Ligand binding to thromboxane receptors on human platelets: correlation with biological activity

Armstrong, Roma A.; Jones, Robert L.; Wilson, Nick

doi:10.1111/j.1476-5381.1983.tb10541.x

Cited by 111 publications

(38 citation statements)

References 28 publications

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“…than [1251]-cis-APO. Armstrong et al (1983) Armstrong et al (1983) on human platelets with [3H]-15(s)-9,1 l-epoxymethano-PGH2 (their value was 1,700 sites per platelet). This density was several times more than that found for the PGD2 receptor on human platelets (Siegl et al, 1979;Cooper & Ahern, 1979 Mais et al (1985a) found that U-46619 was a more potent aggregating agent than STA2 of human platelets (we also found that U-46619 was as potent as STA2), the observed order of displacing potency does not seem to fit with the biological activity.…”

Section: Lamentioning

confidence: 99%

“…As for biochemical characterization of TXA2 receptor(s), several groups using radiolabelled analogues as radioligands have carried out binding studies in human platelets or platelet membranes, and have found binding activities, presumed to be putative TXA2 receptor(s), on human platelets (Hung et al, 1983;Armstrong et al, 1983;Halushka et al, 1985). Although these binding studies have clarified several important properties of the platelet TXA2 receptor, especially as regards the specificity of binding and its correlation with biological activities, there are some discrepancies among the studies.…”

Section: Introductionmentioning

confidence: 99%

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Binding of a radioiodinated 13‐azapinane thromboxane antagonist to platelets: correlation with antiaggregatory activity in different species

Narumiya¹,

Okuma

Ushikubi

1986

British J Pharmacology

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Binding of a 125I‐labelled derivative of the 13‐azapinane thromboxane antagonist (ONO‐11120), [125I]‐9,11‐dimethylmethano‐11,12‐methano‐16‐(3‐iodo‐4‐hydroxyphenyl)‐13,14‐dihydro‐13‐aza‐15‐β‐ω‐tetranor‐thromboxane A2 ([125I]‐PTA‐OH), to washed platelets of human, dog and rabbit was studied. Results were compared with the in vitro inhibitory potency of ONO‐11120 on platelet aggregation induced by arachidonate and a thromboxane agonist, 9,11‐epithio‐11,12‐methanothromboxane A2 (STA2). [125I]‐PTA‐OH bound to washed human platelets in a reversible, saturable and temperature‐dependent manner, and specific binding displaced by 20 μM ONO‐11120 constituted about 40% of the total binding. Scatchard analyses revealed a single class of specific binding and the equilibrium dissociation constant (KD) and maximal concentration of binding sites (Bmax) were 22 nM and 390 fmol per 108 platelets (about 2,300 sites per platelet), respectively. In addition to ONO‐11120, STA2 and another thromboxane receptor agonist, (15S)‐hydroxy‐11,9‐epoxymethano‐prosta‐5Z,13E‐dienoic acid (U‐46619), effectively displaced the binding with IC50 values of 44 and 125 nM respectively. Prostaglandin D2 (PGD2) partially displaced the binding only at a concentration above 1 μM. PGE1 and thromboxane B2 (TXB2) were without effect up to 100 μM. Similar binding of [125I]‐PTA‐OH was observed on dog platelets. The KD and Bmax were 12 nM and 110 fmol per 108 platelets (about 680 sites per platelet), respectively, and these values did not change significantly after adrenaline treatment which potentiated arachidonate‐induced aggregation of platelets in this species. On the other hand, no specific binding of [125I]‐PTA‐OH was found on rabbit platelets. Consistent with the results from binding studies, ONO‐11120, 0.5 μM, completely suppressed arachidonate‐induced aggregation of human platelets, whereas, at concentrations up to 5 μM, this agent did not significantly inhibit aggregation of rabbit platelets induced by the same stimulus. STA2‐induced aggregation of rabbit platelets also showed less sensitivity to ONO‐11120. When a similar extent of irreversible aggregation was induced by STA2 and the inhibitory potency of ONO‐11120 was compared in human and rabbit platelets, about one hundred times greater concentration of ONO‐11120 was required to suppress aggregation of rabbit platelets than that of human platelets. These results suggest that [125I]‐PTA‐OH binds to a platelet thromboxane receptor, and that the structure of the binding site(s) on the receptor may vary between species.

