proteinase activated receptors


Summary: A class of receptors that are activated by the action of PROTEINASES. The most notable examples are the THROMBIN RECEPTORS. The receptors contain cryptic ligands that are exposed upon the selective proteolysis of specific N-terminal cleavage sites.

Top Publications

  1. Camerer E, Cornelissen I, Kataoka H, Duong D, Zheng Y, Coughlin S. Roles of protease-activated receptors in a mouse model of endotoxemia. Blood. 2006;107:3912-21 pubmed
    ..These results raise the possibility that decreases in platelet count in the setting of sepsis may not be caused by disseminated intravascular coagulation but instead report on a sometimes parallel but independent process. ..
  2. Landis R. Protease activated receptors: clinical relevance to hemostasis and inflammation. Hematol Oncol Clin North Am. 2007;21:103-13 pubmed
    ..Aprotinin (Trasylol), a serine protease inhibitor used in cardiac surgery, preserves platelet function, and attenuates the inflammatory response by protecting the PAR 1 receptor on platelets and endothelium. ..
  3. Wielders S, Bennaghmouch A, Reutelingsperger C, Bevers E, Lindhout T. Anticoagulant and antithrombotic properties of intracellular protease-activated receptor antagonists. J Thromb Haemost. 2007;5:571-6 pubmed
    ..Our findings suggest that in spite of their potential anticoagulant activities the in vivo antithrombotic effect of intracellular PAR pepducins is mainly based on inhibiting platelet-platelet interactions. ..
  4. Oikonomopoulou K, Hansen K, Saifeddine M, Tea I, Blaber M, Blaber S, et al. Proteinase-activated receptors, targets for kallikrein signaling. J Biol Chem. 2006;281:32095-112 pubmed
    ..Our data indicate that in physiological settings, hKs may represent important endogenous regulators of the PARs and that different hKs can have differential actions on PAR(1), PAR(2), and PAR(4). ..
  5. Coughlin S. Protease-activated receptors in hemostasis, thrombosis and vascular biology. J Thromb Haemost. 2005;3:1800-14 pubmed
  6. Zhang H, Yang X, Yang H, Zhang Z, Lin Q, Zheng Y, et al. Modulation of mast cell proteinase-activated receptor expression and IL-4 release by IL-12. Immunol Cell Biol. 2007;85:558-66 pubmed
    ..In conclusion, IL-12 may serve as a regulator in keeping the balance of Th1 and Th2 cytokine production in allergic inflammation. ..
  7. Ossovskaya V, Bunnett N. Protease-activated receptors: contribution to physiology and disease. Physiol Rev. 2004;84:579-621 pubmed
    ..Major future challenges will be to understand the role of proteases and PARs in physiological control mechanisms and human diseases and to develop selective agonists and antagonists that can be used to probe function and treat disease. ..
  8. Ruf W, Mueller B. Thrombin generation and the pathogenesis of cancer. Semin Thromb Hemost. 2006;32 Suppl 1:61-8 pubmed
    ..Transmembrane serine proteases as well as matrix metalloproteinase are prime candidates for accessory pathways to regulate metastasis, tumor expansion, and angiogenesis dependent on specific features of the local tumor microenvironment. ..
  9. Martorell L, Martinez Gonzalez J, Rodriguez C, Gentile M, Calvayrac O, Badimon L. Thrombin and protease-activated receptors (PARs) in atherothrombosis. Thromb Haemost. 2008;99:305-15 pubmed publisher
    ..In this paper we review cellular responses triggered by thrombin and their implication in vascular pathophysiology. ..

More Information


  1. Major C, Santulli R, Derian C, Andrade Gordon P. Extracellular mediators in atherosclerosis and thrombosis: lessons from thrombin receptor knockout mice. Arterioscler Thromb Vasc Biol. 2003;23:931-9 pubmed
  2. Hirano K. The roles of proteinase-activated receptors in the vascular physiology and pathophysiology. Arterioscler Thromb Vasc Biol. 2007;27:27-36 pubmed
    ..Elucidating the molecular mechanism regulating the PARs expression is therefore important to develop new strategies for the prevention and treatment of vascular diseases. ..
