Molecular and Cellular Biochemistry

, Volume 263, Issue 1, pp 227–239

Protease activated receptors in cardiovascular function and disease

  • Junor A. Barnes
  • Shamjeet Singh
  • Aldrin V. Gomes


Recent studies have shown that a novel class of protease activated receptors (PARs), which are composed of seven transmembrane G protein-coupled domains, are activated by serine proteases such as thrombin, trypsin and tryptase. Although four types (PAR 1, PAR 2, PAR 3 and PAR 4) of this class of receptors have been identified, their discrete physiological and pathological roles are still being unraveled. Extracellular proteolytic activation of PARs results in the cleavage of specific sites in the extracellular domain and formation of a new N-terminus which functions as a tethered ligand. The newly formed tethered ligand binds intramolecularly to an exposed site in the second transmembrane loop and triggers G-protein binding and intracellular signaling. Recent studies have shown that PAR-1, PAR-2 and PAR-4 have been involved in vascular development and a variety of other biological processes including apoptosis and remodeling. The use of animal model systems, mainly transgenic mice and synthetic tethered ligand domains, have contributed enormously to our knowledge of molecular signaling and the regulatory properties of various PARs in cardiomyocytes. This review focuses on the role of PARs in cardiovascular function and disease. (Mol Cell Biochem 263: 227–239, 2004)

protease activated receptor cardiovascular disease thrombin 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Vu TK, Hung DT, Wheaton VI, Coughlin SR: Molecular cloning of a functional thrombin receptor reveals a novel proteolytic mechanism of receptor activation. Cell 64: 1057–1068, 1991Google Scholar
  2. 2.
    Cocks TM, Moffatt JD: Protease-activated receptors: sentries for in-flammation? Trends Pharmacol Sci 21: 103–108, 2000Google Scholar
  3. 3.
    Dery O, Corvera CU, Steinhoff M, Bunnett NW: Proteinase-activated receptors: novel mechanisms of signaling by serine proteases. Am J Physiol 274: C1429–C1452, 1998Google Scholar
  4. 4.
    Sabri A, Muske G, Zhang H, Pak E, Darrow A, Andrade-Gordon P, Steinberg SF: Signaling properties and functions of two distinct cardiomyocyte protease-activated receptors. Circ Res 86: 1054–1061, 2000Google Scholar
  5. 5.
    Patella V, Marino I, Arbustini E, Lamparter-Schummert B, Verga L, Adt M, Marone G: Stem cell factor in mast cells and increased mast cell density in idiopathic and ischemic cardiomyopathy. Circulation 97: 971–978, 1998Google Scholar
  6. 6.
    Kovanen PT, Kaartinen M, Paavonen T: Infiltrates of activated mast cells at the site of coronary atheromatous erosion or rupture in my-ocardial infarction. Circulation 92: 1084–1088, 1995Google Scholar
  7. 7.
    Kahn ML, Zheng YW, Huang W, Bigornia V, Zeng D, Moff S, Farese RV, Tam C, Coughlin SR: A dual thrombin receptor system for platelet activation. Nature 394: 690–694, 1998Google Scholar
  8. 8.
    Xu WF, Andersen H, Whitmore TE, Presnell SR, Yee DP, Ching A, Gilbert T, Davie EW, Foster DC: Cloning and characterization of human protease-activated receptor 4. Proc Natl Acad Sci USA 95: 6642–6646, 1998Google Scholar
  9. 9.
    Pierce KL, Premont RT, Lefkowitz RJ: Seven-Transmembrane receptors. Nature Rev 3: 639–650, 2002Google Scholar
  10. 10.
    Rockman HA, Koch WJ, Lefkowitz RJ: Seven-transmembrane-spanning receptors and heart function. Nature 415: 206–212, 2002Google Scholar
  11. 11.
    Nystedt S, Emilsson K, Wahlestedt C, Sundelin J: Molecular cloning of a potential proteinase activated receptor. Proc Natl Acad Sci USA 91: 9208–9212, 1994Google Scholar
  12. 12.
    Kawabata A, Kuroda R: Protease-activated receptor (PAR), a novel family of G protein-coupled seven trans-membrane domain receptors: activation mechanisms and physiological roles. Jpn J Pharmacol 82: 171–174, 2000Google Scholar
  13. 13.
    Coughlin SR, Camerer E: Participation in inflammation. J Clin Invest 111: 25–27, 2003Google Scholar
  14. 14.
    Mackie EJ, Pagel CN, Smith R, de Niese MR, Song SJ, Pike RN: Protease-activated receptors: a means of converting extracellular proteolysis into intracellular signals. IUBMB Life 53: 277–281, 2002Google Scholar
  15. 15.