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Section: Lamentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Binding of a radioiodinated 13‐azapinane thromboxane antagonist to platelets: correlation with antiaggregatory activity in different species

Narumiya¹,

Okuma

Ushikubi

1986

British J Pharmacology

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“…Displacement of[3H1-9,11-epoxymethano PGH2 binding Displacement of [3H]-9, 1 I-epoxymethano PGH2 (71 nM, specific activity 14 Ci mmol ') from washed human platelets was measured as described previously (Armstrong et al, 1983). Bound and free radioligand were separated by rapid centrifugation after incubation for 4 min at room temperature.…”

Section: Introductionmentioning

confidence: 99%

Prostaglandin endoperoxide analogues which are both thromboxane receptor antagonists and prostacyclin mimetics

Armstrong

Jones

MacDermot

et al. 1986

British J Pharmacology

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1Two prostaglandin endoperoxide analogues, EP 035 and EP 157, behave as specific thromboxane receptor antagonists on isolated smooth muscle preparations such as rabbit aorta, dog saphenous vein and guinea-pig trachea. However, in human platelet-rich plasma (PRP) they produce an unsurmountable block ofaggregation induced by a wide range ofagents (ADP, platelet-activating factor, thrombin); this inhibitory profile is typical of that seen with either prostaglandin 12 (PGI2) or PGD2. 2 EP 035 and EP 157 induce large increases in cyclic AMP levels (up to 20 times basal) in human PRP. Simultaneous exposure to PGE, markedly reduces their effect on cyclic AMP; exposure to PGD2 is much less effective in this respect. The adenylate cyclase inhibitor SQ 22,536 opposes the inhibitory action of EP 035, EP 157, iloprost (a stable PGO2 analogue) and PGD2 on platelet aggregation. However, the xanthone derivative AH 6809 blocks the inhibitory action of PGD2 but does not affect EP 035, EP 157 and PGO2 and its structural analogues. 3 EP 035 and EP 157 displace [3H]-iloprost binding to the PGI2 receptor on human platelet membranes. Displacing ability is ranked as follows: iloprost > 6a-carba PGI2> EP 157 > EP 035 > EP 164 (a-dinor derivative of EP 157). This order of potency is the same as that found for activation of adenylate cyclase in homogenates of washed human platelets and for inhibition of aggregation in washed human platelets. 4 The activities of EP 035 and EP 157 were studied in two other systems containing PGI2 receptoradenylate cyclase complexes, the NCB-20 cell line and human lung tissue. In both cases stimulation of adenylate cyclase was found but maximum rates were below that achieved with iloprost. These effects of EP 035 and EP 157 could be correlated with their abilities to displace [3H]-iloprost binding. 5 These results indicate that EP 035 and EP 157 inhibit the aggregation of human platelets by acting as agonists at the PGI2 receptor linked to adenylate cyclase. They represent a class of compound with both thromboxane receptor blocking activity and prostacyclin mimetic activity.

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“…Therefore, because of a lack of or decreased synergistic action, higher concentrations of collagen may be required in porcine platelets for aggregation than are required in human platelets. Indeed, we cannot detect the aggregation of porcine platelets by the addition of the stable thromboxane A, analogue U44069 [25,26], which induces shape change and irreversible aggregation of human platelets. However, various platelet proteins have been proposed as possible receptors for collagen [27].…”

Section: Discussionmentioning

confidence: 99%

Involvement of Protein‐Tyrosine Kinase p72^syk in Collagen‐Induced Signal Transduction in Platelets

