Targeting proteinase-activated receptors: therapeutic potential and challenges (original) (raw)
Rieser, P. The insulin-like action of pepsin and pepsinogen. Acta Endocrinol.54, 375–379 (1967). CAS Google Scholar
Rieser, P. & Rieser, C. H. Anabolic responses of diaphragm muscle to insulin and to other pancreatic proteins. Proc. Soc. Exp. Biol. Med.116, 669–671 (1964). CASPubMed Google Scholar
Burger, M. M. Proteolytic enzymes initiating cell division and escape from contact inhibition of growth. Nature227, 170–171 (1970). CASPubMed Google Scholar
Sefton, B. M. & Rubin, H. Release from density dependent growth inhibition by proteolytic enzymes. Nature227, 843–845 (1970). CASPubMed Google Scholar
Chen, L. B. & Buchanan, J. M. Mitogenic activity of blood components. I. Thrombin and prothrombin. Proc. Natl Acad. Sci. USA72, 131–135 (1975). CASPubMedPubMed Central Google Scholar
Carney, D. H. & Cunningham, D. D. Transmembrane action of thrombin initiates chick cell division. J. Supramol. Struct.9, 337–350 (1978). CASPubMed Google Scholar
Carney, D. H. & Cunningham, D. D. Initiation of chick cell division by trypsin action at the cell surface. Nature268, 602–606 (1977). CASPubMed Google Scholar
Coughlin, S. R. Protease-activated receptors in hemostasis, thrombosis and vascular biology. J. Thromb. Haemost.3, 1800–1814 (2005). CASPubMed Google Scholar
Ramachandran, R. & Hollenberg, M. D. Proteinases and signalling: pathophysiological and therapeutic implications via PARs and more. Br. J. Pharmacol.153 (Suppl. 1), 263–282 (2008). Google Scholar
Adams, M. N. et al. Structure, function and pathophysiology of protease activated receptors. Pharmacol. Ther.130, 248–282 (2011). CASPubMed Google Scholar
Vu, T. K., Hung., D. T., Wheaton, V. I. & Coughlin, S. R. Molecular cloning of a functional thrombin receptor reveals a novel proteolytic mechanism of receptor activation. Cell64, 1057–1068 (1991). This study described the cloning of the human thrombin receptor and identified the novel 'tethered ligand' mechanism of activation. CASPubMed Google Scholar
Rasmussen, U. B. et al. cDNA cloning and expression of a hamster α-thrombin receptor coupled to Ca2+ mobilization. FEBS Lett.288, 123–128 (1991). This was one of the first reports to describe the cloning and functional expression of the thrombin receptor in mammalian cells. CASPubMed Google Scholar
Nystedt, S., Emilsson, K., Wahlestedt, C. & Sundelin, J. Molecular cloning of a potential proteinase activated receptor. Proc. Natl Acad. Sci. USA91, 9208–9212 (1994). CASPubMedPubMed Central Google Scholar
Nystedt, S., Emilsson, K., Larsson, A. K., Strombeck, B. & Sundelin, J. Molecular cloning and functional expression of the gene encoding the human proteinase-activated receptor 2. Eur. J. Biochem.232, 84–89 (1995). CASPubMed Google Scholar
Ishihara, H. et al. Protease-activated receptor 3 is a second thrombin receptor in humans. Nature386, 502–506 (1997). CASPubMed Google Scholar
Kahn, M. L. et al. A dual thrombin receptor system for platelet activation. Nature394, 690–694 (1998). CASPubMed Google Scholar
Xu, W. F. et al. Cloning and characterization of human protease-activated receptor 4. Proc. Natl Acad. Sci. USA95, 6642–6646 (1998). CASPubMedPubMed Central Google Scholar
Nakanishi-Matsui, M. et al. PAR3 is a cofactor for PAR4 activation by thrombin. Nature404, 609–613 (2000). CASPubMed Google Scholar
McLaughlin, J. N., Patterson, M. M. & Malik, A. B. Protease-activated receptor-3 (PAR3) regulates PAR1 signaling by receptor dimerization. Proc. Natl Acad. Sci. USA104, 5662–5667 (2007). CASPubMedPubMed Central Google Scholar
Scarborough, R. M. et al. Tethered ligand agonist peptides. Structural requirements for thrombin receptor activation reveal mechanism of proteolytic unmasking of agonist function. J. Biol. Chem.267, 13146–13149 (1992). CASPubMed Google Scholar
Hollenberg, M. D., Saifeddine, M., Al-Ani, B. & Kawabata, A. Proteinase-activated receptors: structural requirements for activity, receptor cross-reactivity, and receptor selectivity of receptor-activating peptides. Can. J. Physiol. Pharmacol.75, 832–841 (1997). CASPubMed Google Scholar
McGuire, J. J., Dai, J., Andrade-Gordon, P., Triggle, C. R. & Hollenberg, M. D. Proteinase-activated receptor-2 (PAR2): vascular effects of a PAR2-derived activating peptide via a receptor different than PAR2. J. Pharmacol. Exp. Ther.303, 985–992 (2002). CASPubMed Google Scholar
Liu, Q. et al. The distinct roles of two GPCRs, MrgprC11 and PAR2, in itch and hyperalgesia. Sci. Signal.4, ra45 (2011). CASPubMedPubMed Central Google Scholar
Defea, K. β-arrestins and heterotrimeric G-proteins: collaborators and competitors in signal transduction. Br. J. Pharmacol.153 (Suppl. 1), 298–309 (2008). Google Scholar
Dulon, S. et al. Proteinase-activated receptor-2 and human lung epithelial cells: disarming by neutrophil serine proteinases. Am. J. Respir. Cell. Mol. Biol.28, 339–346 (2003). CASPubMed Google Scholar
Renesto, P. et al. Specific inhibition of thrombin-induced cell activation by the neutrophil proteinases elastase, cathepsin G, and proteinase 3: evidence for distinct cleavage sites within the aminoterminal domain of the thrombin receptor. Blood89, 1944–1953 (1997). CASPubMed Google Scholar
Ramachandran, R. et al. Neutrophil elastase acts as a biased agonist for proteinase activated receptor-2 (PAR2). J. Biol. Chem.286, 24638–24648 (2011). This was one of the first studies to identify an endogenous proteolytic mechanism that can stimulate biased signalling through PAR2. CASPubMedPubMed Central Google Scholar
Rajagopal, S., Rajagopal, K. & Lefkowitz, R. J. Teaching old receptors new tricks: biasing seven-transmembrane receptors. Nature Rev. Drug Discov.9, 373–386 (2011). This is an excellent overview of biased signalling involving GPCRs and β-arrestin. Google Scholar
Kenakin, T. & Miller, L. J. Seven transmembrane receptors as shapeshifting proteins: the impact of allosteric modulation and functional selectivity on new drug discovery. Pharmacol. Rev.62, 265–304 (2010). This is a comprehensive overview of the concept of functional selectivity in GPCRs and its relevance to drug discovery. CASPubMedPubMed Central Google Scholar
Kenakin, T. Functional selectivity and biased receptor signaling. J. Pharmacol. Exp. Ther.336, 296–302 (2011). CASPubMed Google Scholar
Shapiro, M. J., Trejo, J., Zeng, D. & Coughlin, S. R. Role of the thrombin receptor's cytoplasmic tail in intracellular trafficking. Distinct determinants for agonist-triggered versus tonic internalization and intracellular localization. J. Biol. Chem.271, 32874–32880 (1996). CASPubMed Google Scholar