    Connolly AJ, Ishihara H, Kahn ML, Farese RV, Coughlin SR: Role of the thrombin receptor in development and evidence for a second receptor. Nature 381: 516–519, 1996Google Scholar
  16. 16.
    Hollenberg MD: Protease-activated receptors: PAR4 and counting: How long is the course? Trends Pharmacol Sci 20: 271–273, 1999Google Scholar
  17. 17.
    Connolly AJ, Suh DY, Hunt TK, Coughlin SR: Mice lacking the throm-bin receptor, PAR1, have normal skin wound healing. AmJ Pathol 151: 1199–1204, 1997Google Scholar
  18. 18.
    Ishihara H, Connolly AJ, Zeng D, Kahn ML, Zheng YW, Timmons C, Tram T, Coughlin SR: Protease-activated receptor 3 is a second thrombin receptor in humans. Nature 386: 502–506, 1997Google Scholar
  19. 19.
    Sabri A, Alcott SG, Elouardighi H, Pak E, Derian C, Andrade-Gordon P, Kinnally K, Steinberg SF: Neutrophil cathepsin G promotes detachment-induced cardiomyocyte apoptosis via a protease-activated receptor-independent mechanism. J Biol Chem 278: 23944–23954, 2003Google Scholar
  20. 20.
    Kahn ML, Hammes SR, Botka C, Coughlin SR: Gene and locus structure and chromosomal localization of the protease-activated receptor gene family. J Biol Chem 273: 23290–23296, 1998Google Scholar
  21. 21.
    Bohm SK, Kong W, Bromme D, Smeekens SP, Anderson DC, Connolly A, Kahn M, Nelken NA, Coughlin SR, Payan DG, Bunnett NW: Molecular cloning, expression and potential functions of the human proteinase-activated receptor-2. Biochem J 314(Pt 3): 1009–1016, 1996Google Scholar
  22. 22.
    Coughlin SR: Thrombin signaling and protease-activated receptors. Nature 407: 258–264, 2000Google Scholar
  23. 23.
    Weiss EJ, Hamilton JR, Lease KE, Coughlin SR: Protection against thrombosis in mice lacking PAR3. Blood 100: 3240–3244, 2002Google Scholar
  24. 24.
    Cook JJ, Sitko GR, Bednar B, Condra C, Mellott MJ, Feng DM, Nutt RF, Shafer JA, Gould RJ, Connolly TM: An antibody against the exosite of the cloned thrombin receptor inhibits experimental arterial thrombosis in the African green monkey. Circulation 91: 2961–2971, 1995Google Scholar
  25. 25.
    Coughlin SR: How the protease thrombin talks to cells. Proc Natl Acad Sci USA 96: 11023–11027, 1999Google Scholar
  26. 26.
    Vergnolle N, Hollenberg MD, Wallace JL: Pro-and anti-inflammatory actions of thrombin: A distinct role for proteinase-activated receptor-1 (PAR1). Br J Pharmacol 126: 1262–1268, 1999Google Scholar
  27. 27.
    Cirino G, Cicala C, Bucci MR, Sorrentino L, Maraganore JM, Stone SR: Thrombin functions as an inflammatory mediator through activation of its receptor. J Exp Med 183: 821–827, 1996Google Scholar
  28. 28.
    Kawabata A, Kuroda R, Nishikawa H, Asai T, Kataoka K, Taneda M: Enhancement of vascular permeability by specific activation of protease-activated receptor-1 in rat hindpaw: A protective role of endogenous and exogenous nitric oxide. Br J Pharmacol 126: 1856–1862, 1999Google Scholar
  29. 29.
    de Garavilla L, Vergnolle N, Young SH, Ennes H, Steinhoff M, Ossovskaya VS, D'Andrea MR, Mayer EA, Wallace JL, Hollenberg MD, Andrade-Gordon P, Bunnett NW: Agonists of proteinase-activated receptor 1 induce plasma extravasation by a neurogenic mechanism. Br J Pharmacol 133: 975–987, 2001Google Scholar
  30. 30.
    Even-Ram S, Uziely B, Cohen P, Grisaru-Granovsky S, Maoz M, Ginzburg Y, Reich R, Vlodavsky I, Bar-Shavit R: Thrombin recep-tor overexpression in malignant and physiological invasion processes. Nat Med 4: 909–914, 1998Google Scholar
  31. 31.
    Mohle R, Green D, Moore MA, Nachman RL, Rafii S: Constitutive production and thrombin-induced release of vascular endothelial growth factor by human megakaryocytes and platelets. Proc Natl Acad Sci USA 94: 663–668, 1997Google Scholar
  32. 32.
    Vaughan PJ, Pike CJ, Cotman CW, Cunningham DD: Thrombin recep-tor activation protects neurons and astrocytes from cell death produced by environmental insults. J Neurosci 15: 5389–5401, 1995Google Scholar
  33. 33.
