Disease relevance of F2r

• Thus, PAR1 and PAR3 mediate anti-apoptotic signaling by APC in neurons, which may suggest novel treatments for neurodegenerative disorders [1].
• In WT mice, TFLLRNPNDK, a PAR-1 selective activating peptide, caused hypotension and HR decreases at 1 micromol/kg [2].
• The contribution of PAR-1 to inflammatory cell-mediated renal injury was assessed in murine crescentic glomerulonephritis (GN) [3].
• Tissue factor deficiency and PAR-1 deficiency are protective against renal ischemia reperfusion injury [4].
• Protease-activated receptor 1 (PAR-1) is required and rate-limiting for thrombin-enhanced experimental pulmonary metastasis [5].

High impact information on F2r

• Pepducin-based intervention of thrombin-receptor signaling and systemic platelet activation [6].
• PAR3 is a thrombin receptor that is expressed in mouse megakaryocytes [7].
• Strikingly, tr-/- platelets respond strongly to thrombin, whereas tr-/- fibroblasts lose their ability to respond to thrombin [8].
• We conclude that the thrombin receptor plays an unexpected role in embryonic development, suggesting a possible new function for the 'coagulation' proteases themselves [8].
• Here we show that although disruption of the thrombin receptor (tr) gene in mice causes about half of the tr-/- embryos to die at embryonic day 9-10, half survive to become grossly normal adult mice with no bleeding diathesis [8].

Chemical compound and disease context of F2r

• SFLLRN still induced hypotension in PAR-1(-/-) mice, but HR decrease and secondary hypertension following L-NAME were absent [2].
• Because NMDA activity mediates hyperalgesia, we tested the hypothesis that PAR-1 receptors also regulate pain processing [9].
• Our data suggest that PAR-1 is antinociceptive in processing of visceral pain, whereas PAR-2 expressed in the colonic luminal surface, upon activation, produces delayed sensitization of capsaicin receptors, resulting in facilitation of visceral pain and referred hyperalgesia [10].
• We also demonstrate that pulmonary edema and TGF-beta activity are similarly reduced in Par1-/- mice following bleomycin-induced lung injury [11].
• Intratracheal instillation of the PAR1-specific peptide TFLLRN increases lung edema during high-tidal-volume ventilation, and this effect is completely inhibited by a blocking antibody against the alpha(v)beta6 integrin [11].

Biological context of F2r

• Thrombin receptor expression became more restricted with time and by the fetal growth stage (E16.5) was most readily detected in certain neurons, endocardial and endothelial cells, and within lung and liver [12].
• By contrast, in fibroblasts, PAR1 by itself accounted for virtually all Xa-induced phosphoinositide hydrolysis [13].
• Thrombin receptor mRNA was expressed widely in mesenchymal cell populations during early organogenesis (E9.5) and was particularly abundant in developing heart and blood vessels [12].
• Conserved structure and adjacent location of the thrombin receptor and protease-activated receptor 2 genes define a protease-activated receptor gene cluster [14].
• Moreover, the accentuated response to PAR-1 activation in PAR-2-deficient mice suggests a compensatory response and potential receptor cross-talk [2].

Anatomical context of F2r

• Activated protein C (APC), a serine protease with anticoagulant and anti-inflammatory activities, exerts direct cytoprotective effects on endothelium via endothelial protein C receptor-dependent activation of protease activated receptor 1 (PAR1) [1].
• Thus PAR1 is the major thrombin receptor in mouse endothelial cells, but PAR4 also contributes [15].
• 5. In several instances, tissue factor-expressing epithelia were surrounded by thrombin receptor-expressing mesenchyme [12].
• The results demonstrate that thrombin stimulates proliferation and inhibits differentiation of osteoblasts through activation of PAR-1 [16].
• The aim of this study was to determine if PAR-1 and PAR-2 mediate gastrointestinal smooth muscle relaxation and to clarify the underlying mechanisms [17].