Shapiro, M. J. & Coughlin, S. R. Separate signals for agonist-independent and agonist-triggered trafficking of protease-activated receptor 1. J. Biol. Chem.273, 29009–29014 (1998). CASPubMed Google Scholar
Ishii, K. et al. Inhibition of thrombin receptor signaling by a G-protein coupled receptor kinase. Functional specificity among G-protein coupled receptor kinases. J. Biol. Chem.269, 1125–1130 (1994). CASPubMed Google Scholar
Tiruppathi, C. et al. G protein-coupled receptor kinase-5 regulates thrombin-activated signaling in endothelial cells. Proc. Natl Acad. Sci. USA97, 7440–7445 (2000). CASPubMedPubMed Central Google Scholar
Wolfe, B. L., Marchese, A. & Trejo, J. Ubiquitination differentially regulates clathrin-dependent internalization of protease-activated receptor-1. J. Cell Biol.177, 905–916 (2007). CASPubMedPubMed Central Google Scholar
Paing, M. M., Johnston, C. A., Siderovski, D. P. & Trejo, J. Clathrin adaptor AP2 regulates thrombin receptor constitutive internalization and endothelial cell resensitization. Mol. Cell Biol.26, 3231–3242 (2006). CASPubMedPubMed Central Google Scholar
Paing, M. M., Stutts, A. B., Kohout, T. A., Lefkowitz, R. J. & Trejo, J. β-arrestins regulate protease-activated receptor-1 desensitization but not internalization or down-regulation. J. Biol. Chem.277, 1292–1300 (2002). CASPubMed Google Scholar
Chen, B. et al. Adaptor protein complex-2 (AP-2) and epsin-1 mediate protease-activated receptor-1 internalization via phosphorylation- and ubiquitination-dependent sorting signals. J. Biol. Chem.286, 40760–40770 (2011). CASPubMedPubMed Central Google Scholar
Bohm, S. K. et al. Mechanisms of desensitization and resensitization of proteinase-activated receptor-2. J. Biol. Chem.271, 22003–22016 (1996). CASPubMed Google Scholar
Seatter, M. J. et al. The role of the C-terminal tail in protease-activated receptor-2-mediated Ca2+ signalling, proline-rich tyrosine kinase-2 activation, and mitogen-activated protein kinase activity. Cell Signal.16, 21–29 (2004). CASPubMed Google Scholar
Ricks, T. K. & Trejo, J. Phosphorylation of protease-activated receptor-2 differentially regulates desensitization and internalization. J. Biol. Chem.284, 34444–34457 (2009). CASPubMedPubMed Central Google Scholar
Dery, O., Thoma, M. S., Wong, H., Grady, E. F. & Bunnett, N. W. Trafficking of proteinase-activated receptor-2 and β-arrestin-1 tagged with green fluorescent protein. β-arrestin-dependent endocytosis of a proteinase receptor. J. Biol. Chem.274, 18524–18535 (1999). CASPubMed Google Scholar
Hasdemir, B., Murphy, J. E., Cottrell, G. S. & Bunnett, N. W. Endosomal deubiquitinating enzymes control ubiquitination and down-regulation of protease-activated receptor 2. J. Biol. Chem.284, 28453–28466 (2009). CASPubMedPubMed Central Google Scholar
Hasdemir, B., Bunnett, N. W. & Cottrell, G. S. Hepatocyte growth factor-regulated tyrosine kinase substrate (HRS) mediates post-endocytic trafficking of protease-activated receptor 2 and calcitonin receptor-like receptor. J. Biol. Chem.282, 29646–29657 (2007). CASPubMed Google Scholar
Shapiro, M. J., Weiss, E. J., Faruqi, T. R. & Coughlin, S. R. Protease-activated receptors 1 and 4 are shut off with distinct kinetics after activation by thrombin. J. Biol. Chem.275, 25216–25221 (2000). CASPubMed Google Scholar
Li, D., D'Angelo, L., Chavez, M. & Woulfe, D. S. Arrestin-2 differentially regulates PAR4 and ADP receptor signaling in platelets. J. Biol. Chem.286, 3805–3814 (2011). CASPubMed Google Scholar
Jacobs, S. & Cuatrecasas, P. The mobile receptor hypothesis and “cooperativity” of hormone binding. Application to insulin. Biochim. Biophys. Acta433, 482–495 (1976). CASPubMed Google Scholar
de Haen, C. The non-stoichiometric floating receptor model for hormone sensitive adenylyl cyclase. J. Theor. Biol.58, 383–400 (1976). CASPubMed Google Scholar
Urban, J. D. et al. Functional selectivity and classical concepts of quantitative pharmacology. J. Pharmacol. Exp. Ther.320, 1–13 (2007). CASPubMed Google Scholar
McLaughlin, J. N. et al. Functional selectivity of G protein signaling by agonist peptides and thrombin for the protease-activated receptor-1. J. Biol. Chem.280, 25048–25059 (2005). This was one of the first studies to demonstrate clearly that different agonists could elicit distinct functional responses when acting at PAR1. CASPubMed Google Scholar
Russo, A., Soh, U. J., Paing, M. M., Arora, P. & Trejo, J. Caveolae are required for protease-selective signaling by protease-activated receptor-1. Proc. Natl Acad. Sci. USA106, 6393–6397 (2009). CASPubMedPubMed Central Google Scholar
Awasthi, V., Mandal, S. K., Papanna, V., Rao, L. V. & Pendurthi, U. R. Modulation of tissue factor–factor VIIa signaling by lipid rafts and caveolae. Arterioscler. Thromb. Vasc. Biol.27, 1447–1455 (2007). CASPubMedPubMed Central Google Scholar
Hamilton, J. R., Nguyen, P. B. & Cocks, T. M. Atypical protease-activated receptor mediates endothelium-dependent relaxation of human coronary arteries. Circ. Res.82, 1306–1311 (1998). CASPubMed Google Scholar
Roy, S. S., Saifeddine, M., Loutzenhiser, R., Triggle, C. R. & Hollenberg, M. D. Dual endothelium-dependent vascular activities of proteinase-activated receptor-2-activating peptides: evidence for receptor heterogeneity. Br. J. Pharmacol.123, 1434–1440 (1998). CASPubMedPubMed Central Google Scholar
Ballerio, R. et al. Distinct roles for PAR1- and PAR2-mediated vasomotor modulation in human arterial and venous conduits. J. Thromb. Haemost.5, 174–180 (2007). CASPubMed Google Scholar
Hamilton, J. R., Frauman, A. G. & Cocks, T. M. Increased expression of protease-activated receptor-2 (PAR2) and PAR4 in human coronary artery by inflammatory stimuli unveils endothelium-dependent relaxations to PAR2 and PAR4 agonists. Circ. Res.89, 92–98 (2001). CASPubMed Google Scholar
Moffatt, J. D. & Cocks, T. M. Endothelium-dependent and -independent responses to protease-activated receptor-2 (PAR-2) activation in mouse isolated renal arteries. Br. J. Pharmacol.125, 591–594 (1998). CASPubMedPubMed Central Google Scholar
Laniyonu, A. A. & Hollenberg, M. D. Vascular actions of thrombin receptor-derived polypeptides: structure–activity profiles for contractile and relaxant effects in rat aorta. Br. J. Pharmacol.114, 1680–1686 (1995). CASPubMedPubMed Central Google Scholar
Kagota, S., Chia, E. & McGuire, J. J. Preserved arterial vasodilation via endothelial protease-activated receptor-2 in obese type 2 diabetic mice. Br. J. Pharmacol.164, 358–371 (2011). CASPubMedPubMed Central Google Scholar
McGuire, J. J., Van Vliet, B. N. & Halfyard, S. J. Blood pressures, heart rate and locomotor activity during salt loading and angiotensin II infusion in protease-activated receptor 2 (PAR2) knockout mice. BMC Physiol.8, 20 (2008). PubMedPubMed Central Google Scholar