    Kawabata A, Kuroda R, Minami T, Kataoka K, Taneda M: Increased vascular permeability by a specific agonist of protease-activated receptor-2 in rat hindpaw. Br J Pharmacol 125: 419–422, 1998Google Scholar
  34. 34.
    Vergnolle N: Proteinase-activated receptor-2-activating peptides in-duce leukocyte rolling, adhesion, and extravasation in vivo. J Immunol 163: 5064–5069, 1999Google Scholar
  35. 35.
    Steinhoff M, Vergnolle N, Young SH, Tognetto M, Amadesi S, Ennes HS, Trevisani M, Hollenberg MD, Wallace JL, Caughey GH, Mitchell SE, Williams LM, Geppetti P, Mayer EA, Bunnett NW: Agonists of proteinase-activated receptor 2 induce inflammation by a neurogenic mechanism. Nat Med 6: 151–158, 2000Google Scholar
  36. 36.
    Cocks TM, Fong B, Chow JM, Anderson GP, Frauman AG, Goldie RG, Henry PJ, Carr MJ, Hamilton JR, Moffatt JD: A protective role for protease-activated receptors in the airways. Nature 398: 156–160, 1999Google Scholar
  37. 37.
    Napoli C, Cicala C, Wallace JL, de Nigris F, Santagada V, Caliendo G, Franconi F, Ignarro LJ, Cirino G: Protease-activated receptor-2 modulates myocardial ischemia-reperfusion injury in the rat heart. Proc Natl Acad Sci USA 97: 3678–3683, 2000Google Scholar
  38. 38.
    Kawabata A, Kinoshita M, Nishikawa H, Kuroda R, Nishida M, Araki H, Arizono N, Oda Y, Kakehi K: The protease-activated receptor-2 agonist induces gastric mucus secretion and mucosal cytoprotection. J Clin Invest 107: 1443–1450, 2001Google Scholar
  39. 39.
    Fiorucci S, Mencarelli A, Palazzetti B, Distrutti E, Vergnolle N, Hollenberg MD, Wallace JL, Morelli A, Cirino G: Proteinase-activated receptor 2 is an anti-inflammatory signal for colonic lamina propria lymphocytes in a mouse model of colitis. Proc Natl Acad Sci USA 98: 13936–13941, 2001Google Scholar
  40. 40.
    Milia AF, Salis MB, Stacca T, Pinna A, Madeddu P, Trevisani M, Geppetti P, Emanueli C: Protease-activated receptor-2 stimulates an-giogenesis and accelerates hemodynamic recovery in a mouse model of hindlimb ischemia. Circ Res 91: 346–352, 2002Google Scholar
  41. 41.
    Vergnolle N, Bunnett NW, Sharkey KA, Brussee V, Compton SJ, Grady EF, Cirino G, Gerard N, Basbaum AI, Andrade-Gordon P, Hollenberg MD, Wallace JL: Proteinase-activated receptor-2 and hyperalgesia: A novel pain pathway. Nat Med 7: 821–826, 2001Google Scholar
  42. 42.
    Kawabata A: PAR2: structure, function and relevance to human dis-ease of the gastric mucosa. Expert Reviews in Molecular Medicine ( 2002Google Scholar
  43. 43.
    Vergnolle N, Wallace JL, Bunnett NW, Hollenberg MD: Protease-activated receptors in inflammation, neuronal signaling and pain. Trends Pharmacol Sci 22: 146–152, 2001Google Scholar
  44. 44.
    Kahn ML, Nakanishi-Matsui M, Shapiro MJ, Ishihara H, Coughlin SR: Protease-activated receptors 1 and 4 mediate activation of human platelets by thrombin. J Clin Invest 103: 879–887, 1999Google Scholar
  45. 45.
    Nakanishi-Matsui M, Zheng YW, Sulciner DJ, Weiss EJ, Ludeman MJ, Coughlin SR: PAR3 is a cofactor for PAR4 activation by thrombin. Nature 404: 609–613, 2000Google Scholar
  46. 46.
    Sambrano GR, Weiss EJ, Zheng YW, Huang W, Coughlin SR: Role of thrombin signalling in platelets in haemostasis and thrombosis. Nature 413: 74–78, 2001Google Scholar
  47. 47.
    Kawabata A, Saifeddine M, Al-Ani B, Leblond L, Hollenberg MD: Evaluation of proteinase-activated receptor-1 (PAR1) agonists and antagonists using a cultured cell receptor desensitization assay: Activation of PAR2 by PAR1-targeted ligands. J Pharmacol Exp Ther 288: 358–370, 1999Google Scholar
  48. 48.