  3. Wang L, Luo J, Fu Y, He S. Induction of interleukin-8 secretion and activation of ERK1/2, p38 MAPK signaling pathways by thrombin in dermal fibroblasts. Int J Biochem Cell Biol. 2006;38:1571-83 pubmed
    ..Discovery of the signaling pathways of thrombin in HDFs may help to understand the role of thrombin in inflammation and tissue remodeling. ..
  4. Vergnolle N. Clinical relevance of proteinase activated receptors (pars) in the gut. Gut. 2005;54:867-74 pubmed
  5. Saban R, D Andrea M, Andrade Gordon P, Derian C, Dozmorov I, Ihnat M, et al. Mandatory role of proteinase-activated receptor 1 in experimental bladder inflammation. BMC Physiol. 2007;7:4 pubmed
    ..It remains to be determined whether or not mechanisms targeting PAR1 gene silencing or PAR1 blockade will ameliorate the clinical manifestations of cystitis. ..
  6. Dattilio A, Vizzard M. Up-regulation of protease activated receptors in bladder after cyclophosphamide induced cystitis and colocalization with capsaicin receptor (VR1) in bladder nerve fibers. J Urol. 2005;173:635-9 pubmed
    ..These results suggest the involvement of PARs in bladder inflammation that contributes to altered sensory processing and reflex function. ..
  7. Moormann C, Artuc M, Pohl E, Varga G, Buddenkotte J, Vergnolle N, et al. Functional characterization and expression analysis of the proteinase-activated receptor-2 in human cutaneous mast cells. J Invest Dermatol. 2006;126:746-55 pubmed
    ..Thus, PAR2 may be an important regulator of skin mast cell function during cutaneous inflammation and hypersensitivity. ..
  8. Steinhoff M, Buddenkotte J, Shpacovitch V, Rattenholl A, Moormann C, Vergnolle N, et al. Proteinase-activated receptors: transducers of proteinase-mediated signaling in inflammation and immune response. Endocr Rev. 2005;26:1-43 pubmed
    ..Novel compounds that can modulate PAR function may be potent candidates for the treatment of inflammatory or immune diseases. ..
  9. Akiyama T, Merrill A, Zanotto K, Carstens M, Carstens E. Scratching behavior and Fos expression in superficial dorsal horn elicited by protease-activated receptor agonists and other itch mediators in mice. J Pharmacol Exp Ther. 2009;329:945-51 pubmed publisher
    ..These results indicate that PAR-2 and PAR-4 agonists, histamine, and 5-HT elicit itch-related scratching and activate superficial dorsal horn neurons that may participate in scratch reflex and ascending itch signaling pathways. ..
  10. Moffatt J. Proteinase-activated receptors in the lower urinary tract. Naunyn Schmiedebergs Arch Pharmacol. 2007;375:1-9 pubmed
    ..Finally, it seems probable that PARs, particularly PAR1, may play important roles in the growth and metastasis of prostate cancers. ..
  11. Kirkeby A, Torup L, Bochsen L, Kjalke M, Abel K, Theilgaard Monch K, et al. High-dose erythropoietin alters platelet reactivity and bleeding time in rodents in contrast to the neuroprotective variant carbamyl-erythropoietin (CEPO). Thromb Haemost. 2008;99:720-8 pubmed publisher
    ..These findings suggest that while EPO affects various aspects of platelet function, CEPO is devoid of such effects. ..
  12. ten Cate H, Falanga A. Overview of the postulated mechanisms linking cancer and thrombosis. Pathophysiol Haemost Thromb. 2008;36:122-30 pubmed publisher
    ..The interplay between cancer and blood coagulation merits further experimental and clinical research. ..
  13. Balezina O, Gerasimenko N, Dugina T, Strukova S. [Characteristic properties of thrombin neurotropic activity]. Usp Fiziol Nauk. 2004;35:37-49 pubmed
    ..A family of specialized membrane receptors--so called PARs (Proteinase Activated Receptors) and their presence in several parts of CNS is described...
  14. Camerer E. Protease signaling in tumor progression. Thromb Res. 2007;120 Suppl 2:S75-81 pubmed
    ..Whether PARs make important contributions to the biology of human tumors and/or whether they will provide useful markers of the malignant phenotype remains to be determined. ..
  15. Reed C, Kita H. The role of protease activation of inflammation in allergic respiratory diseases. J Allergy Clin Immunol. 2004;114:997-1008; quiz 1009 pubmed
    ..Future research promises to promote our understanding of the pathogenesis of allergic respiratory diseases and point the way to new therapies. ..
