Disease relevance of F2r

• Intestinal irradiation up-regulates PAR-1 and causes a dose-dependent, sustained deficiency of microvascular TM that is independently associated with the severity of radiation toxicity [1].
• We examined radiation-induced changes in endothelial thrombomodulin (TM) and protease-activated receptor-1 (PAR-1) in irradiated intestine, and their relationship to structural, cellular, and molecular aspects of radiation injury [1].
• Studies on the effects of pertussis toxin (PTX), phospholipase C antagonist and 2-APB, showed that in OLN-93 cells (i). the calcium signaling cascade from PAR-1 was mediated through PTX-insensitive G proteins, (ii). activation of phospholipase C and liberation of InsP(3) were events upstream of the Ca(2+) release from the stores [2].
• We examined the change in mRNA expression levels of PAR-1 to 4 as a result of transient focal ischemia in rat brain, induced by microinjection of endothelin near the middle cerebral artery [3].
• Taken together, these data suggest involvement of the thrombin receptors PAR-1, PAR-3, and PAR-4 in the pathophysiology of brain ischemia [3].

High impact information on F2r

• PAR3 can mediate thrombin-triggered phosphoinositide hydrolysis and is expressed in a variety of tissues, including human bone marrow and mouse megakaryocytes, making it a candidate for the sought-after second platelet thrombin receptor [4].
• Treatment of quiescent rat aortic smooth muscle cells with either alpha-thrombin or a thrombin receptor-derived agonist peptide (SFLLRNP) resulted in pronounced increases in [3H]thymidine incorporation that were concentration dependent and reached a maximum of approximately 15-fold above serum-starved controls [5].
• Thrombin receptor activation elicits rapid protein tyrosine phosphorylation and stimulation of the raf-1/MAP kinase pathway preceding delayed mitogenesis in cultured rat aortic smooth muscle cells: evidence for an obligate autocrine mechanism promoting cell proliferation induced by G-protein-coupled receptor agonist [5].
• Enhancement of incisional wound healing and neovascularization in normal rats by thrombin and synthetic thrombin receptor-activating peptides [6].
• Protease-activated receptor-2 (PAR-2) is a member of seven transmembrane domain G protein-coupled receptors activated by proteolytic cleavage whose better known member is the thrombin receptor [7].

Chemical compound and disease context of F2r

• These data indicate that activation of spinal PAR 2 and possibly PAR 1 results in the stimulation of the spinal cyclooxygenase cascade and a prostaglandin-dependent thermal hyperalgesia [8].
• Aortic TR mRNA was upregulated by angiotensin II (Ang II)-induced hypertension (10.7 +/- 2.5 times control, P < .02), which correlated with a 4-fold increase in thrombin-induced constriction in isolated endothelium-denuded aortic rings [9].
• Thrombin and PAR-1 activating peptide increase iNOS expression in cytokine-stimulated C6 glioma cells [10].
• Washed platelets from a patient with Bernard-Soulier syndrome did not respond to bothrombin even in the presence of exogenous fibrinogen, suggesting that the initial binding of bothrombin on platelets is GP Ib, but not a recently cloned thrombin receptor [11].
• On the other hand, inactivation of Rho GTPases by Clostridium difficile toxin B and treatment with general tyrosine kinase inhibitors suppressed PAR1- and ET(A)R- as well as phorbol ester-induced PLD stimulation and was associated with a fall in the cellular level of phosphatidylinositol 4,5-bisphosphate (PIP(2)) [12].

Biological context of F2r

• Expression of protease-activated receptors (PARs) in OLN-93 oligodendroglial cells and mechanism of PAR-1-induced calcium signaling [2].
• A rat aortic smooth muscle (RASM) cell cDNA library was screened with a 500-base pair (bp) sequence from the human thrombin receptor, obtained by polymerase chain reaction (PCR) amplification of cDNA synthesized from human erythropoietic leukemia (HEL) cell mRNA with PCR primers based on the published human thrombin receptor sequence [13].
• PAR1 activation resulted in renal vasoconstriction and a marked reduction in the glomerular filtration rate (GFR) [14].
• To test whether this process resulted from a signal transduction cascade initiated by activation of ThR, in particular PAR-1, we applied to the levator auris longus (LAL) muscle of newborn rats two synthetic peptides (SFLL and FSLL) [15].
• The agonists for PAR-2 or PAR-1 produced vasodilation in the endothelium-intact arterial rings, which was abolished by removal of the endothelium [16].