Hirano, K. & Hirano, M. Current perspective on the role of the thrombin receptor in cerebral vasospasm after subarachnoid hemorrhage. J. Pharmacol. Sci.114, 127–133 (2010). CASPubMed Google Scholar
Hollenberg, M. D. Novel insights into the delayed vasospasm following subarachnoid haemorrhage: importance of proteinase signalling. Br. J. Pharmacol. 30 Jun 2011 (doi:10.1111/j.1476-5381.2011.01564.x). Google Scholar
Kameda, K. et al. Combined argatroban and anti-oxidative agents prevents increased vascular contractility to thrombin and other ligands after subarachnoid hemorrhage. Br. J. Pharmacol. 13 May 2011 (doi:10.1111/j.1476-5381.2011.01485.x). Google Scholar
Hung., D. T., Vu, T. K., Wheaton, V. I., Ishii, K. & Coughlin, S. R. Cloned platelet thrombin receptor is necessary for thrombin-induced platelet activation. J. Clin. Invest.89, 1350–1353 (1992). CASPubMedPubMed Central Google Scholar
Cook, J. J. et al. An antibody against the exosite of the cloned thrombin receptor inhibits experimental arterial thrombosis in the African green monkey. Circulation91, 2961–2971 (1995). CASPubMed Google Scholar
Kahn, M. L., Nakanishi-Matsui, M., Shapiro, M. J., Ishihara, H. & Coughlin, S. R. Protease-activated receptors 1 and 4 mediate activation of human platelets by thrombin. J. Clin. Invest.103, 879–887 (1999). CASPubMedPubMed Central Google Scholar
Leger, A. J. et al. Blocking the protease-activated receptor 1–4 heterodimer in platelet-mediated thrombosis. Circulation113, 1244–1254 (2006). CASPubMed Google Scholar
Covic, L., Gresser, A. L. & Kuliopulos, A. Biphasic kinetics of activation and signaling for PAR1 and PAR4 thrombin receptors in platelets. Biochemistry39, 5458–5467 (2000). CASPubMed Google Scholar
Sevigny, L. M. et al. Protease-activated receptor-2 modulates protease-activated receptor-1-driven neointimal hyperplasia. Arterioscler. Thromb. Vasc. Biol.31, e100–e106 (2011). CASPubMedPubMed Central Google Scholar
Sambrano, G. R. et al. Cathepsin G activates protease-activated receptor-4 in human platelets. J. Biol. Chem.275, 6819–6823 (2000). CASPubMed Google Scholar
Oikonomopoulou, K. et al. Kallikrein-mediated cell signalling: targeting proteinase-activated receptors (PARs). Biol. Chem.387, 817–824 (2006). CASPubMed Google Scholar
Santulli, R. J. et al. Evidence for the presence of a protease-activated receptor distinct from the thrombin receptor in human keratinocytes. Proc. Natl Acad. Sci. USA92, 9151–9155 (1995). CASPubMedPubMed Central Google Scholar
Oikonomopoulou, K. et al. Proteinase-activated receptors, targets for kallikrein signaling. J. Biol. Chem.281, 32095–32112 (2006). CASPubMed Google Scholar
Cornelissen, I. et al. Roles and interactions among protease-activated receptors and P2ry12 in hemostasis and thrombosis. Proc. Natl Acad. Sci. USA107, 18605–18610 (2011). Google Scholar
Vergnolle, N., Hollenberg, M. D., Sharkey, K. A. & Wallace, J. L. Characterization of the inflammatory response to proteinase-activated receptor-2 (PAR2)-activating peptides in the rat paw. Br. J. Pharmacol.127, 1083–1090 (1999). This study first established a role for PAR2 in regulating peripheral inflammation. CASPubMedPubMed Central Google Scholar
Vergnolle, N., Hollenberg, M. D. & Wallace, J. L. Pro- and anti-inflammatory actions of thrombin: a distinct role for proteinase-activated receptor-1 (PAR1). Br. J. Pharmacol.126, 1262–1268 (1999). This study first established a role for PAR1 in regulating peripheral inflammation. CASPubMedPubMed Central Google Scholar
Asfaha, S., Brussee, V., Chapman, K., Zochodne, D. W. & Vergnolle, N. Proteinase-activated receptor-1 agonists attenuate nociception in response to noxious stimuli. Br. J. Pharmacol.135, 1101–1106 (2002). CASPubMedPubMed Central Google Scholar
Asfaha, S. et al. Protease-activated receptor-4: a novel mechanism of inflammatory pain modulation. Br. J. Pharmacol.150, 176–185 (2007). CASPubMed Google Scholar
Steinhoff, M. et al. Agonists of proteinase-activated receptor 2 induce inflammation by a neurogenic mechanism. Nature Med.6, 151–158 (2000). This study first identified a role for neuronal PAR2 in regulating inflammatory responses. CASPubMed Google Scholar
Vergnolle, N. et al. Proteinase-activated receptor-2 and hyperalgesia: A novel pain pathway. Nature Med.7, 821–826 (2001). CASPubMed Google Scholar
Russell, F. A. & McDougall, J. J. Proteinase activated receptor (PAR) involvement in mediating arthritis pain and inflammation. Inflamm. Res.58, 119–126 (2009). CASPubMed Google Scholar
Ferrell, W. R. et al. Essential role for proteinase-activated receptor-2 in arthritis. J. Clin. Invest.111, 35–41 (2003). This study established PAR2 as a potential therapeutic target for joint inflammation. CASPubMedPubMed Central Google Scholar
Kelso, E. B. et al. Therapeutic promise of proteinase-activated receptor-2 antagonism in joint inflammation. J. Pharmacol. Exp. Ther.316, 1017–1024 (2006). This study illustrated multiple strategies for targeting PAR2 to block the receptor-mediated inflammatory responses. CASPubMed Google Scholar
Howell, D. C. et al. Absence of proteinase-activated receptor-1 signaling affords protection from bleomycin-induced lung inflammation and fibrosis. Am. J. Pathol.166, 1353–1365 (2005). CASPubMedPubMed Central Google Scholar
Scotton, C. J. et al. Increased local expression of coagulation factor X contributes to the fibrotic response in human and murine lung injury. J. Clin. Invest.119, 2550–2563 (2009). CASPubMedPubMed Central Google Scholar
Chambers, R. C., Leoni, P., Blanc-Brude, O. P., Wembridge, D. E. & Laurent, G. J. Thrombin is a potent inducer of connective tissue growth factor production via proteolytic activation of protease-activated receptor-1. J. Biol. Chem.275, 35584–35591 (2000). CASPubMed Google Scholar
Chambers, R. C. et al. Thrombin stimulates fibroblast procollagen production via proteolytic activation of protease-activated receptor 1. Biochem. J.333 (Pt 1), 121–127 (1998). CASPubMedPubMed Central Google Scholar
Bogatkevich, G. S., Tourkina, E., Silver, R. M. & Ludwicka-Bradley, A. Thrombin differentiates normal lung fibroblasts to a myofibroblast phenotype via the proteolytically activated receptor-1 and a protein kinase C-dependent pathway. J. Biol. Chem.276, 45184–45192 (2001). CASPubMed Google Scholar
Riewald, M., Petrovan, R. J., Donner, A., Mueller, B. M. & Ruf, W. Activation of endothelial cell protease activated receptor 1 by the protein C pathway. Science296, 1880–1882 (2002). This was the first study to demonstrate that biased PAR1 signalling by APC is distinct from thrombin-stimulated signalling, implying a role for APC–PAR1 signalling in sepsis. CASPubMed Google Scholar