  16. Holzhausen M, Spolidorio L, Vergnolle N. Role of protease-activated receptor-2 in inflammation, and its possible implications as a putative mediator of periodontitis. Mem Inst Oswaldo Cruz. 2005;100 Suppl 1:177-80 pubmed
  17. Kim T, Heinlein C, Hackman R, Nelson P. Phenotypic analysis of mice lacking the Tmprss2-encoded protease. Mol Cell Biol. 2006;26:965-75 pubmed
    ..Alternatively, TMPRSS2 may contribute a specialized but nonvital function that is apparent only in the context of stress, disease, or other systemic perturbation. ..
  18. Palmer M, Lee S, Maniak P, Carlson D, Fahrenkrug S, O Grady S. Protease-activated receptor regulation of Cl- secretion in Calu-3 cells requires prostaglandin release and CFTR activation. Am J Physiol Cell Physiol. 2006;290:C1189-98 pubmed
    ..In addition, PAR-stimulated Cl(-) secretion requires activation of CFTR and at least two distinct K(+) channels located in the basolateral membrane. ..
  19. Gloro R, Ducrotte P, Reimund J. Protease-activated receptors: potential therapeutic targets in irritable bowel syndrome?. Expert Opin Ther Targets. 2005;9:1079-95 pubmed
  20. Kawabata A, Matsunami M, Sekiguchi F. Gastrointestinal roles for proteinase-activated receptors in health and disease. Br J Pharmacol. 2008;153 Suppl 1:S230-40 pubmed
    ..There is also fundamental and clinical evidence for involvement of PAR2 in colonic pain. PARs are thus considered key molecules in regulation of GI functions and targets for development of drugs for treatment of various GI diseases. ..
  21. Wu S, Shin J, Zhang G, Cohen M, Franco A, Sears C. The Bacteroides fragilis toxin binds to a specific intestinal epithelial cell receptor. Infect Immun. 2006;74:5382-90 pubmed
    ..However, activation of recognized protease-activated receptors does not mimic or block BFT biological activity or binding, suggesting that additional protease-activated receptors on intestinal epithelial cells remain to be identified. ..
  22. Noorbakhsh F, Vergnolle N, Hollenberg M, Power C. Proteinase-activated receptors in the nervous system. Nat Rev Neurosci. 2003;4:981-90 pubmed
    ..Here, we review the roles of PARs in the central and peripheral nervous systems during health and disease, with a focus on neuroinflammatory and degenerative disorders. ..
  23. Hollenberg M. Getting the message across: pathophysiology and signaling via receptors for polypeptide hormones and proteinases. Clin Invest Med. 2010;33:E133 pubmed
    ..The therapeutic implications of considering PARs as drug targets are also discussed. ..
  24. Cenac N, Vergnolle N. Proteases and protease-activated receptors (PARs): novel signals for pain. Curr Top Med Chem. 2005;5:569-76 pubmed
    ..The present article summarizes recent research progress on proteases and PARs as nociceptive signaling molecules in the nervous system and presents them as exciting new targets for therapeutic intervention in pain. ..
  25. Seeley S, Covic L, Jacques S, Sudmeier J, Baleja J, Kuliopulos A. Structural basis for thrombin activation of a protease-activated receptor: inhibition of intramolecular liganding. Chem Biol. 2003;10:1033-41 pubmed
    ..A lipidated-ligand binding site peptide was found to be an effective inhibitor of thrombin-induced platelet aggregation. ..
  26. Severino B, Santagada V, Perissutti E, Fiorino F, Frecentese F, de Angelis F, et al. Recent advances in synthesis of PAR ligands as therapeutic strategy for inflammatory diseases. Mini Rev Med Chem. 2009;9:653-63 pubmed
    ..This mini-review will focus on recent advances in the synthesis of PAR ligands highlighting their therapeutic potential in the treatment of various inflammatory diseases. ..
