Characterization of a functional thrombin receptor. Issues and opportunities.

Coughlin, Shaun R.; Vu, T.-K. H.; Hung, David T.; Wheaton, V. I.

doi:10.1172/jci115592

Cited by 279 publications

(165 citation statements)

References 40 publications

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“…Thus, thrombin not only plays an essential role in blood coagulation but also signi®cantly in¯uences the development of CHD. 146,147 Although the e ects of thrombin and PDGF are counteracted by several inhibitors present in plasma, 148 these e ects are, in part, inhibited by PGI 2 through a platelet-mediated interaction. 149 Thus, through its multi-inhibitory e ects, PGI 2 exerts a signi®cant bene®cial e ect in the prevention of atherosclerosis.…”

Section: Pdgf and Thrombin In Scimentioning

confidence: 99%

Risk factors for atherogenesis and cardiovascular autonomic function in persons with spinal cord injury

et al. 1999

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Persons with spinal cord injury (SCI) have been recognized to have several metabolic changes that adversely impact their risk for cardiovascular disease. An increased prevalence of disorders of carbohydrate metabolism and dyslipidemia may be related predominantly to paralysis with immobilization and associated loss of lean body tissue and gain in relative adiposity. Studies have reported an increased risk of vascular disease in those with SCI. As such, an understanding of the constellation of carbohydrate and lipid changes that occur after SCI is relevant to the clinical practice of medicine in this population. Oral glucose tolerance testing and associated studiesImpaired glucose tolerance and diabetes mellitus are more prevalent in individuals with SCI than in those who are able-bodied. 1 ± 4 In most of the individuals with SCI and abnormal carbohydrate tolerance, resistance to insulin mediation of glucose uptake by peripheral tissues may be demonstrable. In the presence of insulin resistance, the normal homeostatic response to glucose challenge is increased pancreatic b-cell secretion of insulin. If the compensatory response of the pancreas is insu cient to control the serum glucose concentration, worsening of carbohydrate tolerance will ensue.Bauman et al 3 performed a 75 g oral glucose tolerance test in 100 male veterans with SCI and in 50 able-bodied veteran controls. According to criteria established by the World Health Organization, 5 22% of those with SCI were diabetic whereas only 6% of the control group were diabetic. Eighty-two per cent of the controls had normal oral glucose tolerance, compared with 38% of those with quadriplegia and 50% of those with paraplegia. Subjects with SCI had signi®cantly higher mean plasma glucose and insulin values at several points during the oral glucose tolerance test when compared with controls ( Figure 1). In subgroups, determinants of insulin sensitivity were measured: per cent lean body mass, per cent fat mass, and cardiopulmonary ®tness. Values for insulin sensitivity were linearly related with those of ®tness (VO 2 max) determined from a progressive incremental upper-body exercise stress test. Insulin sensitivity was suggestively correlated with lean body mass, and negatively correlated with body fat. Thus, in a relatively small subgroup of untrained subjects with paraplegia, the strongest determinant of insulin sensitivity was cardiopulmonary ®tness.In 201 non-veteran subjects with SCI, Bauman et al 2 studied the relationship of oral carbohydrate tolerance after a 75 g glucose load to several variables, including level and completeness of lesion, gender, ethnicity, age, duration of injury, and anthropometric measures. Of the total group, 27 (13%) had diabetes mellitus and 56 (29%) had impaired glucose tolerance. 2,6 The subjects with complete tetraplegia had sign®cantly worse carbohydrate tolerance (Figure 2) and were more frequently classi®ed with a disorder of carbohydrate tolerance than the other neurological de®cit subgroups. 2 There were no signi®cant gend...

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Section: Pdgf and Thrombin In Scimentioning

confidence: 99%

Risk factors for atherogenesis and cardiovascular autonomic function in persons with spinal cord injury

et al. 1999

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“…The decrease or absence of high-affinity a-thrombin binding to Bernard-Soulier platelets, which lack GP~ba (17), provided further evidence that GPIb was a thrombin receptor. In experiments using crosslinking of a-thrombin to human platelets, the only identifiable site of binding was GPIb (18,19).The proposed roles of GPIba in thrombin binding include acting as a high-affinity receptor for localizing a-thrombin near the cell surface or serving as a site for excess thrombin binding (20). In this scheme, GPIba acts primarily as a neutralizing site for excess thrombin generation or as an independent modulator of platelet function through an undefined mechanism.…”

mentioning

confidence: 99%

“…The proposed roles of GPIba in thrombin binding include acting as a high-affinity receptor for localizing a-thrombin near the cell surface or serving as a site for excess thrombin binding (20). In this scheme, GPIba acts primarily as a neutralizing site for excess thrombin generation or as an independent modulator of platelet function through an undefined mechanism.…”

mentioning

confidence: 99%

High-affinity alpha-thrombin binding to platelet glycoprotein Ib alpha: identification of two binding domains.

