Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.21.5 (thrombin)
33,306 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Platelet aggregates, stabilized by fibrin, rapidly form hemostatic plugs when blood vessels are severed or arterial thrombi at sites of vessel injury, such as ruptured atherosclerotic plaques, or regions where blood flow is disturbed, such as at stenoses. These thrombi cause the thromboembolic complications of atherosclerosis: heart attacks, strokes, and peripheral vascular disease. Platelet adhesion to subendothelial components such as collagen activates signalling pathways that lead to thromboxane A2 formation and secretion of platelet granule contents, including ADP. Both these substances cause platelet aggregation, a process in which the integrin, glycoprotein IIb/IIIa, becomes a receptor for fibrinogen, which forms bridges between adjacent platelets. On the surface of stimulated platelets, coagulation is accelerated and thrombin is generated; it is a potent inducer of platelet aggregation and secretion and also causes fibrin to form around the aggregates, stabilizing them. There are receptors on the platelet surface for thrombin, thromboxane A2, collagen, ADP, platelet-activating factor, fibrinogen, von Willebrand factor, and other ligands. Agents that inhibit platelet aggregation and the signalling pathways that are activated by the various aggregating agents are under intensive investigation in many laboratories.
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PMID:Role of platelets in thrombosis and hemostasis. 806 74

A platelet aggregation inhibitor was identified in the salivary gland of the tick Ornithodoros moubata and isolated by gel filtration and reverse phase high pressure liquid chromatography. The purified inhibitor is a approximately 6-kDa protein, which we have named disagregin. It inhibits ADP-stimulated platelet aggregation in plasma with an IC50 = 104 +/- 17 nM. Disagregin also inhibits platelet aggregation induced by other agonists, including collagen, epinephrine, platelet-activating factor, thrombin, and the thrombin receptor peptide SFLLRNPNDKYEPF. It does not, however, affect platelet shape change induced by these agonists or thrombin-induced dense granule release. Disagregin inhibits platelet aggregation by binding to the platelet fibrinogen receptor. 125I-Disagregin forms a specific complex with both subunits of the fibrinogen receptor, glycoproteins IIb and IIIa, in the presence of a chemical cross-linker. It binds to unstimulated platelets with a Kd = 42.5 +/- 7.5 nM (23,800 +/- 1600 sites/platelet) and to ADP-stimulated platelets with Kd = 39.4 +/- 6.6 nM (24,050 +/- 1500 sites/platelet). Unlabeled disagregin and the snake venom disintegrin echistatin both compete for this binding. Disagregin also completely blocks platelet adhesion to fibrinogen while partially inhibiting platelet adhesion to fibronectin and having little effect on platelet adhesion to collagen. Disagregin had no effect on the adhesion of human umbilical cord vein endothelial cells to fibrinogen or vitronectin. These cells lack the glycoprotein IIb-IIIa complex; therefore, this result is consistent with the ability of disagregin to bind selectively to platelet glycoproteins IIb and IIIa. Sequence analysis of disagregin revealed 60 residues composing a unique protein. Unlike other fibrinogen antagonists it does not contain the Arg-Gly-Asp cell recognition sequence or a conservative substitution, and it has no structural homology with the Arg-Gly-Asp-containing snake venom disintegrins. Thus, disagregin is unique both in structure and function and may serve as a useful tool for the design of therapeutically useful antithrombotic agents.
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PMID:Disagregin is a fibrinogen receptor antagonist lacking the Arg-Gly-Asp sequence from the tick, Ornithodoros moubata. 812 28

We examined the distribution of glycoprotein Ib (GPIb) and glycoprotein IIb-IIIa (GPIIb-IIIa) receptors on suspension- and surface-activated platelets before and after exposure to thrombin (1 U/ml, 10 minutes). Frozen thin sections prepared from fixed suspension-activated platelets or grids containing fixed surface-activated platelets were stained with specific antibodies to GPIb (antiglycocalicin) and GPIIb-IIIa (AP2 or 7E3), incubated with the corresponding gold-labeled secondary antibody, and examined in the electron microscope. GPIb and GPIIb-IIIa were evenly distributed on membranes of resting and suspension-activated platelets. GPIb and GPIIb-IIIa were present in the open canalicular system (OCS) of resting and, more prominently, in dilated OCS channels of thrombin suspension-activated platelets. On surface-activated platelets more intense labeling for GPIb was observed along pseudopods of dendritic cells whereas GPIIb-IIIa receptors were slightly increased over the peripheral zone. Morphometric study of labeling on fully spread, surface-activated platelets revealed that the density of GPIb increased significantly after thrombin treatment (60.7 +/- 13.1 vs 40.9 +/- 8.3 gold particles/microns 2, p < 0.05). A flow cytometry assay employing the same antiglycocalicin antibody revealed no down-regulation or clearance of GPIb after exposure of platelets to thrombin. GPIIb-IIIa distribution on spread platelets after exposure to thrombin remained basically unchanged (28.4 +/- 10.5 vs 32.6 +/- 10.9 particles/microns2 in nonactivated platelets). These findings indicate that clearance of GPIIb-IIIa and GPIb on suspension-activated platelets does not take place to the extent suggested in previous studies and does not occur spontaneously or after thrombin activation on surface-activated platelets. Although the presence of mobile receptors on platelets is essential for spreading on immobile surfaces and each other, their clearance to the OCS is not a fundamental mechanism regulating adhesion.
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PMID:Persistence of mobile receptors on surface- and suspension-activated platelets. 814 2