    Hollenberg MD, 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, 1997Google Scholar
  49. 49.
    AndradeGordon P, Maryanoff BE, Derian CK, Zhang HC, Addo MF, Darrow AL, Eckardt AJ, Hoekstra WJ, McComsey DF, Oksenberg D, Reynolds EE, Santulli RJ, Scarborough RM, Smith CE, White KB: Design, synthesis, and biological characterization of a peptide-mimetic antagonist for a tethered-ligand receptor. Proc Natl Acad Sci USA 96: 12257–12262, 1999Google Scholar
  50. 50.
    Kato Y, Kita Y, Nishio M, Hirasawa Y, Ito K, Yamanaka T, Motoyama Y, Seki J: In vitro antiplatelet profile of FR171113, a novel non-peptide thrombin receptor antagonist. Eur J Pharmacol 384: 197–202, 1999Google Scholar
  51. 51.
    Sheng Z, Knowlton K, Chen J, Hoshijima M, Brown JH, Chien KR: Cardiotrophin 1 (CT-1) inhibition of cardiac myocyte apoptosis via a mitogen-activated protein kinase-dependent pathway. Divergence from downstream CT-1 signals for myocardial cell hypertrophy. J Biol Chem 272: 5783–5791, 1997Google Scholar
  52. 52.
    Sugden PH: Signaling in myocardial hypertrophy: Life after cal-cineurin? Circ Res 84: 633–646, 1999.237Google Scholar
  53. 53.
    Al-Ani B, Saifeddine M, Kawabata A, Renaux B, Mokashi S, Hollenberg MD: 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, 1999Google Scholar
  54. 54.
    Kim S, Foster C, Lecchi A, Quinton TM, Prosser DM, Jin J, Cattaneo M, Kunapuli SP: Protease-activated receptors 1 and 4 do not stimulate G(i) signaling pathways in the absence of secreted ADP and cause human platelet aggregation independently of G(i) signaling. Blood 99: 3629–3636, 2002Google Scholar
  55. 55.
    Hollenberg MD, 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, 1999Google Scholar
  56. 56.
    Hollenberg MD, 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, 2001Google Scholar
  57. 57.
    Andersen H, Greenberg DL, Fujikawa K, Xu W, Chung DW, Davie EW: Protease-activated receptor 1 is the primary mediator of thrombin-stimulated platelet procoagulant activity. Proc Natl Acad Sci USA 96: 11189–11193, 1999Google Scholar
  58. 58.
    Faruqi TR, Weiss EJ, Shapiro MJ, Huang W, Coughlin SR: Structure-function analysis of protease-activated receptor 4 tethered ligand peptides. Determinants of specificity and utility in assays of receptor function. J Biol Chem 275: 19728–19734, 2000Google Scholar
  59. 59.
    Andrade Gordon P, Derian CK, Maryanoff BE, Zhang HC, Addo MF, Cheung WM, Damiano BP, D'Andrea MR, Darrow AL, de Garavilla L, Eckardt AJ, Giardino EC, Haertlein BJ, McComsey DF: Adminis-tration 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, 2001Google Scholar
  60. 60.
    Nishikawa H, Kawabata A, Kawai K, Kuroda R: Guinea pig platelets do not respond to GYPGKF, a protease-activated receptor-4-activating peptide: A property distinct from human platelets. Blood Coagul Fibrinolysis 11: 111–113, 2000Google Scholar
  61. 61.
    Hung DT, Wong YH, Vu TK, Coughlin SR: The cloned platelet thrombin receptor couples to at least two distinct effectors to stimulate phosphoinositide hydrolysis and inhibit adenylyl cyclase. J Biol Chem 267: 20831–20834, 1992Google Scholar
  62. 62.
    Macfarlane SR, Seatter MJ, Kanke T, Hunter GD, Plevin R: Proteinase-activated receptors. Pharmacol Rev 53: 245–282, 2001Google Scholar
  63. 63.
    Steinberg SF, Robinson RB, Lieberman HB, Stern DM, Rosen MR: Thrombin modulates phosphoinositide metabolism, cytosolic calcium, and impulse initiation in the heart. Circ Res 68: 1216–1229, 1991Google Scholar
  64. 64.
    Jiang T, Kuznetsov V, Pak E, Zhang H, Robinson RB, Steinberg SF: Thrombin receptor actions in neonatal rat ventricular myocytes. Circ Res 78: 553–563, 1996Google Scholar
  65. 65.
    Lerner DJ, Chen M, Tram T, Coughlin SR: Agonist recognition by proteinase-activated receptor 2 and thrombin receptor. Importance of extracellular loop interactions for receptor function. J Biol Chem 271: 13943–13947, 1996Google Scholar
  66. 66.