Associations of F2r with chemical compounds

• Both the PAR-1-activating peptide and thrombin stimulated incorporation of 5-bromo-2'-deoxyuridine (two to four-fold, P < 0.001) and reduced alkaline phosphatase activity (approximately three-fold, P < 0.05) in cells from wild-type mice [16].
• The reductions in crescent formation, inflammatory cell infiltration, and serum creatinine were similar in PAR-1(-/-) and hirudin-treated mice, but hirudin afforded significantly greater protection from fibrin deposition [3].
• The enhancing and inhibiting effects were specific for thrombin (reversed with inactive diisopropyl-fluorophosphate [DFP]-thrombin) and mediated via the protease-activated receptor 1 (PAR-1) [18].
• Thus, activation of PAR-1 sites by thrombin in the CNS appears to inhibit NMDA-mediated nociception by a pathway involving endothelin type A receptors [9].
• Similarly, ThrR deficiency had no detectable effect in adult ThrR-/- mice on basal heart rate, arterial blood pressure, vasomotor responses to angiotensin II and acetycholine, and coagulation parameters, even though the ThrR is expressed in many cardiovascular tissue types [19].

Physical interactions of F2r

• It is proposed that granzyme A interacts with the thrombin receptor found on platelets in a manner that is insufficient to cause aggregation, but sufficient to compete with thrombin for the receptor [20].

Enzymatic interactions of F2r

• A synthetic peptide spanning the N-terminal thrombin receptor activation sequence was cleaved by granzyme A at the authentic thrombin cleavage site Leu-Asp-Pro-Arg-Ser [21].

Co-localisations of F2r

• PAR-1 immunoreactivity was found on epithelial cells and on neurons in submucosal ganglia where it was colocalized with both VIP and neuropeptide Y [22].

Regulatory relationships of F2r

• The finding of robust thrombin receptor expression before prothrombin mRNA was detected raises the question of whether other proteases or peptide ligands can activate the thrombin receptor [12].
• In addition, only PAR-1 activation induced hypertension following L-NAME, reflecting concurrent PAR-1-mediated vasoconstriction [23].
• Antibodies to the thrombin receptor inhibited both thrombin and granzyme A-mediated neurite retraction [21].
• Tissue factor-initiated thrombin generation activates the signaling thrombin receptor on malignant melanoma cells [24].
• We hypothesized that PAR-1 activation would induce mast cell adhesion to fibronectin (FN) [25].

Other interactions of F2r

• By contrast, deficiencies of protease-activated receptor 1 (PAR1) or PAR2 did not provide protection [26].
• In contrast to the thrombin receptor, prothrombin mRNA was limited to the embryonic liver and was not detected until E12.5, well after the onset of receptor expression. mRNA for tissue factor, one important trigger for thrombin generation in the adult, was detected in embryonic epithelia from E9.5-12 [12].
• Granzyme A released upon stimulation of cytotoxic T lymphocytes activates the thrombin receptor on neuronal cells and astrocytes [21].
• Endothelial-specific Galpha13 knockout embryos died at embryonic days 9.5-11.5 and resembled the PAR1 knockout [27].
• We compared renal injury after 25 minutes of bilateral renal ischemia and varying periods of reperfusion in C57BL/6 mice, those expressing low levels of TF (low-TF), hirudin-treated C57BL/6, and mice lacking either PAR-1 or PAR-2 [4].

Analytical, diagnostic and therapeutic context of F2r

• We examined the expression of thrombin receptor, prothrombin, and tissue factor by in situ hybridization in mouse development [12].
• Molecular cloning of a thrombin receptor revealed a G protein-coupled receptor that is activated by a novel proteolytic mechanism [14].
• Preactivation of HUVEC with either PAR39-44 or thrombin resulted in heterologous desensitization to the corresponding agonist, an effect that was mediated primarily by TR internalization as evaluated by immunofluorescence and quantitative ELISA [28].
• Four murine tumor cells (Lewis lung, CT26 colon CA, B16F10 melanoma, and CCL163 fibroblasts) contain PAR-1, as detected by reverse transcriptase-polymerase chain reaction (RT-PCR) [5].
• Thus, PAR-1 ligation and expression enhances and regulates tumor metastasis [5].

References