Gralnick¹,

Williams²,

McKeown³

et al. 1994

Proc. Natl. Acad. Sci. U.S.A.

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The platelet thrombin binding site(s) has been a controversial issue. Vu and coworkers (4-6) have cloned a platelet thrombin receptor which is a member of the 7-transmembrane loop-receptor family. This receptor is cleaved by thrombin between residues R41 and S42, exposing a new amino-terminal peptide, which serves as a tethered ligand whose binding site resides within the first six amino acids. This tethered ligand peptide binds to an undefined site that induces receptor activation (7-9).Prior to the discovery and cloning of the seven-transmembrane loop receptor, several studies had defined platelet glycoprotein lb (GPIb) as an a-thrombin receptor. These studies described the binding of thrombin to GPIb and the inhibition of a-thrombin binding to GPIb by glycocalicin (a proteolytic fragment of GPIba) and monoclonal antibodies directed against . The decrease or absence of high-affinity a-thrombin binding to Bernard-Soulier platelets, which lack GP~ba (17), provided further evidence that GPIb was a thrombin receptor. In experiments using crosslinking of a-thrombin to human platelets, the only identifiable site of binding was GPIb (18,19).The proposed roles of GPIba in thrombin binding include acting as a high-affinity receptor for localizing a-thrombin near the cell surface or serving as a site for excess thrombin binding (20). In this scheme, GPIba acts primarily as a neutralizing site for excess thrombin generation or as an independent modulator of platelet function through an undefined mechanism. We have studied the high-affinity binding of a-thrombin to human platelets and have examined the inhibitory effects of synthetic peptides derived from portions of the sequence of the GPIba chain and from the seventransmembrane loop thrombin receptor in order to assess the site(s) of high-and moderate-affinity thrombin binding to platelets and thrombin-induced platelet aggregation.MATERIALS AND METHODS Platelet Preparation. Blood was obtained by venipuncture using a two-syringe technique. The blood from the second syringe was placed into polypropylene tubes containing 0.1 ml of sodium citrate anticoagulant, final concentration 10.9 pM. Platelet-rich plasma was prepared from whole blood after centrifugation at 750 x g for 3 min at 250C. Then 6-10 ml of platelet-rich plasma was placed on a discontinuous Larcoll (Sigma) gradient, 20%o (3 ml) and 10% (5 ml), and the platelets were separated from the plasma proteins by centrifugation at 2000 x g for 30 min. The platelets were then resuspended in Hepes buffer at pH 7.35. All platelets were used within 2 hr of being obtained.Thrombin Lalin. Human a-thrombin was prepared and radiolabeled as described (21). Two hundred fifty microliters of a-thrombin solution (1 pg/2 units of activity) was treated with 5 Ad oflactoperoxidase beads, 5 td of0.5 mM KI, 0.5 mCi (18.5 MBq) of Na125I, and 1 A4 of 0.015% H202 for 5 min at room temperature. Free 125I was separated from bound 125I on a 10-ml column of Sephadex G-25 fine equilibrated with 0.05 M Tris/0.1 M NaCl at pH 7.35. Fractions were ...

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“…As a result, it activates the coagulation system and platelet response; therefore, thrombin is thought to play a central role in hemostasis and thrombosis. Cloning of a functional thrombin receptor has been described 3) and the proteolytic mechanism for activation has been elucidated 4) . The thrombin receptor is a G protein-coupled receptor (protease activated receptor, PAR) activated by a unique mechanism involving proteolytic cleavage of the receptor by thrombin.…”

Section: Measurement Of Platelet Aggregationmentioning

confidence: 99%

Oral Antithrombotic Effects of Acylhydrazone Derivatives

Frattani

Coriolano

Lima

et al. 2013

JAT

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Aim:In the search for new antithrombotic drug candidates, the synthesis and anti-platelet activity of a new series of N-acylhydrazones that were designed as thrombin inhibitors has been previously described. The aim of this work was to further characterize the effects of these compounds on thrombin-induced platelet aggregation and induced thrombosis in vivo. Methods: In this work, four compounds were tested, LASSBio-693, 694, 743 and 752, on platelet aggregation induced by thrombin, ADP and TRAP-4A. These compounds were further tested using a mouse pulmonary thromboembolism model induced by collagen (500 μg/kg) and norepinephrine (80 μg/kg) or thrombin (2,000 UI), and a deep venous thrombosis model.

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Characterization of a functional thrombin receptor. Issues and opportunities.

Cited by 279 publications

References 40 publications

Risk factors for atherogenesis and cardiovascular autonomic function in persons with spinal cord injury

Risk factors for atherogenesis and cardiovascular autonomic function in persons with spinal cord injury

High-affinity alpha-thrombin binding to platelet glycoprotein Ib alpha: identification of two binding domains.

Oral Antithrombotic Effects of Acylhydrazone Derivatives

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