Riewald, M. & Ruf, W. Protease-activated receptor-1 signaling by activated protein C in cytokine-perturbed endothelial cells is distinct from thrombin signaling. J. Biol. Chem.280, 19808–19814 (2005). CASPubMed Google Scholar
Yasui, H. et al. Intratracheal administration of activated protein C inhibits bleomycin-induced lung fibrosis in the mouse. Am. J. Respir. Crit. Care Med.163, 1660–1668 (2001). CASPubMed Google Scholar
Deng, X., Mercer, P. F., Scotton, C. J., Gilchrist, A. & Chambers, R. C. Thrombin induces fibroblast CCL2/JE production and release via coupling of PAR1 to Gαq and cooperation between ERK1/2 and Rho kinase signaling pathways. Mol. Biol. Cell19, 2520–2533 (2008). CASPubMedPubMed Central Google Scholar
Ando, S. et al. Proteinase-activated receptor 4 stimulation-induced epithelial-mesenchymal transition in alveolar epithelial cells. Respir. Res.8, 31 (2007). PubMedPubMed Central Google Scholar
Ramachandran, R. et al. Inflammatory mediators modulate thrombin and cathepsin-G signaling in human bronchial fibroblasts by inducing expression of proteinase-activated receptor-4. Am. J. Physiol. Lung Cell. Mol. Physiol.292, L788–L798 (2007). CASPubMed Google Scholar
Ramachandran, R., Morice, A. H. & Compton, S. J. Proteinase-activated receptor 2 agonists upregulate granulocyte colony-stimulating factor, IL-8, and VCAM-1 expression in human bronchial fibroblasts. Am. J. Respir. Cell. Mol. Biol.35, 133–141 (2006). CASPubMed Google Scholar
Akers, I. A. et al. Mast cell tryptase stimulates human lung fibroblast proliferation via protease-activated receptor-2. Am. J. Physiol. Lung Cell. Mol. Physiol.278, L193–L201 (2000). CASPubMed Google Scholar
Schmidlin, F. et al. Protease-activated receptor 2 mediates eosinophil infiltration and hyperreactivity in allergic inflammation of the airway. J. Immunol.169, 5315–5321 (2002). PubMed Google Scholar
Ebeling, C. et al. Proteinase-activated receptor 2 activation in the airways enhances antigen-mediated airway inflammation and airway hyperresponsiveness through different pathways. J. Allergy Clin. Immunol.115, 623–630 (2005). CASPubMed Google Scholar
Ebeling, C., Lam, T., Gordon, J. R., Hollenberg, M. D. & Vliagoftis, H. Proteinase-activated receptor-2 promotes allergic sensitization to an inhaled antigen through a TNF-mediated pathway. J. Immunol.179, 2910–2917 (2007). CASPubMed Google Scholar
Arizmendi, N. G. et al. Mucosal allergic sensitization to cockroach allergens is dependent on proteinase activity and proteinase-activated receptor-2 activation. J. Immunol.186, 3164–3172 (2011). CASPubMed Google Scholar
Adam, E. et al. The house dust mite allergen Der p 1, unlike Der p 3, stimulates the expression of interleukin-8 in human airway epithelial cells via a proteinase-activated receptor-2-independent mechanism. J. Biol. Chem.281, 6910–6923 (2006). CASPubMed Google Scholar
Asokananthan, N. et al. Activation of protease-activated receptor (PAR)-1, PAR-2, and PAR-4 stimulates IL-6, IL-8, and prostaglandin E2 release from human respiratory epithelial cells. J. Immunol.168, 3577–3585 (2002). CASPubMed Google Scholar
Asokananthan, N. et al. House dust mite allergens induce proinflammatory cytokines from respiratory epithelial cells: the cysteine protease allergen, Der p 1, activates protease-activated receptor (PAR)-2 and inactivates PAR-1. J. Immunol.169, 4572–4578 (2002). CASPubMed Google Scholar
Page, K., Ledford, J. R., Zhou, P., Dienger, K. & Wills-Karp, M. Mucosal sensitization to German cockroach involves protease-activated receptor-2. Respir. Res.11, 62 (2010). PubMedPubMed Central Google Scholar
Cocks, T. M. et al. A protective role for protease-activated receptors in the airways. Nature398, 156–160 (1999). This study demonstrated that epithelial PAR2 activation can stimulate the release of tracheal relaxing prostaglandins, suggesting a protective role for PAR2 in airway inflammatory diseases. CASPubMed Google Scholar
Moffatt, J. D., Jeffrey, K. L. & Cocks, T. M. Protease-activated receptor-2 activating peptide SLIGRL inhibits bacterial lipopolysaccharide-induced recruitment of polymorphonuclear leukocytes into the airways of mice. Am. J. Respir. Cell. Mol. Biol.26, 680–684 (2002). CASPubMed Google Scholar
Mule, F., Pizzuti, R., Capparelli, A. & Vergnolle, N. Evidence for the presence of functional protease activated receptor 4 (PAR4) in the rat colon. Gut53, 229–234 (2004). CASPubMedPubMed Central Google Scholar
Hollenberg, M. D., Saifeddine, M., Al-Ani, B. & Gui, Y. Proteinase-activated receptor 4 (PAR4): action of PAR4-activating peptides in vascular and gastric tissue and lack of cross-reactivity with PAR1 and PAR2. Can. J. Physiol. Pharmacol.77, 458–464 (1999). CASPubMed Google Scholar
Buresi, M. C., Buret, A. G., Hollenberg, M. D. & MacNaughton, W. K. Activation of proteinase-activated receptor 1 stimulates epithelial chloride secretion through a unique MAP kinase- and cyclo-oxygenase-dependent pathway. FASEB J.16, 1515–1525 (2002). CASPubMed Google Scholar
Buresi, M. C. et al. Activation of proteinase-activated receptor-1 inhibits neurally evoked chloride secretion in the mouse colon in vitro. Am. J. Physiol. Gastrointest. Liver Physiol.288, G337–G345 (2005). CASPubMed Google Scholar
Kong, W. et al. Luminal trypsin may regulate enterocytes through proteinase-activated receptor 2. Proc. Natl Acad. Sci. USA94, 8884–8889 (1997). CASPubMedPubMed Central Google Scholar
van der Merwe, J. Q., Hollenberg, M. D. & MacNaughton, W. K. EGF receptor transactivation and MAP kinase mediate proteinase-activated receptor-2-induced chloride secretion in intestinal epithelial cells. Am. J. Physiol. Gastrointest. Liver Physiol.294, G441–G451 (2008). CASPubMed Google Scholar
Lau, C., Lytle, C., Straus, D. S. & DeFea, K. A. Apical and basolateral pools of proteinase-activated receptor-2 direct distinct signaling events in the intestinal epithelium. Am. J. Physiol. Cell Physiol.300, C113–C123 (2011). CASPubMed Google Scholar
Chin, A. C. et al. Proteinase-activated receptor 1 activation induces epithelial apoptosis and increases intestinal permeability. Proc. Natl Acad. Sci. USA100, 11104–11109 (2003). CASPubMedPubMed Central Google Scholar
Mule, F., Baffi, M. C. & Cerra, M. C. Dual effect mediated by protease-activated receptors on the mechanical activity of rat colon. Br. J. Pharmacol.136, 367–374 (2002). CASPubMedPubMed Central Google Scholar
