Inositol phospholipid metabolism in human platelets stimulated by ADP

Vickers, J D; Kinlough-Rathbone, R L; Packham, Marian A.; Mustard, J. F.

doi:10.1111/j.1432-1033.1990.tb19367.x

Cited by 45 publications

(25 citation statements)

References 30 publications

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“…Packham et al [18] have previously shown that under these conditions the platelets aggregate reversibly, but do not secrete the contents of storage granules or form thromboxane A,. These experiments indicate that two signal transduction events are necessary to cause the decreases in PtdInsP, and PtdInsP that we have detected at 10 s in ADP-stimulated human platelets (in these experiments and [19]). Initially, ADP stimulation causes shape change and activates receptors for fibrinogen (presumably GPIIb/IIIa).…”

Section: Discussionmentioning

confidence: 64%

“…In previous studies, with both rabbit [35] and human [19] platelets, we have presented evidence that the decreases in PtdInsP, and PtdInsP detected at 10 s are unlikely to be due to the action of phospholipase C on PtdInsP,, based on the absence of increases in (a) inositol trisphosphate labelling in platelets prelabelled with ['Hlinositol and (b) PtdOH specific radioactivity in platelets prelabelled with ['Hlglycerol. The inositol phosphates were not examined in this study but, consistent with the previous studies 119, 351, the specific radioactivity of PtdOH labelled with [3H]glycerol did not increase at 1 0 s in response to ADP.…”

Section: Discussionmentioning

confidence: 99%

“…The inositol phosphates were not examined in this study but, consistent with the previous studies 119, 351, the specific radioactivity of PtdOH labelled with [3H]glycerol did not increase at 1 0 s in response to ADP. An increase in PtdOH specific radioactivity would be expected if phospholipase C or D were activated since the specific radioactivities of ['Hlglycerol labelling of the inositol phospholipids and phosphatidylcholine were higher than that of PtdOH, and PtdOH formed from diacylglycerol produced by the action of phospholipase C or directly by the action of phospholipase D on the inositol phospholipids or phosphatidylcholine would consequently have a higher specific radioactivity [ 19,29,351. The failure in the current study of RGDS to block the increase in PtdOH labelling with [32P]phosphate and ['H]glycerol at 10 s when the decreases in PtdInsP, and PtdInsP were inhibited by RGDS, strengthens the argument that degradation of PtdInsP, by phospholipase C is not the cause of the decrease in PtdInsP, and increase in PtdOH at 10 s.…”

Section: Discussionmentioning

confidence: 99%

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ADP‐stimulated fibrinogen binding is necessary for some of the inositol phospholipid changes found in ADP‐stimulated platelets

Vickers

1993

European Journal of Biochemistry

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ADP-stimulation of washed human platelets suspended in Tyrode/albumin solution containing Ca' + (2 mM) and fibrinogen (0.4 mg/ml) causes extensive, reversible aggregation without appreciable secretion of granule contents. Under these conditions ADP (10 pM) stimulation decreased the amounts of phosphatidylinositol 4,5-bisphosphate (PtdInsP,) and phosphatidylinositol 4-phosphate (PtdInsP) at 10 s. Omitting fibrinogen from the suspending medium or blocking fibrinogen binding to the platelets using Arg-Gly-Asp-Ser (RGDS, 0.23 mM) inhibited these decreases in PtdInsP, and PtdinsP. in contrast, ADP-induced decreases in PtdInsP, and increases in PtdInsP at 60 s compared to 10 s were not affected by RGDS or the absence of fibrinogen. in platelets prelabelled with [3H]glycerol and ['2P]phosphate, changes in labelling of the inositol phospholipids paralleled the changes in amount. The ADP-induced changes in phosphatidic acid (PtdOH) at 10 s were unaffected by RGDS; this finding supported previous reports that phospholipase C was not the cause of the early decreases in PtdInsP, and PtdinsP. These results indicate that the early decreases in PtdInsP, and PtdInsP at 10 s are dependent on fibrinogen binding to the platelets and occur after fibrinogen binding which is activated by ADP stimulation. It is proposed that the fibrinogen-dependent changes in PtdInsP, and PtdInsP inay have a feedback role augmenting platelet aggregation or other responses of platelets that might occur after fibrinogen binding, possibly due to effects on actin polymerisation.The receptor for fibrinogen on platelets, the glycoprotein IIbAIIa complex (integrin al&, [l]), has been shown to undergo conformational change in activated platelets to expose the fibrinogen binding site [2-41. In addition, evidence is now accumulating that the binding of fibrinogen to the glycoprotein IIb/IIIa complex (GPIIbDIIa) may cause changes in the complex which affect internal processes in the platelet. An early report to this effect by Isenberg et al. [ 5 ] showed that clustering of GPIIb/IIIa complexes in ADP-stimulated platelets required binding of fibrinogen and did not involve cross-linking by fibrinogen. In a subsequent study, Isenberg et al.[6] demonstrated stimulation of actinomysin-dependent clustering of GPIIb/IIIa in the surface-connected canalicular system of otherwise unstimulated platelets caused by addition of antibodies to GPIIb (Tab) and GPIIIa (AP3). There have been other reports in which monoclonal antibodies to GPIIbAIIa have been shown to cause platelet aggregation [7-91. Since in these cases aggregation was shown to be fibrinogen-dependent, aggregation is not due to platelet cross-linking by the antibodies and demonstration that aggregation was inhibitable by agents (such as prostaglandin E,) which block internal signal transduction pathways indicated that the confornational change in fibrinogen receptors was not only directly induced by antibody binding to GPIIb