Fujii

Yanagi

Sada

et al. 1994

European Journal of Biochemistry

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Previous studies have demonstrated that activation of platelets by collagen results in a dramatic increase in tyrosine phosphorylation of several cellular proteins, including ppl 25FAK, through the interaction of collagen with integrin (GP Ia-IIa). In this study, we report that p7Tyk is a potential candidate for the protein-tyrosine phosphorylation event following collagen stimulation in porcine platelets. Washed platelets were stimulated with collagen and the activation of p7Tyk was assessed in an immunoprecipitation kinase assay. The activity of p72"yk increased within 1 min, reached a maximum at 5 min after stimulation by collagen, and the phosphorylation at tyrosine residues of p7TYk in platelets also occurred in the same time course as the activation of ~7 2 "~. Prior treatment of platelets with cytochalasin D to inhibit actin polymerization, or with aspirin and apyrase to inhibit the secondary reaction, or EGTA and the acetoxymethyl ester of 5,5'-dimethyl-bis-(o-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid to chelate both extracellular and intracellular Ca", did not affect the activation of p7Tyk induced by collagen. Furthermore, herbimycin A, a potent proteintyrosine-kinase inhibitor, was capable of reducing collagen-evoked p7Tyk activation, Ca2+ mobilization and platelet aggregation. These results suggest that upon stimulation by collagen p7Tyk is physically activated by a process that is independent of the effects of Ca", ADP, and actin polymerization, and may participate in the regulation of Caz+ mobilization mediated by collagen in platelets.Following injury to the blood-vessel wall, thrombogenic components in the vessel wall and perivascular space, in particular the collagenous elements, are brought into contact with the circulating blood. Platelets are the circulating blood cells that mainly participate in hemostatic reactions and are activated by diverse substances of which collagen is one of the strongest agonists, especially in the vascular subendothelium [l -31. Activation of platelets by collagen causes many events including shape change, aggregation and secretion that are considered to be regulated through coordination of intracellular signaling pathways, including Ca2+ mobilization and protein-kinase-C activation. Previous studies have demonstrated that activation of platelets by collagen results in a dramatic increase in tyrosine phosphorylation of several cellular proteins including ~~1 2 5~~~ through the interaction of collagen with integrin a& (GP Ia-IIa). This protein-tyrosine phosphorylation is independent of both GPIIb-IIIa and ADP and is accompanied by cytoskeletal reorganization and changes in cell shape [4-71. However, the key enzymes that Correspondence to H. Yamamura, Department of Biochemistry, Fukui Medical School, Matsuoka, Fukui, Japan 910-11Abbreviations. SH2 and SH3, src homology region-2 and src homology region-3 ; AM, acetoxymethyl; BAFTA, 53'-dimethyl- Enzymes. Protein-tyrosine kinase (EC 2.7.1.112); protein kinase C (EC 2.7.1.37).control the level of protein-tyrosine...

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Ligand binding to thromboxane receptors on human platelets: correlation with biological activity

Cited by 111 publications

References 28 publications

Binding of a radioiodinated 13‐azapinane thromboxane antagonist to platelets: correlation with antiaggregatory activity in different species

Binding of a radioiodinated 13‐azapinane thromboxane antagonist to platelets: correlation with antiaggregatory activity in different species

Prostaglandin endoperoxide analogues which are both thromboxane receptor antagonists and prostacyclin mimetics

Involvement of Protein‐Tyrosine Kinase p72^syk in Collagen‐Induced Signal Transduction in Platelets

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Ligand binding to thromboxane receptors on human platelets: correlation with biological activity

Cited by 111 publications

References 28 publications

Binding of a radioiodinated 13‐azapinane thromboxane antagonist to platelets: correlation with antiaggregatory activity in different species

Binding of a radioiodinated 13‐azapinane thromboxane antagonist to platelets: correlation with antiaggregatory activity in different species

Prostaglandin endoperoxide analogues which are both thromboxane receptor antagonists and prostacyclin mimetics

Involvement of Protein‐Tyrosine Kinase p72syk in Collagen‐Induced Signal Transduction in Platelets

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Involvement of Protein‐Tyrosine Kinase p72^syk in Collagen‐Induced Signal Transduction in Platelets