Saifeddine, M., Al-Ani, B., Sandhu, S., Wijesuriya, S. J. & Hollenberg, M. D. Contractile actions of proteinase-activated receptor-derived polypeptides in guinea-pig gastric and lung parenchymal strips: evidence for distinct receptor systems. Br. J. Pharmacol.132, 556–566 (2001). CASPubMedPubMed Central Google Scholar
Mule, F., Baffi, M. C., Capparelli, A. & Pizzuti, R. Involvement of nitric oxide and tachykinins in the effects induced by protease-activated receptors in rat colon longitudinal muscle. Br. J. Pharmacol.139, 598–604 (2003). CASPubMedPubMed Central Google Scholar
Zhao, A. & Shea-Donohue, T. PAR-2 agonists induce contraction of murine small intestine through neurokinin receptors. Am. J. Physiol. Gastrointest. Liver Physiol.285, G696–G703 (2003). CASPubMed Google Scholar
Kawabata, A. et al. In vivo evidence that protease-activated receptors 1 and 2 modulate gastrointestinal transit in the mouse. Br. J. Pharmacol.133, 1213–1218 (2001). CASPubMedPubMed Central Google Scholar
Cenac, N. et al. Induction of intestinal inflammation in mouse by activation of proteinase-activated receptor-2. Am. J. Pathol.161, 1903–1915 (2002). CASPubMedPubMed Central Google Scholar
Hyun, E., Andrade-Gordon, P., Steinhoff, M. & Vergnolle, N. Protease-activated receptor-2 activation: a major actor in intestinal inflammation. Gut57, 1222–1229 (2008). CASPubMed Google Scholar
Hyun, E., Andrade-Gordon, P., Steinhoff, M., Beck, P. L. & Vergnolle, N. Contribution of bone marrow-derived cells to the pro-inflammatory effects of protease-activated receptor-2 in colitis. Inflamm. Res.59, 699–709 (2010). CASPubMedPubMed Central Google Scholar
Hansen, K. K. et al. A major role for proteolytic activity and proteinase-activated receptor-2 in the pathogenesis of infectious colitis. Proc. Natl Acad. Sci. USA102, 8363–8368 (2005). CASPubMedPubMed Central Google Scholar
Cottrell, G. S. et al. Protease-activated receptor 2, dipeptidyl peptidase I, and proteases mediate Clostridium difficile toxin A enteritis. Gastroenterology132, 2422–2437 (2007). CASPubMed Google Scholar
Cenac, N. et al. Role for protease activity in visceral pain in irritable bowel syndrome. J. Clin. Invest.117, 636–647 (2007). CASPubMedPubMed Central Google Scholar
Gecse, K. et al. Increased faecal serine protease activity in diarrhoeic IBS patients: a colonic lumenal factor impairing colonic permeability and sensitivity. Gut57, 591–599 (2008). CASPubMed Google Scholar
Cenac, N. et al. Proteinase-activated receptor-1 is an anti-inflammatory signal for colitis mediated by a type 2 immune response. Inflamm. Bowel Dis.11, 792–798 (2005). PubMed Google Scholar
Wee, J. L. et al. Protease-activated receptor-1 down-regulates the murine inflammatory and humoral response to Helicobacter pylori. Gastroenterology138, 573–582 (2009). PubMed Google Scholar
Fiorucci, S. et al. Proteinase-activated receptor 2 is an anti-inflammatory signal for colonic lamina propria lymphocytes in a mouse model of colitis. Proc. Natl Acad. Sci. USA98, 13936–13941 (2001). CASPubMedPubMed Central Google Scholar
Cattaruzza, F. et al. Protective effect of proteinase-activated receptor 2 activation on motility impairment and tissue damage induced by intestinal ischemia/reperfusion in rodents. Am. J. Pathol.169, 177–188 (2006). CASPubMedPubMed Central Google Scholar
Striggow, F. et al. Four different types of protease-activated receptors are widely expressed in the brain and are up-regulated in hippocampus by severe ischemia. Eur. J. Neurosci.14, 595–608 (2001). CASPubMed Google Scholar
Henrich-Noack, P., Riek-Burchardt, M., Baldauf, K., Reiser, G. & Reymann, K. G. Focal ischemia induces expression of protease-activated receptor1 (PAR1) and PAR3 on microglia and enhances PAR4 labeling in the penumbra. Brain Res.1070, 232–241 (2006). CASPubMed Google Scholar
Suo, Z., Wu, M., Citron, B. A., Gao, C. & Festoff, B. W. Persistent protease-activated receptor 4 signaling mediates thrombin-induced microglial activation. J. Biol. Chem.278, 31177–31183 (2003). CASPubMed Google Scholar
Wang, H., Ubl, J. J. & Reiser, G. Four subtypes of protease-activated receptors, co-expressed in rat astrocytes, evoke different physiological signaling. Glia37, 53–63 (2002). CASPubMed Google Scholar
Scarisbrick, I. A., Isackson, P. J., Ciric, B., Windebank, A. J. & Rodriguez, M. MSP, a trypsin-like serine protease, is abundantly expressed in the human nervous system. J. Comp. Neurol.431, 347–361 (2001). CASPubMed Google Scholar
Bernett, M. J. et al. Crystal structure and biochemical characterization of human kallikrein 6 reveals that a trypsin-like kallikrein is expressed in the central nervous system. J. Biol. Chem.277, 24562–24570 (2002). CASPubMed Google Scholar
Sokolova, E. & Reiser, G. Prothrombin/thrombin and the thrombin receptors PAR-1 and PAR-4 in the brain: localization, expression and participation in neurodegenerative diseases. Thromb. Haemost.100, 576–581 (2008). CASPubMed Google Scholar
Yoshida, S. & Shiosaka, S. Plasticity-related serine proteases in the brain. Int. J. Mol. Med.3, 405–409 (1999). CASPubMed Google Scholar
Turgeon, V. L. & Houenou, L. J. The role of thrombin-like (serine) proteases in the development, plasticity and pathology of the nervous system. Brain Res. Brain Res. Rev.25, 85–95 (1997). CASPubMed Google Scholar
Noorbakhsh, F., Vergnolle, N., Hollenberg, M. D. & Power, C. Proteinase-activated receptors in the nervous system. Nature Rev. Neurosci.4, 981–990 (2003). CAS Google Scholar
Luo, W., Wang, Y. & Reiser, G. Protease-activated receptors in the brain: receptor expression, activation, and functions in neurodegeneration and neuroprotection. Brain Res. Rev.56, 331–345 (2007). CASPubMed Google Scholar
Vaughan, P. J., Pike, C. J., Cotman, C. W. & Cunningham, D. D. Thrombin receptor activation protects neurons and astrocytes from cell death produced by environmental insults. J. Neurosci.15, 5389–5401 (1995). CASPubMedPubMed Central Google Scholar
Donovan, F. M., Pike, C. J., Cotman, C. W. & Cunningham, D. D. Thrombin induces apoptosis in cultured neurons and astrocytes via a pathway requiring tyrosine kinase and RhoA activities. J. Neurosci.17, 5316–5326 (1997). CASPubMedPubMed Central Google Scholar
Acharjee, S. et al. Proteinase-activated receptor-1 mediates dorsal root ganglion neuronal degeneration in HIV/AIDS. Brain134, 3209–3221 (2011). PubMedPubMed Central Google Scholar
Gan, J., Greenwood, S. M., Cobb, S. R. & Bushell, T. J. Indirect modulation of neuronal excitability and synaptic transmission in the hippocampus by activation of proteinase-activated receptor-2. Br. J. Pharmacol.163, 984–994 (2011). CASPubMedPubMed Central Google Scholar
Lohman, R. J., O'Brien, T. J. & Cocks, T. M. Protease-activated receptor-2 regulates trypsin expression in the brain and protects against seizures and epileptogenesis. Neurobiol. Dis.30, 84–93 (2008). CASPubMed Google Scholar