  27. De Campo B, Henry P. Protease-activated receptors (PARs) are partly pro-inflammatory and partly anti-inflammatory: will PAR agonists or antagonists participate in future drug therapies?. Curr Drug Targets. 2006;7:629-37 pubmed
  28. Fernandez J, Vento A, Jormalainen M, Griffin J, Pesonen E, Syrjälä M, et al. Activated protein C in the cardioplegic solution on a porcine model of coronary ischemia-reperfusion has deleterious hemodynamic effects. Cardiovasc Drugs Ther. 2006;20:113-21 pubmed
    ..The observed phenomenon could be explained by systolic hypotension potentially produced by the release of vasoactive substances generated by the APC activation of PARs in the endothelium. ..
  29. Kiran M, Kumar V, Viji R, Sherin G, Rajasekharan K, Sudhakaran P. Opposing effects of curcuminoids on serum stimulated and unstimulated angiogenic response. J Cell Physiol. 2008;215:251-64 pubmed
    ..These results suggest that PI3K-Akt and MAPK pathways involved in the expression of angiogenic phenotype respond differently to the extracellular microenvironment. ..
  30. O Brien L, Gupta A, Grinnell B. Activated protein C and sepsis. Front Biosci. 2006;11:676-98 pubmed
    ..The emerging data further suggest that APC effectively modulates the complex changes that occur during multi-system activation and dysfunction in sepsis. ..
  31. Shpacovitch V, Feld M, Bunnett N, Steinhoff M. Protease-activated receptors: novel PARtners in innate immunity. Trends Immunol. 2007;28:541-50 pubmed
    ..Understanding protease-immune interactions could lead to novel strategies for the treatment of infectious and immune-related diseases. ..
  32. Hughan S, Hughes C, McCarty O, Schweighoffer E, Soultanova I, Ware J, et al. GPVI potentiation of platelet activation by thrombin and adhesion molecules independent of Src kinases and Syk. Arterioscler Thromb Vasc Biol. 2007;27:422-9 pubmed
    ..Further, we reveal a novel role for GPVI in supporting thrombin-induced activation, independent of Syk and Src kinases. ..
  33. Kawabata A, Kawao N. Physiology and pathophysiology of proteinase-activated receptors (PARs): PARs in the respiratory system: cellular signaling and physiological/pathological roles. J Pharmacol Sci. 2005;97:20-4 pubmed
    ..PARs thus appear to play critical roles in the respiratory systems, and the agonists/antagonists for PARs may serve as the novel therapeutic strategy for treatment of certain respiratory diseases including asthma. ..
  34. White M, McHowat J. Protease activation of calcium-independent phospholipase A2 leads to neutrophil recruitment to coronary artery endothelial cells. Thromb Res. 2007;120:597-605 pubmed
    ..This suggests that in conditions such as thrombosis and atherosclerosis that multiple mechanisms can activate the inflammatory response. ..
  35. Surprenant A. Pain TRP-ed up by PARs. J Physiol. 2007;578:631 pubmed
  36. Gabazza E, Taguchi O, Kamada H, Hayashi T, Adachi Y, Suzuki K. Progress in the understanding of protease-activated receptors. Int J Hematol. 2004;79:117-22 pubmed
    ..Expression of PARs has been detected in most tissues and in numerous cells, and thus these molecules have been implicated in several physiological processes and in the pathogenesis of several diseases. ..
  37. Beyak M. Visceral afferents - determinants and modulation of excitability. Auton Neurosci. 2010;153:69-78 pubmed publisher
  38. Russell F, McDougall J. Proteinase activated receptor (PAR) involvement in mediating arthritis pain and inflammation. Inflamm Res. 2009;58:119-26 pubmed publisher
    b>Proteinase activated receptors (PARs) are a newly identified family of G-protein-coupled receptors that are activated by proteinases released into tissues during inflammation...
  39. Wheeler Jones C. Regulation of endothelial prostacyclin synthesis by protease-activated receptors: mechanisms and significance. Pharmacol Rep. 2008;60:109-18 pubmed
    ..Our findings therefore have important implications for defining the vascular effects of current and future therapeutic agents that target COXs, PARs, and the signalling elements controlling their expression. ..
  40. Wang H, Zheng Y, He S. Induction of release and up-regulated gene expression of interleukin (IL)-8 in A549 cells by serine proteinases. BMC Cell Biol. 2006;7:22 pubmed
    ..The proteinases, possibly through activation of PARs can stimulate IL-8 release from A549 cells, suggesting that they are likely to contribute to IL-8 related airway inflammatory disorders in man. ..