The stimulation of human platelets with physiological agonists results in the incorporation of several proteins into the cytoskeleton, fibrinogen binding, and platelet aggregation. We recently demonstrated that the Ras-related low molecular weight GTP-binding protein Rap2B associates with the cytoskeleton in activated platelets and that this interaction requires platelet aggregation. In the present study we demonstrate that agonist-induced actin polymerization is necessary for the translocation of Rap2B to the cytoskeleton, suggesting that Rap2B interacts with the newly formed actin filaments. Moreover, the association of Rap2B with Triton X-100-insoluble material from platelets was totally blocked by treatment of intact platelets with monoclonal antibodies against the fibrinogen receptor glycoprotein IIb-IIIa. Platelets from patients affected by Glanzmann thrombastenia, a genetic disorder in which platelet plasma membranes lack glycoprotein IIb-IIIa but possess normal levels of Ras-related proteins, failed to incorporate Rap2B into the cytoskeleton upon activation by thrombin. Comparative immunoblotting revealed that the translocation of Rap2B to the cytoskeleton during platelet aggregation was accompanied by the simultaneous translocation of glycoprotein IIb-IIIa. Moreover, the cytoskeleton from aggregated platelets contained Rap2B and glycoprotein IIb-IIIa in comparable amounts. These results demonstrate the association of Rap2B and glycoprotein IIb-IIIa and their translocation to the cytoskeleton in aggregated human platelets.
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PMID:Glycoprotein IIb-IIIa and the translocation of Rap2B to the platelet cytoskeleton. 818 95

The human integrin glycoprotein IIb/IIIa complex plays a central role in haemostasis as an inducible receptor for fibrinogen and other adhesive proteins at the platelet plasma membrane. Current evidence indicates that the ligand-binding domain of GPIIb/IIIa is discontinuous and placed at the subunit interface. Here we show that a synthetic peptide containing the polypeptide stretch GPIIb 656-667, which is hidden within the resting platelet GPIIb/IIIa heterodimer but becomes exposed following platelet activation with thrombin, binds to soluble fibrinogen (n = 2.3 +/- 1.3; Kd = 2 +/- 0.8 x 10(-5) M). This interaction is Ca(2+)-independent and can be partially inhibited with synthetic fibrinogen gamma-chain peptide 400-411 but not with GRGDS. In addition, peptide GPIIb 656-667 inhibits in a dose-dependent manner the aggregation of activated platelets (IC50 = 170 microM). Altogether, our results indicate that the GPIIb 656-667 region may form part of the inducible fibrinogen binding site and may not overlap with the integrin RGD-recognition domain.
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PMID:Glycoprotein IIb peptide 656-667 mimics the fibrinogen gamma chain 402-411 binding site on platelet integrin GPIIb/IIIa. 824 58

The interaction of fibronectin with glycoprotein IIb/IIIa (GPIIb/IIIa) was studied. Fibronectin bound to thrombin-stimulated platelets in a calcium-dependent, specific, and saturable manner with 98,000 molecules/platelet (Kd = 2.76 x 10(-7) M). The binding was inhibited by other adhesive proteins with IC50S of 0.076-0.105 microM and the anti-GPIIb/IIIa monoclonal antibody (LJ-CP8). The binding was also inhibited by the cyclic GRGDSPA peptide and the linear GRGDSPA peptide with IC50S of 0.223 microM and 3.75 microM, respectively. Native fibronectin, the cyclic peptide, and the linear peptide blocked thrombin-induced aggregation with IC50 of 0.95 microM, 32 microM, and 190 microM, respectively. These observations imply that the conformation of RGD-containing sequence may play an important role for an increasing affinity of the binding, and fibronectin may prevent thrombus formation by interfering with the interaction between fibrinogen and activated GPIIb/IIIa.
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PMID:Effect of cyclic Arg-Gly-Asp-containing peptide on fibronectin binding to activated platelets; role of fibronectin on platelet aggregation. 828 62