    Boluyt MO, Zheng JS, Younes A, Long X, O'Neill L, Silverman H, Lakatta EG, Crow MT: Rapamycin inhibits alpha 1-adrenergic receptor-stimulated cardiac myocyte hypertrophy but not activation of hypertrophy-associated genes. Evidence for involvement of p70 S6 kinase. Circ Res 81: 176–186, 1997Google Scholar
  67. 67.
    Drexler H: Nitric oxide synthases in the failing human heart: A doubled-edged sword? Circulation 99: 2972–2975, 1999Google Scholar
  68. 68.
    Covic L, Gresser AL, Kuliopulos A: Biphasic kinetics of activation and signaling for PAR1 and PAR4 thrombin receptors in platelets. Biochemistry 39: 5458–5467, 2000Google Scholar
  69. 69.
    Heemskerk JW, Feijge MA, Henneman L, Rosing J, Hemker HC: The Ca2+-mobilizing potency of alpha-thrombin and thrombin-receptor-activating peptide on human platelets–concentration and time effects of thrombin-induced Ca2 +signaling. Eur J Biochem 249: 547–555, 1997Google Scholar
  70. 70.
    Lau LF, Pumiglia K, Cote YP, Feinstein MB: Thrombin-receptor agonist peptides, in contrast to thrombin itself, are not full agonists for activation and signal transduction in human platelets in the absence of platelet-derived secondary mediators. Biochem J 303(Pt 2): 391–400, 1994Google Scholar
  71. 71.
    Lasne D, Donato J, Falet H, Rendu F: Different abilities of thrombin receptor activating peptide and thrombin to induce platelet calcium rise and full release reaction. Thromb Haemost 74: 1323–1328, 1995Google Scholar
  72. 72.
    Aoki T, Tomiyama Y, Honda S, Senzaki K, Tanaka A, Okubo M, Takahashi F, Takasugi H, Seki J: Difference of (Ca2+)i movements in platelets stimulated by thrombin and TRAP: The involvement of alpha(IIb)beta3-mediated TXA2 synthesis. Thromb Haemost 79: 1184–1190, 1998Google Scholar
  73. 73.
    Hammes SR, Coughlin SR: Protease-activated receptor-1 can mediate responses to SFLLRN in thrombin-desensitized cells: Evidence for a novel mechanism for preventing or terminating signaling by PAR1's tethered ligand. Biochemistry 38: 2486–2493, 1999Google Scholar
  74. 74.
    Kuliopulos A, Nelson NP, Yamada M, Walsh CT, Furie B, Furie BC, Roth DA: Localization of the affinity peptide-substrate inactivator site on recombinant vitamin K-dependent carboxylase. J Biol Chem 269: 21364–21370, 1994Google Scholar
  75. 75.
    Sage SO, Merritt JE, Hallam TJ, Rink TJ: Receptor-mediated calcium entry in fura-2-loaded human platelets stimulated with ADPand thrombin. Dual-wavelengths studies with Mn2+. Biochem J 258: 923–926, 1989Google Scholar
  76. 76.
    Lu PJ, Hsu AL, Wang DS, Chen CS: Phosphatidylinositol 3,4,5-trisphosphate triggers platelet aggregation by activating Ca2+influx. Biochemistry 37: 9776–9783, 1998Google Scholar
  77. 77.
    Banfic H, Downes CP, Rittenhouse SE: Biphasic activation of PKB alpha/Akt in platelets. Evidence for stimulation both by phosphatidylinositol 3,4-bisphosphate, produced via a novel pathway, and by phos-phatidylinositol 3,4,5-trisphosphate. J Biol Chem 273: 11630–11637, 1998Google Scholar
  78. 78.
    Kinlough-Rathbone RL, Perry DW, Guccione MA, Rand ML, Packham MA: Degranulation of human platelets by the thrombin receptor peptide SFLLRN: Comparison with degranulation by thrombin. Thromb Haemost 70: 1019–1023, 1993Google Scholar
  79. 79.
    Kinlough-Rathbone RL, Perry DW, Packham MA: Contrasting effects of thrombin and the thrombin receptor peptide, SFLLRN, on aggregation and release of 14C-serotonin by human platelets pretreated with chymotrypsin or serratia marcescens protease. Thromb Haemost 73: 122–125, 1995Google Scholar
  80. 80.
    Mazzucato M, Marco LD, Masotti A, Pradella P, Bahou WF, Ruggeri ZM: Characterization of the initial alpha-thrombin interaction with glycoprotein Ib alpha in relation to platelet activation. J Biol Chem 273: 1880–1887, 1998Google Scholar
  81. 81.