Lohman, R. J., Jones, N. C., O'Brien, T. J. & Cocks, T. M. A regulatory role for protease-activated receptor-2 in motivational learning in rats. Neurobiol. Learn. Mem.92, 301–309 (2009). CASPubMed Google Scholar
Junge, C. E. et al. The contribution of protease-activated receptor 1 to neuronal damage caused by transient focal cerebral ischemia. Proc. Natl Acad. Sci. USA100, 13019–13024 (2003). CASPubMedPubMed Central Google Scholar
Hamill, C. E., Mannaioni, G., Lyuboslavsky, P., Sastre, A. A. & Traynelis, S. F. Protease-activated receptor 1-dependent neuronal damage involves NMDA receptor function. Exp. Neurol.217, 136–146 (2009). CASPubMedPubMed Central Google Scholar
Xue, M., Hollenberg, M. D., Demchuk, A. & Yong, V. W. Relative importance of proteinase-activated receptor-1 versus matrix metalloproteinases in intracerebral hemorrhage-mediated neurotoxicity in mice. Stroke40, 2199–2204 (2009). CASPubMed Google Scholar
Boven, L. A. et al. Up-regulation of proteinase-activated receptor 1 expression in astrocytes during HIV encephalitis. J. Immunol.170, 2638–2646 (2003). This was one of the first studies to show that PAR1 can be involved in CNS neurotoxicity. CASPubMed Google Scholar
Hamill, C. E. et al. Exacerbation of dopaminergic terminal damage in a mouse model of Parkinson's disease by the G-protein-coupled receptor protease-activated receptor 1. Mol. Pharmacol.72, 653–664 (2007). CASPubMed Google Scholar
Lee, E. J. et al. α-synuclein activates microglia by inducing the expressions of matrix metalloproteinases and the subsequent activation of protease-activated receptor-1. J. Immunol.185, 615–623 (2010). CASPubMed Google Scholar
Nicole, O. et al. Activation of protease-activated receptor-1 triggers astrogliosis after brain injury. J. Neurosci.25, 4319–4329 (2005). CASPubMedPubMed Central Google Scholar
Wang, Y., Luo, W., Stricker, R. & Reiser, G. Protease-activated receptor-1 protects rat astrocytes from apoptotic cell death via JNK-mediated release of the chemokine GRO/CINC-1. J. Neurochem.98, 1046–1060 (2006). CASPubMed Google Scholar
Thiyagarajan, M., Fernandez, J. A., Lane, S. M., Griffin, J. H. & Zlokovic, B. V. Activated protein C promotes neovascularization and neurogenesis in postischemic brain via protease-activated receptor 1. J. Neurosci.28, 12788–12797 (2008). CASPubMedPubMed Central Google Scholar
Noorbakhsh, F. et al. Proteinase-activated receptor-2 induction by neuroinflammation prevents neuronal death during HIV infection. J. Immunol.174, 7320–7329 (2005). CASPubMed Google Scholar
Noorbakhsh, F. et al. Proteinase-activated receptor 2 modulates neuroinflammation in experimental autoimmune encephalomyelitis and multiple sclerosis. J. Exp. Med.203, 425–435 (2006). PubMedPubMed Central Google Scholar
Afkhami-Goli, A. et al. Proteinase-activated receptor-2 exerts protective and pathogenic cell type-specific effects in Alzheimer's disease. J. Immunol.179, 5493–5503 (2007). CASPubMed Google Scholar
Jin, G. et al. Deficiency of PAR-2 gene increases acute focal ischemic brain injury. J. Cereb. Blood Flow Metab.25, 302–313 (2005). CASPubMed Google Scholar
Mao, Y., Zhang, M., Tuma, R. F. & Kunapuli, S. P. Deficiency of PAR4 attenuates cerebral ischemia/reperfusion injury in mice. J. Cereb. Blood Flow Metab.30, 1044–1052 (2010). CASPubMedPubMed Central Google Scholar
Guo, H. et al. Activated protein C prevents neuronal apoptosis via protease activated receptors 1 and 3. Neuron41, 563–572 (2004). CASPubMed Google Scholar
Even-Ram, S. C. et al. Tumor cell invasion is promoted by activation of protease activated receptor-1 in cooperation with the αvβ5 integrin. J. Biol. Chem.276, 10952–10962 (2001). CASPubMed Google Scholar
Even-Ram, S. et al. Thrombin receptor overexpression in malignant and physiological invasion processes. Nature Med.4, 909–914 (1998). CASPubMed Google Scholar
Bar-Shavit, R. et al. PAR1 plays a role in epithelial malignancies: transcriptional regulation and novel signaling pathway. IUBMB Life63, 397–402 (2011). CASPubMed Google Scholar
Nyberg, P., Ylipalosaari, M., Sorsa, T. & Salo, T. Trypsins and their role in carcinoma growth. Exp. Cell Res.312, 1219–1228 (2006). CASPubMed Google Scholar
Soreide, K., Janssen, E. A., Korner, H. & Baak, J. P. Trypsin in colorectal cancer: molecular biological mechanisms of proliferation, invasion, and metastasis. J. Pathol.209, 147–156 (2006). CASPubMed Google Scholar
Zwicker, J. I., Furie, B. C. & Furie, B. Cancer-associated thrombosis. Crit. Rev. Oncol. Hematol.62, 126–136 (2007). PubMed Google Scholar
Rickles, F. R. Mechanisms of cancer-induced thrombosis in cancer. Pathophysiol. Haemost. Thromb.35, 103–110 (2006). PubMed Google Scholar
Trivedi, V. et al. Platelet matrix metalloprotease-1 mediates thrombogenesis by activating PAR1 at a cryptic ligand site. Cell137, 332–343 (2009). This study showed that enzymes other than serine proteinases can activate PAR1 signalling by unmasking a non-canonical tethered ligand. CASPubMedPubMed Central Google Scholar
Boire, A. et al. PAR1 is a matrix metalloprotease-1 receptor that promotes invasion and tumorigenesis of breast cancer cells. Cell120, 303–313 (2005). CASPubMed Google Scholar
Salah, Z. et al. Identification of a novel functional androgen response element within hPar1 promoter: implications to prostate cancer progression. FASEB J.19, 62–72 (2005). CASPubMed Google Scholar
Ramsay, A. J. et al. Kallikrein-related peptidase 4 (KLK4) initiates intracellular signaling via protease-activated receptors (PARs). KLK4 and PAR-2 are co-expressed during prostate cancer progression. J. Biol. Chem.283, 12293–12304 (2008). CASPubMed Google Scholar
Gratio, V. et al. Kallikrein-related peptidase 14 acts on proteinase-activated receptor 2 to induce signaling pathway in colon cancer cells. Am. J. Pathol.179, 2625–2636 (2011). CASPubMedPubMed Central Google Scholar
Gratio, V. et al. Kallikrein-related peptidase 4: a new activator of the aberrantly expressed protease-activated receptor 1 in colon cancer cells. Am. J. Pathol.176, 1452–1461 (2010). CASPubMedPubMed Central Google Scholar
Krenzer, S. et al. Expression and function of the kallikrein-related peptidase 6 in the human melanoma microenvironment. J. Invest. Dermatol.131, 2281–2288 (2011). CASPubMedPubMed Central Google Scholar
Wang, J., Boerma, M., Kulkarni, A., Hollenberg, M. D. & Hauer-Jensen, M. Activation of protease activated receptor 2 by exogenous agonist exacerbates early radiation injury in rat intestine. Int. J. Radiat. Oncol. Biol. Phys.77, 1206–1212 (2010). CASPubMedPubMed Central Google Scholar