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Section: Discussionmentioning

confidence: 64%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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ADP‐stimulated fibrinogen binding is necessary for some of the inositol phospholipid changes found in ADP‐stimulated platelets

Vickers

1993

European Journal of Biochemistry

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“…Although ADP is clearly able to induce PLC activation under our experimental conditions, as revealed by measurement of PKC activation (Fig. 1) and intracellular Ca 2ϩ mobilization (data not shown), we have been unable to reliably measure agonistinduced accumulation of inositol phosphates or DAG, probably because of the weakness of the response (data not shown), as suggested by early studies (30). Therefore, we took advantage from the evidence that the P2Y12 receptor is also implicated in PKC activation induced by U46619, which is a stronger activator of PLC.…”

Section: The P2y12 Receptor Does Not Influence G Q -Mediated Activatimentioning

confidence: 65%

The Gi-coupled P2Y12 Receptor Regulates Diacylglycerol-mediated Signaling in Human Platelets

Guidetti

Lova

Bernardi

et al. 2008

Journal of Biological Chemistry

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Stimulation of G q -coupled receptors activates phospholipase C and is supposed to promote both intracellular Ca 2؉ mobilization and protein kinase C (PKC) activation. We found that ADPinduced phosphorylation of pleckstrin, the main platelet substrate for PKC, was completely inhibited not only by an antagonist of the G q -coupled P2Y1 receptor but also upon blockade of the G i -coupled P2Y12 receptor. The role of G i on PKC regulation required stimulation of phosphatidylinositol 3-kinase rather than inhibition of adenylyl cyclase. P2Y12 antagonists also inhibited pleckstrin phosphorylation, Rap1b activation, and platelet aggregation induced upon G q stimulation by the thromboxane A 2 analogue U46619. Importantly, activation of phospholipase C and intracellular Ca 2؉ mobilization occurred normally. Phorbol 12-myristate 13-acetate overcame the inhibitory effect of P2Y12 receptor blockade on PKC activation but not on Rap1b activation and platelet aggregation. By contrast, inhibition of diacylglycerol kinase restored both PKC and Rap1b activity and caused platelet aggregation. Stimulation of P2Y12 receptor or direct inhibition of diacylglycerol kinase potentiated the effect of membrane-permeable sn-1,2-dioctanoylglycerol on platelet aggregation and pleckstrin phosphorylation, in association with inhibition of its phosphorylation to phosphatidic acid. These results reveal a novel and unexpected role of the G i -coupled P2Y12 receptor in the regulation of diacylglycerol-mediated events in activated platelets.It is generally accepted that, with a very few exceptions, platelet response to soluble agonists originates from the convergence of at least two different signal transduction pathways typically initiated by the heterotrimeric G-proteins G q and G i . Several receptors for platelet agonists are coupled to G q , including the P2Y1 receptor for ADP, the TP␣ receptor for the thromboxane A 2 (TxA 2 ), 3 and the PAR1 and PAR4 receptors for thrombin (1, 2). Signaling downstream G q involves the stimulation of members of the ␤ subfamily of phospholipase C (PLC), which generate the second messengers inositol 1,4,5-trisphosphosphate (IP 3 ) and diacylglycerol (DAG), responsible for Ca 2ϩ mobilization from intracellular stores and protein kinase C (PKC) activation, respectively (3). This pathway is necessary but not sufficient to elicit a full platelet response, and the concomitant activation of a G i -coupled receptor is absolutely mandatory (4). To fulfill this requirement, some agonists, like ADP, directly stimulate multiple G-protein coupled receptors, one of which is associated to G i (5, 6), whereas others, such as TxA 2 , rely on the auxiliary action of secondary messengers released by activated platelets to stimulate a G i -coupled receptor (7). Despite their essential role, there are very few G i -coupled receptors on the platelet surface, and these include the ␣2-adrenergic receptor for epinephrine and the P2Y12 receptor for ADP (8, 9). Therefore, ADP, which is also one of the major component of the platelet releas...

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“…ADP'nin trombositlerde PA düzeyi üzerine etkisini araştıran gruplardan bir kısmı PA düzeyinin arttığını, bir kısmı ise değişmediğini bildirmektedir. Ayrıca türler arasında da farklar olduğu vurgulanmaktadır (71). Bir çok araştırıcı ADP ile uyarılan trombositlerde İP oluşumunu gösterememiştir .…”

Section: C-gmpunclassified

Trombosi̇t Akti̇vasyonu

ERSÖZ¹

1997

Ankara Üniversitesi Tıp Fakültesi Mecmuası

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Inositol phospholipid metabolism in human platelets stimulated by ADP

Cited by 45 publications

References 30 publications

ADP‐stimulated fibrinogen binding is necessary for some of the inositol phospholipid changes found in ADP‐stimulated platelets

ADP‐stimulated fibrinogen binding is necessary for some of the inositol phospholipid changes found in ADP‐stimulated platelets

The Gi-coupled P2Y12 Receptor Regulates Diacylglycerol-mediated Signaling in Human Platelets

Trombosi̇t Akti̇vasyonu

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