    Yang X, Sun L, Ghosh S, Rao AK: Human platelet signaling defect characterized by impaired production of inositol-1,4,5-triphosphate and phosphatidic acid and diminished Pleckstrin phosphorylation: Evidence for defective phospholipase C activation. Blood 88: 1676–1683, 1996Google Scholar
  82. 82.
    Offermanns S, Toombs CF, Hu YH, Simon MI: Defective platelet activation in G alpha(q)-deficient mice. Nature 389: 183–186, 1997Google Scholar
  83. 83.
    Gabbeta J, Yang X, Kowalska MA, Sun L, Dhanasekaran N, Rao AK: Platelet signal transduction defect with G alpha subunit dysfunction and diminished Galphaq in a patient with abnormal platelet responses. Proc Natl Acad Sci USA 94: 8750–8755, 1997Google Scholar
  84. 84.
    Clark EA, Brugge JS: Integrins and signal transduction pathways: The road taken. Science 268: 233–239, 1995Google Scholar
  85. 85.
    Law DA, DeGuzman FR, Heiser P, Ministri-Madrid K, Killeen N, Phillips DR: Integrin cytoplasmic tyrosine motif is required for outside-in alphaIIbbeta3 signalling and platelet function. Nature 401: 808–811, 1999Google Scholar
  86. 86.
    Lind SE, Janmey PA, Chaponnier C, Herbert TJ, Stossel TP: Reversible binding of actin to gelsolin and profilin in human platelet extracts. J Cell Biol 105: 833–842, 1987Google Scholar
  87. 87.
    Shattil SJ, Ginsberg MH, Brugge JS: Adhesive signaling in platelets. Curr Opin Cell Biol 6: 695–704, 1994Google Scholar
  88. 88.
    Kovacsovics TJ, Hartwig JH: Thrombin-induced GPIb-IX centralization on the platelet surface requires actin assembly and myosin II activation. Blood 87: 618–629, 1996Google Scholar
  89. 89.
    Molino M, Blanchard N, Belmonte E, Tarver AP, Abrams C, Hoxie JA, Cerletti C, Brass LF: Proteolysis of the human platelet and endothelial cell thrombin receptor by neutrophil-derived cathepsin G. J Biol Chem 270: 11168–11175, 1995Google Scholar
  90. 90.
    Parry MA, Myles T, Tschopp J, Stone SR: Cleavage of the thrombin receptor: Identification of potential activators and inactivators. Biochem J 320(Pt 1): 335–341, 1996Google Scholar
  91. 91.
    Si-Tahar M, Renesto P, Falet H, Rendu F, Chignard M: The phospho-lipase C/protein kinase C pathway is involved in cathepsin G-induced human platelet activation: Comparison with thrombin. Biochem J 313 (Pt 2): 401–408, 1996Google Scholar
  92. 92.
    Weksler BB, Jaffe EA, Brower MS, Cole OF: Human leukocyte cathep-sin G and elastase specifically suppress thrombin-induced prostacyclin production in human endothelial cells. Blood 74: 1627–1634, 1989Google Scholar
  93. 93.
    Cumashi A, Ansuini H, Celli N, De Blasi A, O Brien PJ, Brass LF, Molino M: Neutrophil proteases can inactivate human PAR3 and abolish the co-receptor function of PAR3 on murine platelets. Thromb Haemost 85: 533–538, 2001Google Scholar
  94. 94.
    Shamamian P, Schwartz JD, Pocock BJ, Monea S, Whiting D, Marcus SG, Mignatti P: Activation of progelatinase A (MMP-2) by neu-trophil elastase, cathepsin G, and proteinase3: A role for inflammatory cells in tumor invasion and angiogenesis. J Cell Physiol 189: 197–206, 2001Google Scholar
  95. 95.
    Levkau B, Herren B, Koyama H, Ross R, Raines EW: Caspase-mediated cleavage of focal adhesion kinase pp125FAK and disassembly of focal adhesions in human endothelial cell apoptosis. J Exp Med 187: 579–586, 1998Google Scholar
  96. 96.
    Rokudai S, Fujita N, Hashimoto Y, Tsuruo T: Cleavage and inactivation of antiapoptotic Akt/PKB by caspases during apoptosis. J Cell Physiol 182: 290–296, 2000Google Scholar
  97. 97.
    Bachelder RE, Ribick MJ, Marchetti A, Falcioni R, Soddu S, Davis KR, Mercurio AM: p53 inhibits alpha 6 beta 4 integrin survival signaling by promoting the caspase 3-dependent cleavage of AKT/PKB. J Cell Biol 147: 1063–1072, 1999Google Scholar
  98. 98.
    Communal C, Sumandea M, de Tombe P, Narula J, Solaro RJ, Hajjar RJ: Functional consequences of caspase activation in cardiac myocytes. Proc Natl Acad Sci USA 99: 6252–6256, 2002Google Scholar
  99. 99.