Vergnolle, N. Protease-activated receptors as drug targets in inflammation and pain. Pharmacol. Ther.123, 292–309 (2009). CASPubMed Google Scholar
Sevigny, L. M. et al. Interdicting protease-activated receptor-2-driven inflammation with cell-penetrating pepducins. Proc. Natl Acad. Sci. USA108, 8491–8496 (2011). This was one of the first studies to provide proof of concept that PAR2 pepducin antagonists are able to inhibit inflammatory responsesin vivo. CASPubMedPubMed Central Google Scholar
Dowal, L. et al. Identification of an antithrombotic allosteric modulator that acts through helix 8 of PAR1. Proc. Natl Acad. Sci. USA108, 2951–2956 (2011). CASPubMedPubMed Central Google Scholar
Ruda, E. M., Scrutton, M. C., Manley, P. W. & Tuffin, D. P. Thrombin receptor antagonists: structure-activity relationships for the platelet thrombin receptor and effects on prostacyclin synthesis by human umbilical vein endothelial cells. Biochem. Pharmacol.39, 373–381 (1990). CASPubMed Google Scholar
Ruda, E. M., Petty, A., Scrutton, M. C., Tuffin, D. P. & Manley, P. W. Identification of small peptide analogues having agonist and antagonist activity at the platelet thrombin receptor. Biochem. Pharmacol.37, 2417–2426 (1988). CASPubMed Google Scholar
Andrade-Gordon, P. et al. Design, synthesis, and biological characterization of a peptide-mimetic antagonist for a tethered-ligand receptor. Proc. Natl Acad. Sci. USA96, 12257–12262 (1999). This study reported the first successful synthesis and use of a PAR1-targeted peptidomimetic antagonist. CASPubMedPubMed Central Google Scholar
Maryanoff, B. E., Zhang, H. C., Andrade-Gordon, P. & Derian, C. K. Discovery of potent peptide-mimetic antagonists for the human thrombin receptor, protease-activated receptor-1 (PAR-1). Curr. Med. Chem. Cardiovasc. Hematol. Agents1, 13–36 (2003). CASPubMed Google Scholar
Andrade-Gordon, P. et al. Administration of a potent antagonist of protease-activated receptor-1 (PAR-1) attenuates vascular restenosis following balloon angioplasty in rats. J. Pharmacol. Exp. Ther.298, 34–42 (2001). CASPubMed Google Scholar
Derian, C. K. et al. Blockade of the thrombin receptor protease-activated receptor-1 with a small-molecule antagonist prevents thrombus formation and vascular occlusion in nonhuman primates. J. Pharmacol. Exp. Ther.304, 855–861 (2003). CASPubMed Google Scholar
Chackalamannil, S. et al. Discovery of potent orally active thrombin receptor (protease activated receptor 1) antagonists as novel antithrombotic agents. J. Med. Chem.48, 5884–5887 (2005). CASPubMed Google Scholar
Chackalamannil, S. et al. Discovery of a novel, orally active himbacine-based thrombin receptor antagonist (SCH 530348) with potent antiplatelet activity. J. Med. Chem.51, 3061–3064 (2008). CASPubMed Google Scholar
Becker, R. C. et al. Safety and tolerability of SCH 530348 in patients undergoing non-urgent percutaneous coronary intervention: a randomised, double-blind, placebo-controlled Phase II study. Lancet373, 919–928 (2009). CASPubMed Google Scholar
TRA*CER, Executive and Steering Committees. The thrombin receptor antagonist for clinical event reduction in acute coronary syndrome (TRA*CER) trial: study design and rationale. Am. Heart J.158, 327–334 (2009).
Morrow, D. A. et al. Evaluation of a novel antiplatelet agent for secondary prevention in patients with a history of atherosclerotic disease: design and rationale for the thrombin-receptor antagonist in secondary prevention of atherothrombotic ischemic events (TRA 2 ˚P)-TIMI 50 trial. Am. Heart J.158, 335–341 (2009). CASPubMed Google Scholar
Tricoci, P. et al. Thrombin-receptor antagonist vorapaxar in acute coronary syndromes. 13 Nov 2011 (doi:10.1056/NEJMoa1109719). CAS Google Scholar
Feistritzer, C. & Riewald, M. Endothelial barrier protection by activated protein C through PAR1-dependent sphingosine 1-phosphate receptor-1 crossactivation. Blood105, 3178–3184 (2005). CASPubMed Google Scholar
Schuepbach, R. A., Feistritzer, C., Fernandez, J. A., Griffin, J. H. & Riewald, M. Protection of vascular barrier integrity by activated protein C in murine models depends on protease-activated receptor-1. Thromb. Haemost.101, 724–733 (2009). CASPubMedPubMed Central Google Scholar
Kaneider, N. C. et al. 'Role reversal' for the receptor PAR1 in sepsis-induced vascular damage. Nature Immunol.8, 1303–1312 (2007). CAS Google Scholar
Serebruany, V. L., Kogushi, M., Dastros-Pitei, D., Flather, M. & Bhatt, D. L. The in-vitro effects of E5555, a protease-activated receptor (PAR)-1 antagonist, on platelet biomarkers in healthy volunteers and patients with coronary artery disease. Thromb. Haemost.102, 111–119 (2009). CASPubMed Google Scholar
O'Donoghue, M. L. et al. Safety and tolerability of atopaxar in the treatment of patients with acute coronary syndromes: the lessons from antagonizing the cellular effects of thrombin–acute coronary syndromes trial. Circulation123, 1843–1853 (2011). CASPubMed Google Scholar
Wiviott, S. D. et al. Randomized trial of atopaxar in the treatment of patients with coronary artery disease: the lessons from antagonizing the cellular effect of thrombin–coronary artery disease trial. Circulation123, 1854–1863 (2011). CASPubMed Google Scholar
Goto, S., Ogawa, H., Takeuchi, M., Flather, M. D. & Bhatt, D. L. Double-blind, placebo-controlled Phase II studies of the protease-activated receptor 1 antagonist E5555 (atopaxar) in Japanese patients with acute coronary syndrome or high-risk coronary artery disease. Eur. Heart J.31, 2601–2613 (2010). CASPubMedPubMed Central Google Scholar
Chieng-Yane, P. et al. Protease-activated receptor-1 antagonist F 16618 reduces arterial restenosis by down-regulation of tumor necrosis factor α and matrix metalloproteinase 7 expression, migration, and proliferation of vascular smooth muscle cells. J. Pharmacol. Exp. Ther.336, 643–651 (2011). CASPubMed Google Scholar
Perez, M. et al. Discovery of novel protease activated receptors 1 antagonists with potent antithrombotic activity in vivo. J. Med. Chem.52, 5826–5836 (2009). CASPubMed Google Scholar
Planty, B. et al. Exploration of a new series of PAR1 antagonists. Bioorg. Med. Chem. Lett.20, 1735–1739 (2010). CASPubMed Google Scholar
Al-Ani, B., Saifeddine, M., Wijesuriya, S. J. & Hollenberg, M. D. Modified proteinase-activated receptor-1 and -2 derived peptides inhibit proteinase-activated receptor-2 activation by trypsin. J. Pharmacol. Exp. Ther.300, 702–708 (2002). CASPubMed Google Scholar
Goh, F. G., Ng, P. Y., Nilsson, M., Kanke, T. & Plevin, R. Dual effect of the novel peptide antagonist K-14585 on proteinase-activated receptor-2-mediated signalling. Br. J. Pharmacol.158, 1695–1704 (2009). CASPubMedPubMed Central Google Scholar
