induced Rap1B activation was also observed upon blockade of the P2Y12 but not of the P2Y1 receptor for ADP. These results demonstrate that stimulation of a G i -dependent signaling pathway by either ADP of epinephrine is necessary and sufficient to activate the small GTPase Rap1B.

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Section: Activation Of Rap1b In Human Platelets Stimulated Bymentioning

confidence: 99%

A Gi-dependent Pathway Is Required for Activation of the Small GTPase Rap1B in Human Platelets

Lova

Paganini

Sinigaglia

et al. 2002

Journal of Biological Chemistry

117

131

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“…1,2 The amount of ATP released from erythrocytes is approximately 10 times the amount of ADP, 3 and ATP and ADP in platelet secretory granules are present in approximately equimolar concentrations. 4 The released ADP can interact with P2Y 1 and P2Y 12 (formally known as P 2T ) receptors on platelets and induce platelet aggregation, [5][6][7] which contributes to normal hemostasis and to thrombus formation. However, the effect of the released ATP is unclear.…”

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confidence: 99%

Mechanisms Involved in Adenosine Triphosphate–Induced Platelet Aggregation in Whole Blood

Stafford

Pink

White

et al. 2003

ATVB

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Objective-Effects on platelet aggregation of adenosine triphosphate (ATP) released from damaged cells and from platelets undergoing exocytosis have not been clearly established. In this study we report on the effects of ATP on platelet aggregation in whole blood. Methods and Results-Aggregation, measured using a platelet-counting technique, occurred in response to ATP and was maximal at 10 to 100 mol/L. It was abolished by MRS2179, AR-C69931, and creatine phosphate/creatine phosphokinase, implying that conversion to adenosine diphosphate (ADP) is required. ATP did not induce aggregation in platelet-rich plasma, but aggregation did occur when apyrase or hexokinase was added. Aggregation also occurred after addition of leukocytes to platelet-rich plasma (as a source of ecto-ATPase), and this was potentiated on removal of adenosine by adenosine deaminase, indicating that adenosine production modulates the response. Dipyridamole, which inhibits adenosine uptake into erythrocytes, inhibited aggregation induced by ATP in whole blood, and adenosine deaminase reversed this. DN9693 and forskolin synergized with dipyridamole to inhibit ATP-induced aggregation. 4 The released ADP can interact with P2Y 1 and P2Y 12 (formally known as P 2T ) receptors on platelets and induce platelet aggregation, 5-7 which contributes to normal hemostasis and to thrombus formation. However, the effect of the released ATP is unclear. It is known that ATP can interact with P2X 1 receptors on platelets, causing a transient Ca 2ϩ mobilization, 8,9 but this does not result in platelet aggregation, and the importance of P2X 1 receptors to overall platelet function is unknown. It is also known that ATP acts as an antagonist of the effects of ADP at P2Y 1 and P2Y 12 receptors 10,11 and that high concentrations can inhibit ADP-induced platelet aggregation. 12 When considering the possible effects of ATP on platelets in vitro and in vivo, the presence of enzymes present on blood cells and endothelial cells and in plasma that metabolize ATP must be taken into account. These include enzymes that convert ATP to ADP and ADP to AMP (NTPDase-1, also known as ATP diphosphohydrolase, CD 39 and EC 3.6.1.5), 13,14 ATP to AMP and ADP to AMP (5Ј-monophosphate phosphoanhydrolase/phosphodiesterase, NMPP), 15 and AMP to adenosine (5Ј-nucleotidase), 13 the latter being an inhibitor of platelet aggregation. 10,16 Also, adenosine can be taken up and neutralized by erythrocytes and other blood cells, thus limiting its potential inhibitory action. 17,18 Thus, the overall effect of ATP could depend on several competing influences. Conclusions-ATPIn this study, we have investigated the effects of ATP on platelet aggregation in whole blood and in platelet-rich plasma (PRP). We used hirudin as the anticoagulant to ensure that the conditions used were as near physiological as possible. We found that ATP induces platelet aggregation in whole blood but not in PRP, and we have investigated the mechanisms that are involved. Methods MaterialsHirudin (recombinant desulphato-hirudi...

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“…In some cases, each occupied receptor can activate multiple G-proteins, allowing amplification of a signal that might begin with a relatively small number of receptors which range from a few hundred to a few thousand per platelet. GPCR signal transduction mechanism also enables some receptors to signal through more than one effector pathway (see Table 4) [92][93][94][95][96][97]. Finally, since several generic mechanisms exist for the abrogation GPCR activation, efficient on-demand inhibition of platelet activation can be effected under inappropriate circumstances.…”

Section: Intracellular Mechanisms Of Platelet Activationmentioning

confidence: 99%

Antiplatelet Agents

Chackalamannil¹

2010

Burger's Medicinal Chemistry and Drug Discovery

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In addition to their life‐sustaining role in hemostasis and wound healing, platelets play a central role in the pathogenesis of coronary artery, cerebrovascular, and peripheral vascular diseases. Under pathologic conditions such as rupture of an atherosclerotic plaque, the platelet activation mechanism and coagulation mechanism synergize in the formation of an occlusive thrombus leading to ischemic disorders such as acute coronary syndrome and stroke. Antiplatelet agents are the mainstay of pharmacological approach for the treatment of ischemic vascular disorders. Platelets have multiple cell‐surface receptors that, upon activation by specific ligands, trigger a cascade of cellular events resulting in the activation of the integrin glycoprotein (GP) IIb/IIIa receptors. Activated GP IIb/IIIa receptors cross‐link with fibrinogen causing platelet to aggregate. Aggregated platelets get trapped by fibrin meshwork, produced by the proteolysis of fibrinogen by thrombin. Cell‐surface platelet receptors have been the target of antiplatelet therapy. For example, aspirin, the most widely used antiplatelet agent, inhibit the biosynthesis of thromboxane A 2 , the endogenous agonist that activates thromboxane receptors. The ADP antagonists such as clopidogrel and ticlopidine inhibit ADP‐mediated activation of purinergic P2Y 12 receptors. Glycoprotein IIb/IIIa antagonists such as abciximab, eptifibatide, and tirofiban inhibit GP IIb/IIIa receptors, which involve the final common pathway of platelet aggregation. Phosphodiesterase inhibitors are less widely used antiplatelet agents that potentiate intracellular cyclic AMP levels. Promising newer antiplatelet agents such as thrombin receptor antagonists with reduced bleeding liability, third‐generation thienopyridine ADP antagonists with improved potency and reversible ADP antagonists are at advanced stage of development.

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Functional characterization of platelet ADP receptors

Cited by 41 publications

References 62 publications

A Gi-dependent Pathway Is Required for Activation of the Small GTPase Rap1B in Human Platelets

A Gi-dependent Pathway Is Required for Activation of the Small GTPase Rap1B in Human Platelets

Mechanisms Involved in Adenosine Triphosphate–Induced Platelet Aggregation in Whole Blood

Antiplatelet Agents

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