The present overview describes the mode of action of direct and indirect anticoagulants. Furthermore it presents well-accepted and potential indications for the different anticoagulants as concomitant treatment during thrombolysis of deep vein thrombosis, pulmonary embolism and myocardial infarction. The new antithrombotics dermatansulfate, hirudine, synthetic peptide thrombin inhibitors, activated protein C, inhibitors of glycoprotein IIb/IIIa are reviewed. Many small and large studies on the thrombolytic treatment of myocardial infarction demonstrate the benefit of simultaneous application of heparins.
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PMID:[Anticoagulation in thrombolytic therapy: importance and future perspectives]. 833 24

The intracellular distribution of the low-molecular-weight GTP-binding protein rap2B was investigated in resting and agonist-activated human platelets. In both cases, platelets were lysed by Triton X-100, and cell fractions were obtained by differential centrifugations. Using a specific polyclonal antiserum, we found that rap2B in resting platelets was completely detergent-soluble. When platelets were aggregated with thrombin, the thromboxane analogue U46619, or the Ca(2+)-ATPase inhibitor thapsigargin, a significant amount of rap2B became associated with the cytoskeleton. This association was paralleled by a decrease of rap2B in the Triton X-100-soluble fraction. Translocation of rap2B to the cytoskeleton strictly depended on platelet aggregation, and maximal incorporation was found when approximately 50% aggregation was measured. Inhibition of fibrinogen binding to the glycoprotein IIb-IIIa complex completely prevented the interaction of rap2B with the cytoskeleton. These results clearly demonstrate that changes in the intracellular localization of rap2B occur during platelet activation and represent evidence that this low molecular weight GTP-binding protein may be involved in platelet function.
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PMID:Association of the low molecular weight GTP-binding protein rap2B with the cytoskeleton during platelet aggregation. 835 55

The peptide YFLLRNP antagonizes the aggregation of human platelets when induced by low concentrations of alpha-thrombin or the thrombin receptor agonist peptide (SFLLRNP), demonstrating that it interacts specifically with the thrombin receptor. Platelets exposed to YFLLRNP show immediate shape change (pseudopod formation) and potentiation of the ADP and platelet-activating factor response, but no Ca2+ mobilization, P47 (pleckstrin) phosphorylation, secretion, or aggregation. Thus, YFLLRNP induces a state of partial activation of the platelets. Furthermore, with platelets prestimulated with adrenalin (10 microM), YFLLRNP induces aggregation, but no secretion, and only in the presence of added fibrinogen. We also found that prostacyclin inhibits the YFLLRNP-induced shape change; but EDTA, aspirin, and apyrase (ADP scavenger) do not. Thus, the thrombin receptor in platelets may communicate, independently of Ca2+ mobilization and P47 phosphorylation (protein kinase C activation), with intracellular signaling mechanisms that 1) modulate the cytoskeleton structure, 2) potentiate other platelet responses, and 3) stimulate coupling between the thrombin receptor and fibrinogen binding (the glycoprotein IIb-IIIa complex). YFLLRNP may be useful for differentiating between several possible activation states of the platelet thrombin receptor.
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PMID:A peptide ligand of the human thrombin receptor antagonizes alpha-thrombin and partially activates platelets. 839 Sep 90

Previous studies have shown that exogenous glycosphingolipids (GSLs) inhibit the adhesion of thrombin-activated platelets (TAP) to polystyrene plates coated with various RGD-ligands (where RGD is the peptide sequence Arg-Gly-Asp), suggesting that GSLs can modulate the platelet integrin receptor glycoprotein IIb-IIIa. However, albumin was always used as a plastic surface-blocking agent in these studies. In order to evaluate the role of albumin in these experiments, we studied the effect of various GSLs and albumin on the interaction between TAP and hydrophobic surfaces in a solid-phase assay using indium-111-labelled platelets and polystyrene plates. TAP (10(8) platelets/ml) adhered to polystyrene (half-saturation time 40 +/- 3 min) with a maximal adhesion density of 56 +/- 1 x 10(3) platelets/mm2. Platelet adhesion was only slightly affected (< 11% inhibition) by immobilized bovine serum albumin, immobilized mixed bovine brain gangliosides (MBG) or fluid-phase MBG. In contrast, fluid-phase MBG was an effective inhibitor of platelet adhesion to polystyrene (> 46% inhibition), but only after albumin was first immobilized to the plate. Covering albumin-coated polystyrene with MBG, followed by washing, was as effective as fluid-phase MBG at inhibiting platelet adhesion, thus indicating that a ganglioside-albumin interaction at the polystyrene surface was responsible for effective inhibition. When purified GSLs were substituted for MBG, it was found that all those tested (GT1b, GD1a, GM1, asialo GM1 and globoside) had similar inhibitory activity.
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PMID:Glycosphingolipid inhibition of the adhesion of thrombin-activated platelets to surfaces is potentiated by albumin. 840 May 48


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