    Saifeddine M, Al-Ani B, Cheng CH, Wang L, Hollenberg MD: Rat proteinase-activated receptor-2 (PAR-2): cDNA sequence and activ-ity of receptor-derived peptides in gastric and vascular tissue. Br J Pharmacol 118: 521–530, 1996Google Scholar
  100. 100.
    Al-Ani B, Saifeddine M, Hollenberg MD: Detection of functional receptors for the proteinase-activated-receptor-2-activating polypeptide, SLIGRL-NH2, in rat vascular and gastric smooth muscle. Can J Physiol Pharmacol 73: 1203–1207, 1995Google Scholar
  101. 101.
    Hollenberg MD, Saifeddine M, Al-Ani B: Proteinase-activated receptor-2 in rat aorta: Structural requirements for agonist activity of receptor-activating peptides. Mol Pharmacol 49: 229–233, 1996Google Scholar
  102. 102.
    Laniyonu AA, Hollenberg MD: Vascular actions of thrombin receptor-derived polypeptides: Structure-activity profiles for contractile and re-laxant effects in rat aorta. Br J Pharmacol 114: 1680–1686, 1995Google Scholar
  103. 103.
    Hamilton JR, Cocks TM: Heterogeneous mechanisms of endothelium-dependent relaxation for thrombin and peptide activators of protease-activated receptor-1 in porcine isolated coronary artery. Br J Pharmacol 130: 181–188, 2000Google Scholar
  104. 104.
    Nakayama T, Hirano K, Nishimura J, Takahashi S, Kanaide H: Mechanism of trypsin-induced endothelium-dependent vasorelaxation in the porcine coronary artery. Br J Pharmacol 134: 815–826, 2001Google Scholar
  105. 105.
    McGuire JJ, Hollenberg MD, Andrade-Gordon P, Triggle CR: Multiple mechanisms of vascular smooth muscle relaxation by the activation of proteinase-activated receptor 2 in mouse mesenteric arterioles. Br J Pharmacol 135: 155–169, 2002Google Scholar
  106. 106.
    Damiano BP, Cheung WM, Santulli RJ, Fung-Leung WP, Ngo K, Ye RD, Darrow AL, Derian CK, de Garavilla L, Andrade-Gordon P: Cardiovascular responses mediated by protease-activated receptor-2 (PAR-2) and thrombin receptor (PAR-1) are distinguished in mice deficient in PAR-2 or PAR-1. J Pharmacol Exp Ther 288: 671–678, 1999Google Scholar
  107. 107.
    Cicala C, Pinto A, Bucci M, Sorrentino R, Walker B, Harriot P, Cruchley A, Kapas S, Howells GL, Cirino G: Protease-activated receptor-2 involvement in hypotension in normal and endotoxemic rats in vivo. Circulation 99: 2590–2597, 1999Google Scholar
  108. 108.
    Cicala C, Morello S, Santagada V, Caliendo G, Sorrentino L, Cirino G: Pharmacological dissection of vascular effects caused by activation of protease-activated receptors 1 and 2 in anesthetized rats. FASEB J 15: 1433–1435, 2001Google Scholar
  109. 109.
    Cicala C: Protease activated receptor 2 and the cardiovascular system. Br J Pharmacol 135: 14–20, 2002Google Scholar
  110. 110.
    Camerer E, Huang W, Coughlin SR: Tissue factor-and factor X-dependent activation of protease-activated receptor 2 by factor VIIa. Proc Natl Acad Sci USA 97: 5255–5260, 2000Google Scholar
  111. 111.
    Kawabata A, Kuroda R, Nakaya Y, Kawai K, Nishikawa H, Kawao N: Factor Xa-evoked relaxation in rat aorta: Involvement of PAR-2. Biochem Biophys Res Commun 282: 432–435, 2001Google Scholar
  112. 112.
    Cheung WM, D'Andrea MR, Andrade-Gordon P, Damiano BP: Altered vascular injury responses in mice deficient in protease-activated receptor-1. Arterioscler Thromb Vasc Biol 19: 3014–3024, 1999Google Scholar
  113. 113.
    Chaikof EL, Caban R, Yan CN, Rao GN, Runge MS: Growth-related responses in arterial smooth muscle cells are arrested by thrombin receptor antisense sequences. J Biol Chem 270: 7431–7436, 1995Google Scholar
  114. 114.
    D'Andrea MR, Derian CK, Leturcq D, Baker SM, Brunmark A, Ling P, Darrow AL, Santulli RJ, Brass LF, Andrade-Gordon P: Characterization of protease-activated receptor-2 immunoreactivity in normal human tissues. The Journal of Histochemistry and Cytochemistry: Official Journal of the Histochemistry Society 46: 157–164, 1998Google Scholar
  115. 115.
