Protease-activated receptors 1 and 4 mediate activation of human platelets by thrombin

Kahn, Mark L.; Nakanishi‐Matsui, Mayumi; Shapiro, Michael J.; Ishiga, Hiroaki; Coughlin, Shaun R.

doi:10.1172/jci6042

Cited by 754 publications

(706 citation statements)

References 35 publications

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“…Specific agonist peptides, mimicking the new N-terminus, have been designed, for PAR1 the most often used is SFLLRN (PAR1-AP) [5], for PAR4 the most potent is AYPGKF (PAR4-AP) [6]. If both cleavage sites are blocked by antibodies raised against peptides spanning the cleavage sites, the platelet response to thrombin is abolished [7]. It is known that, like other G protein-coupled receptors, PAR1 is quickly uncoupled from signalling and internalised, by sequestration into endosomes via coated pits, after activation by PAR1-AP [8].…”

Section: Introductionmentioning

confidence: 99%

Platelet PAR1 receptor density—Correlation to platelet activation response and changes in exposure after platelet activation

Ramström

Öberg

Åkerström

et al. 2008

Thrombosis Research

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Section: Introductionmentioning

confidence: 99%

Platelet PAR1 receptor density—Correlation to platelet activation response and changes in exposure after platelet activation

Ramström

Öberg

Åkerström

et al. 2008

Thrombosis Research

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“…PAR-1 is a high affinity thrombin receptor in human platelets and it is activated by serine protease, such as thrombin [14]. After activation, it will cleave its extracellular N-terminus and expose a new N-terminal (S 42 FLLRNPNDK 51 ) acting as a tethered ligand to bind the receptor surface C-terminal residues P 85 AFIS 89 , which is named as PAR-1 binding site-1 (LBS-1) [41].…”

Section: Discussionmentioning

confidence: 99%

“…Human platelets express PAR-1 and PAR-4, whereas the mouse platelets express PAR-3 and PAR-4 [10,14,15]. In human platelets, PAR-1 is a high-affinity receptor that is activated at low concentrations of thrombin, and PAR-4 is a low-affinity receptor that mediates thrombin signaling at higher concentrations [14].…”

Section: Introductionmentioning

confidence: 99%

“…In human platelets, PAR-1 is a high-affinity receptor that is activated at low concentrations of thrombin, and PAR-4 is a low-affinity receptor that mediates thrombin signaling at higher concentrations [14]. In mouse platelets, PAR-3 serves as a co-receptor for PAR-4, wherein thrombin binds to PAR-3 and PAR-4, and cleaves the amino terminus of PAR-4 [16].…”

Section: Introductionmentioning

confidence: 99%

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Characterization of a new peptide agonist of the protease-activated receptor-1

Mao

Jin

Kunapuli

2008

Biochemical Pharmacology

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A new peptide (TFRRRLSRATR), from the c-terminal of human platelet P2Y 1 receptor, was synthesized and its biological function was evaluated. This peptide activated platelets in a concentration-dependent manner, causing shape change, aggregation, secretion and calcium mobilization. Of the several receptor antagonists tested, only BMS200261, a PAR-1 specific antagonist, totally abolished the peptide-induced platelet aggregation, secretion and calcium mobilization. The TFRRR-peptide-pretreated washed platelets failed to aggregate in response to SFLLRN (10 μM) but not to AYPGKF (500 μM). In addition, in mouse platelets, peptide concentrations up to 600 μM failed to cause platelet activation, indicating that the TFRRR-peptide activated platelets through the PAR-1 receptor rather than through the PAR-4 receptor. The shape change induced by 10 μM peptide was totally abolished by Y-27632, an inhibitor of p160 ROCK which is the downstream signal of G 12/13 pathways. The TFRRR-peptide, YFLLRNP, and the physiological agonist thrombin selectively activated G12/13 pathways at low concentrations and began to activate both Gq and G12/13 pathways with increased concentrations. Similar to SFLLRN, the TFRRRpeptide caused phosphorylation of Akt and Erk in a P2Y 12 receptor-dependent manner, and p-38 MAP kinase activation in a P2Y 12 -independent manner. The effects of this peptide are elicited by the first six amino acids (TFRRRL) whereas the remaining peptide (LSRATR), TFERRN, or TFEERN had no effects on platelets. We conclude that TFRRRL activates human platelets through the PAR-1 receptors.

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“…Four distinct PARs have been cloned, with PAR1, PAR3 and PAR4 being activated by thrombin. Human platelets express PAR1 and PAR4 and activation of either is su cient to trigger platelet aggregation and secretion (Vu et al, 1991;Xu et al, 1998;Kahn et al, 1999), whereas murine platelets express PAR3 and PAR4, and thrombin signalling is PAR4-dependent (Nakanishi-Matsui et al, 2000). PAR4 is activated when thrombin cleaves its amino-terminal exodomain to unmask a tethered ligand (Kahn et al, 1998).…”

mentioning

confidence: 99%

Thrombin‐induced platelet endostatin release is blocked by a proteinase activated receptor‐4 (PAR4) antagonist

Hollenberg

Wallace

2001

British J Pharmacology

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Endostatin is a potent endogenous inhibitor of angiogenesis that was recently shown to be stored in platelets and released in response to thrombin, but not ADP. In the present study, we have tested the hypothesis that thrombin-induced endostatin release from rat platelets is mediated via proteinase-activated receptor-4 (PAR4). Immunoprecipitation and Western blotting con®rmed that endostatin is contained within rat platelets. Aggregation and release of endostatin could be elicited by thrombin (0.5 ± 1.0 U ml 71 ) or by speci®c PAR4 agonist (AYPGKF-NH 2 ; AY-NH 2 ; 15 ± 50 mM). Signi®cant release of endostatin could be induced by a dose of thrombin below that necessary for induction of aggregation. An adenosine diphosphate (ADP) scavenger, apyrase, inhibited the platelet aggregation induced by thrombin, but not the release of endostatin. In contrast, a selective PAR4 antagonist (trans-cinnamoyl-YPGKF-NH 2 ; tcY-NH 2 ) prevented endostatin release and aggregation induced by thrombin or by AY-NH 2 . We conclude that thrombin-induced endostatin release from rat platelets is PAR4-mediated via an ADP-independent mechanism that can occur independently of platelet aggregation.

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Protease-activated receptors 1 and 4 mediate activation of human platelets by thrombin

Cited by 754 publications

References 35 publications

Platelet PAR1 receptor density—Correlation to platelet activation response and changes in exposure after platelet activation

Platelet PAR1 receptor density—Correlation to platelet activation response and changes in exposure after platelet activation

Characterization of a new peptide agonist of the protease-activated receptor-1

Thrombin‐induced platelet endostatin release is blocked by a proteinase activated receptor‐4 (PAR4) antagonist

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