Anatomical context of F2r

• PAR-1 mRNA increased twofold in irradiated intestinal smooth muscle [1].
• This is the first study, which shows that OLN-93 oligodendrocytes functionally express PAR-1, and identifies the receptor coupling to mobilization of intracellular calcium [2].
• Pretreatment with a thrombin-receptor agonist reduced the amount of edema induced by a large dose of thrombin infused into the ipsilateral basal ganglia 7 days later (81.3 +/- 0.7% vs. 82.6 +/- 0.8% in the control, P < 0.05) [17].
• Role and expression of thrombin receptor PAR-1 in muscle cells and neuromuscular junctions during the synapse elimination period in the neonatal rat [15].
• The responsiveness of mast cells to PAR-AP via a non-PAR-1/non-PAR-2 mechanism complicates the interpretation of in vivo studies using these peptides [18].

Associations of F2r with chemical compounds

• Elevation of [Ca(2+)](i) induced by PAR-1 mainly resulted from Ca(2+) release from intracellular stores [2].
• In the in vivo studies, thrombin-induced brain tolerance was eliminated by RPPGF (Arg-Pro-Pro-Gly-Phe), a thrombin-receptor antagonist [17].
• Thrombin and thrombin receptor-activating peptide preconditioning reduced lactate dehydrogenase release induced by a high dose of thrombin (10 and 20 U/mL), whereas RPPGF blocked the effect of thrombin preconditioning in vitro [17].
• The vasoconstrictor actions of PAR1 activation were abolished by protein kinase C inhibition [14].
• We further demonstrate that the activation of PAR-1 by thrombin induces intracellular calcium movements that are blocked by 2-APB, an inhibitor of inositol 1,4,5-triphosphate (IP3)-induced calcium release [19].

Physical interactions of F2r

• 6. The data obtained with the PEEV-->NETL mutation suggested: (a) that SLIGRL-NH2 and SFLLR-NH2 interact in a distinct manner with PAR2 and (b) that SFLLR-NH2 may interact differently with PAR2 than it does with PAR1 [20].

Regulatory relationships of F2r

• Interventions aimed at preserving or restoring endothelial TM or blocking PAR-1 should be explored as strategies to increase the therapeutic ratio in clinical radiation therapy [1].
• This effect was mediated via the interaction of thrombin with its receptor protease activated receptor (PAR-1) since the peptide thrombin receptor activating peptide (TRAP) reduced PN-1 expression [21].
• Thrombin activates protease-activated receptor-1 (PAR-1) and engages signaling pathways that influence the growth and survival of cardiomyocytes as well as extracellular matrix remodeling by cardiac fibroblasts [22].
• The pathophysiological response to thrombin is mediated by protease-activated receptor-1 (PAR-1), a seven-transmembrane G protein-coupled receptor expressed in the nervous system that is identical to the thrombin receptor in platelets, fibroblasts, and endothelial cells [23].
• Thrombin receptor mRNA synthesis was induced by both basic fibroblast growth factor (maximal stimulation of 1.8-fold at 1 hour) and platelet-derived growth factor (maximal stimulation of 2.4-fold at 8 and 24 hours) in quiesced cultured rat aortic smooth muscle cells [24].

Other interactions of F2r

• Trypsin, in addition to PAR-2, can also activate PAR-1 and PAR-4 [25].
• Strong activation of the MAP kinase cascade and modest activation of p38 by trypsin were also observed in fibroblasts, although in this cell type these effects were not mimicked by SLIGRL nor by the thrombin receptor-activating peptide SFLLRNPNDKYEPF [26].
• The expression of PAR1 and the potent thrombin inhibitor protease nexin-1 (PN-1) was investigated in the developing rat brain and spinal cord and after peripheral nerve lesion [27].
• We have reported earlier that primary cultures of rat brain capillary endothelial (RBCE) cells express at least two receptors for thrombin: PAR-1 and PAR-3 [28].
• Proteinase-activated receptor 2 (PAR-2) is a G protein-coupled receptor related to the thrombin receptor [29].

Analytical, diagnostic and therapeutic context of F2r

• Steady-state PAR-1 mRNA levels in intestinal smooth muscle were determined using laser capture microdissection and competitive reverse transcriptase-polymerase chain reaction [1].
• PAR-1 protein was localized immunohistochemically, and cells expressing TM or PAR-1 transcript were identified by in situ hybridization [1].
• Moreover, Western blot analysis showed that PAR-1 was present in the skeletal muscle, and by immunohistochemistry we detected PAR-1 in muscle fibers concentrated in the synaptic area but also in satellite cells [15].
• Several lines of evidence suggested that PAR-1 is localized in the postsynaptic membrane: PAR-1 immunofluorescence was concentrated at denervated synaptic sites and was present in the myotube membrane in vitro in the absence of neurons and in dissociated single muscle fibers from which nerve terminals and Schwann cells had been removed [15].
• Rather, the enzyme-based cell isolation procedure may partially cleave the thrombin receptor and influence cell responses, since concentrations of SFLLRN which are sub-threshold in enzymatically disaggregated myocytes significantly increase the force of isometric contraction of intact rat papillary muscles [30].

References