    Bono F, Lamarche I, Herbert JM: Induction of vascular smooth muscle cell growth by selective activation of the proteinase activated receptor-2 (PAR-2). Biochem Biophys Res Commun 241: 762–764, 1997Google Scholar
  116. 116.
    Molino M, Raghunath PN, Kuo A, Ahuja M, Hoxie JA, Brass LF, Barnathan ES: Differential expression of functional protease-activated receptor-2 (PAR-2) in human vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 18: 825–832, 1998Google Scholar
  117. 117.
    http://us.expasy.orgGoogle Scholar
  118. 118.
    Vassallo RR, Kieber-Emmons T, Cichowski K, Brass LF: Structure-function relationships in the activation of platelet thrombin receptors by receptor-derived peptides. J Biol Chem 267: 6081–6085, 1992Google Scholar
  119. 119.
    Rydel TJ, Ravichandran KG, Tulinsky A, Bode W, Huber R, Roitsch C, Fenton JW: The structure of a complex of recombinant hirudin and human alpha-thrombin. Science 249: 277–280, 1990Google Scholar
  120. 120.
    Barr AJ, Brass LF, Manning DR: Reconstitution of receptors and GTP-binding regulatory proteins (G proteins) in Sf9 cells. A direct evaluation of selectivity in receptor. G protein coupling. J Biol Chem 272: 2223–2229, 1997Google Scholar
  121. 121.
    Camerer E, Kataoka H, Kahn M, Lease K, Coughlin SR: Genetic evidence that protease-activated receptors mediate factor Xa signaling in endothelial cells. J Biol Chem 277: 16081–16087, 2002Google Scholar
  122. 122.
    Koshikawa N, Nagashima Y, Miyagi Y, Mizushima H, Yanoma S, Yasumitsu H, Miyazaki K: Expression of trypsin in vascular endothelial cells. FEBS Lett 409: 442–448, 1997Google Scholar
  123. 123.
    Molino M, Barnathan ES, Numerof R, Clark J, Dreyer M, Cumashi A, Hoxie JA, Schechter N, Woolkalis M, Brass LF: Interactions of mast cell tryptase with thrombin receptors and PAR-2. J Biol Chem 272: 4043–4049, 1997Google Scholar
  124. 124.
    Fox MT, Harriott P, Walker B, Stone SR: Identification of potential activators of proteinase-activated receptor-2. FEBS Lett 417: 267–269, 1997Google Scholar
  125. 125.
    Selak MA, Chignard M, Smith JB: Cathepsin G is a strong platelet agonist released by neutrophils. Biochem J 251: 293–299, 1988Google Scholar
  126. 126.
    Chambers RC, Leoni P, Blanc-Brude OP, Wembridge DE, Laurent GJ: 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, 2000Google Scholar
  127. 127.
    Chambers RC, Dabbagh K, McAnulty RJ, Gray AJ, Blanc-Brude OP, Laurent GJ: Thrombin stimulates fibroblast procollagen production via proteolytic activation of protease-activated receptor 1. Biochem J 333(Pt 1): 121–127, 1998Google Scholar
  128. 128.
    Vergnolle N, Hollenberg MD, Sharkey KA, Wallace JL: Characterization of the inflammatory response to proteinase-activated receptor-2 (PAR2)-activating peptides in the rat paw. Br J Pharmacol 127: 1083–1090, 1999Google Scholar
  129. 129.
    Hwa JJ, Ghibaudi L, Williams P, Chintala M, Zhang R, Chatterjee M, Sybertz E: Evidence for the presence of a proteinase-activated receptor distinct from the thrombin receptor in vascular endothelial cells. Circ Res 78: 581–588, 1996Google Scholar
  130. 130.
    Vergnolle N: Review article: Proteinase-activated receptors–novel signals for gastrointestinal pathophysiology. Aliment Pharmacol Ther 14: 257–266, 2000Google Scholar
  131. 131.
    Sabri A, Guo J, Elouardighi H, Darrow AL, Andrade-Gordon P, Steinberg SF: Mechanisms of protease-activated receptor-4 actions in cardiomyocytes. Role of Src tyrosine kinase. J Biol Chem 278: 11714–11720, 2003Google Scholar

Copyright information

© Kluwer Academic Publishers 2004

Authors and Affiliations

  • Junor A. Barnes
    • 1
  • Shamjeet Singh
    • 1
  • Aldrin V. Gomes
    • 2
  1. 1.Biochemistry Unit, Faculty of Medical SciencesUniversity of theWest Indies
  2. 2.Department of Molecular and Cellular PharmacologyUniversity of Miami School of MedicineMiami, FLUSA

Personalised recommendations