  41. Moller T, Weinstein J, Hanisch U. Activation of microglial cells by thrombin: past, present, and future. Semin Thromb Hemost. 2006;32 Suppl 1:69-76 pubmed
    ..Prior reports using nonpharmaceutical-grade thrombin need to be reinterpreted critically given these new findings. ..
  42. Lundblad R, White G. The interaction of thrombin with blood platelets. Platelets. 2005;16:373-85 pubmed
    ..Thus, the maximal hemostatic response requires both PAR receptors and the GpIb receptors. ..
  43. Cupit L, Schmidt V, Gnatenko D, Bahou W. Expression of protease activated receptor 3 (PAR3) is upregulated by induction of megakaryocyte phenotype in human erythroleukemia (HEL) cells. Exp Hematol. 2004;32:991-9 pubmed
    ..Furthermore, regulation of PAR3 expression appears to be specifically coupled to the protein kinase C system, but independent of the Ras/Raf/MAP kinase pathway. ..
  44. Yun L, Decarlo A, Hunter N. Blockade of protease-activated receptors on T cells correlates with altered proteolysis of CD27 by gingipains of Porphyromonas gingivalis. Clin Exp Immunol. 2007;150:217-29 pubmed
  45. Luo W, Wang Y, Reiser G. Protease-activated receptors in the brain: receptor expression, activation, and functions in neurodegeneration and neuroprotection. Brain Res Rev. 2007;56:331-45 pubmed
    ..Here, we review the abnormal expression of PARs in the brain under pathological conditions, the functions of PARs in neurodegenerative disorders, and the molecular mechanisms involved. ..
  46. Matsunami M, Sekiguchi T, Kawabata A. [Proteinase-activated receptor]. Nihon Yakurigaku Zasshi. 2006;128:434-6 pubmed
  47. Boehrer S, Nowak D, Hoelzer D, Mitrou P, Chow K. The molecular biology of TRAIL-mediated signaling and its potential therapeutic exploitation in hematopoietic malignancies. Curr Med Chem. 2006;13:2091-100 pubmed
    ..This review outlines the current knowledge on the physiological role of TRAIL and discusses its therapeutic potential with particular focus on malignancies of the hematopoietic system. ..
  48. Barry G, Le G, Fairlie D. Agonists and antagonists of protease activated receptors (PARs). Curr Med Chem. 2006;13:243-65 pubmed
  49. Kreda S, Seminario Vidal L, van Heusden C, O NEAL W, Jones L, Boucher R, et al. Receptor-promoted exocytosis of airway epithelial mucin granules containing a spectrum of adenine nucleotides. J Physiol. 2010;588:2255-67 pubmed publisher
  50. Knecht W, Cottrell G, Amadesi S, Mohlin J, Skåregärde A, Gedda K, et al. Trypsin IV or mesotrypsin and p23 cleave protease-activated receptors 1 and 2 to induce inflammation and hyperalgesia. J Biol Chem. 2007;282:26089-100 pubmed
    ..Thus, trypsin IV and p23 are inhibitor-resistant trypsins that can cleave and activate PARs, causing PAR(1)- and PAR(2)-dependent inflammation and PAR(2)-dependent hyperalgesia. ..
  51. Misaki T, Satoh Y, Saino T, Ogawa A. The role of protease-activated receptors on the intracellular calcium ion dynamics of vascular smooth muscles, with special reference to cerebral arterioles. Arch Histol Cytol. 2006;69:49-60 pubmed
    ..The effects of PARs activation on the [Ca2+]i dynamics and the contraction/relaxation of cerebral arterioles are also discussed in relation to the role of proteases in the regional tissue circulation of the brain. ..
  52. Barnes J, Singh S, Gomes A. Protease activated receptors in cardiovascular function and disease. Mol Cell Biochem. 2004;263:227-39 pubmed
    ..This review focuses on the role of PARs in cardiovascular function and disease. ..
  53. Baek O, Kang O, Choi Y, Choi S, Kim T, Nah Y, et al. Curcumin inhibits protease-activated receptor-2 and -4-mediated mast cell activation. Clin Chim Acta. 2003;338:135-41 pubmed
    ..However, curcumin did not affect the trypsin activity even at 100 micromol/l. Curcumin inhibits PAR2- and PAR4-mediated human mast cell activation, not by inhibition of trypsin activity but by block of ERK pathway. ..