Lohman, R. J. et al. Antagonism of protease activated receptor 2 protects against experimental colitis. J. Pharmacol. Exp. Ther. 25 Oct 2011 (doi:10.1124/jpet.111.187062). This was one of the first studies to show thatin vivopharmacological targeting of PAR2 with a small-molecule peptidomimetic antagonist attenuates experimental colitis. Google Scholar
Barry, G. D. et al. Novel agonists and antagonists for human protease activated receptor 2. J. Med. Chem.53, 7428–7440 (2010). CASPubMed Google Scholar
Suen, J. Y., Gardiner, B., Grimmond, S. & Fairlie, D. P. Profiling gene expression induced by protease-activated receptor 2 (PAR2) activation in human kidney cells. PLoS ONE5, e13809 (2010). PubMedPubMed Central Google Scholar
Suen, J. Y. Regulating Protease Activated Receptor 2. Thesis, Univ. Queensland, Brisbane, Australia (2009). Google Scholar
Hollenberg, M. D. & Saifeddine, M. Proteinase-activated receptor 4 (PAR4): activation and inhibition of rat platelet aggregation by PAR4-derived peptides. Can. J. Physiol. Pharmacol.79, 439–442 (2001). CASPubMed Google Scholar
Wu, C. C. et al. Selective inhibition of protease-activated receptor 4-dependent platelet activation by YD-3. Thromb. Haemost.87, 1026–1033 (2002). CASPubMed Google Scholar
Wu, C. C. et al. The role of PAR4 in thrombin-induced thromboxane production in human platelets. Thromb. Haemost.90, 299–308 (2003). CASPubMed Google Scholar
Al-Ani, B. et al. Proteinase-activated receptor 2 (PAR(2)): development of a ligand-binding assay correlating with activation of PAR(2) by PAR(1)- and PAR(2)-derived peptide ligands. J. Pharmacol. Exp. Ther.290, 753–760 (1999). CASPubMed Google Scholar
O'Brien, P. J. et al. Thrombin responses in human endothelial cells. Contributions from receptors other than PAR1 include the transactivation of PAR2 by thrombin-cleaved PAR1. J. Biol. Chem.275, 13502–13509 (2000). CASPubMed Google Scholar
Tressel, S. L. et al. Pharmacology, biodistribution, and efficacy of GPCR-based pepducins in disease models. Methods Mol. Biol.683, 259–275 (2010). Google Scholar
Covic, L., Misra, M., Badar, J., Singh, C. & Kuliopulos, A. Pepducin-based intervention of thrombin-receptor signaling and systemic platelet activation. Nature Med.8, 1161–1165 (2002). This was one of the first studies to demonstrate the utility of intracellular targeting of PARs as a strategy for modulating signalling and cellular responses through these receptors. CASPubMed Google Scholar
Covic, L., Gresser, A. L., Talavera, J., Swift, S. & Kuliopulos, A. Activation and inhibition of G protein-coupled receptors by cell-penetrating membrane-tethered peptides. Proc. Natl Acad. Sci. USA99, 643–648 (2002). CASPubMedPubMed Central Google Scholar
Yang, E. et al. Blockade of PAR1 signaling with cell-penetrating pepducins inhibits Akt survival pathways in breast cancer cells and suppresses tumor survival and metastasis. Cancer Res.69, 6223–6231 (2009). CASPubMedPubMed Central Google Scholar
Kenakin, T. P. Cellular assays as portals to seven-transmembrane receptor-based drug discovery. Nature Rev. Drug Discov.8, 617–626 (2009). This is an excellent review discussing novel screening methods for targeting the functional selectivity of GPCRs in drug discovery. CAS Google Scholar
Hanyaloglu, A. C. & von Zastrow, M. Regulation of GPCRs by endocytic membrane trafficking and its potential implications. Annu. Rev. Pharmacol. Toxicol.48, 537–568 (2008). CASPubMed Google Scholar
Marchese, A., Paing, M. M., Temple, B. R. & Trejo, J. G protein-coupled receptor sorting to endosomes and lysosomes. Annu. Rev. Pharmacol. Toxicol.48, 601–629 (2008). CASPubMedPubMed Central Google Scholar
Chen, C. H., Paing, M. M. & Trejo, J. Termination of protease-activated receptor-1 signaling by β-arrestins is independent of receptor phosphorylation. J. Biol. Chem.279, 10020–10031 (2004). CASPubMed Google Scholar
Paing, M. M., Temple, B. R. & Trejo, J. A tyrosine-based sorting signal regulates intracellular trafficking of protease-activated receptor-1: multiple regulatory mechanisms for agonist-induced G protein-coupled receptor internalization. J. Biol. Chem.279, 21938–21947 (2004). CASPubMed Google Scholar
Wang, Y., Zhou, Y., Szabo, K., Haft, C. R. & Trejo, J. Down-regulation of protease-activated receptor-1 is regulated by sorting nexin 1. Mol. Biol. Cell13, 1965–1976 (2002). CASPubMedPubMed Central Google Scholar
Swift, S. et al. A novel protease-activated receptor-1 interactor, bicaudal D1, regulates G protein signaling and internalization. J. Biol. Chem.285, 11402–11410 (2010). CASPubMedPubMed Central Google Scholar
Defea, K., Schmidlin, F., Dery, O., Grady, E. F. & Bunnett, N. W. Mechanisms of initiation and termination of signalling by neuropeptide receptors: a comparison with the proteinase-activated receptors. Biochem. Soc. Trans.28, 419–426 (2000). CASPubMed Google Scholar
Roosterman, D., Schmidlin, F. & Bunnett, N. W. Rab5a and rab11a mediate agonist-induced trafficking of protease-activated receptor 2. Am. J. Physiol. Cell Physiol.284, C1319–C1329 (2003). CASPubMed Google Scholar
Bernatowicz, M. S. et al. Development of potent thrombin receptor antagonist peptides. J. Med. Chem.39, 4879–4887 (1996). CASPubMed Google Scholar
Damiano, B. P., Derian, C. K., Maryanoff, B. E., Zhang, H. C. & Gordon, P. A. RWJ-58259: a selective antagonist of protease activated receptor-1. Cardiovasc. Drug Rev.21, 313–326 (2003). CASPubMed Google Scholar
Kato, Y. et al. Inhibition of arterial thrombosis by a protease-activated receptor 1 antagonist, FR171113, in the guinea pig. Eur. J. Pharmacol.473, 163–169 (2003). CASPubMed Google Scholar
Suen, J. Y. et al. Modulating human proteinase activated receptor 2 with a novel antagonist (GB88) and agonist (GB110). Br. J. Pharmacol. 1 Aug 2011 (doi:10.1111/j.1476-5381.2011.01610.x). CASPubMedPubMed Central Google Scholar
Gardell, L. R. et al. Identification and characterization of novel small-molecule protease-activated receptor 2 agonists. J. Pharmacol. Exp. Ther.327, 799–808 (2008). CASPubMed Google Scholar
Kanke, T. et al. Novel antagonists for proteinase-activated receptor 2: inhibition of cellular and vascular responses in vitro and in vivo. Br. J. Pharmacol.158, 361–371 (2009). CASPubMedPubMed Central Google Scholar
Chen, H. S. et al. Synthesis and antiplatelet activity of ethyl 4-(1-benzyl-1_H_-indazol-3-yl)benzoate (YD-3) derivatives. Bioorg. Med. Chem.16, 1262–1278 (2008). CASPubMed Google Scholar
Wu, C. C. et al. YD-3, a novel inhibitor of protease-induced platelet activation. Br. J. Pharmacol.130, 1289–1296 (2000). CASPubMedPubMed Central Google Scholar