Secretion Aggregation

FIGURE 3: Hie two receptor model of thrombin-induced platelet activation. See text for details. Modified from '8, with permission.

3 protein) can be co-immunoprecipitated with GPIb69 but the role of this interaction in the effects of a-thrombin on platelets, as compared with those of vWF, remains to be elucidated. However, the TLP-independent events described earlier, such as the sustained activation of p42/44m*pk and other kinases and their translocation to the cytoskeleton may be provisionally assigned to this high affinity GPIb-dependent pathway. The Ca2+ pool mobilized by this receptor may be different from that mobilized by the moderate affinity, PARI-dependent pathway since immunoinhibition reaches a maximum of 50% in each case.

Taking the two receptor model as a whole, it may be noted that those activities which have been shown to require continuous receptor occupancy, such as arachidonate mobilization and the formation of phosphatide acid, are mediated through the high affinity pathway and represent a receptor-ligand mediated mechanism while those receptor activities that require only transient receptor occupancy, such as the synthesis and breakdown of phosphoinositides, correspond to the moderate affinity proteolytic PARI pathway. The feet that immunoinhibitoiy effects at either receptor can be overcome at elevated thrombin levels merely indicates the relatively high affinities of thrombin binding at both sites (~0.5nM and lOnM, respectively) as compared with the relatively low affinities of the binding antibodies; for example the Kd of the binding of ATAP138 to PARI is ~80nM.29

In summary, the available evidence strongly supports the two receptor model for thrombin-induced platelet activation. In this model a supercomplexed form of GPIb acts as the high affinity receptor while PARI acts as the moderate affinity receptor. The applicability of this model in other cell systems, and the relative contributions of the two receptor pathways in the normal or pathophysiological activation of platelets, remain to be determined.

References

1. Fuster V, Badimon L, Badimon JJ, Chesebro JH: The pathogenesis of coronary artery disease and the acute coronary syndromes. Part 1. New Eng J of Med 326:242,1992

2. Fuster V, Badimon L, Badimon JJ, Chesebro JH: The pathogenesis of coronary artery disease and the acute coronary syndromes. Part 2. New Eng J of Med 326:310,1992

3. De Marco L, Mazaicato M, Masotti A, Fenton JW, Rugged ZM: Function of glycoprotein lb alpha in platelet activation induced by alpha-thrombin. J Biol Chem 266:23776,1991

4. Shuman MA, Levine SP: Thrombin generation and secretion of platelet factor 4 during blood clotting. J Clin Invest 61:1102,1978

5. Munson PJ: Ligand: A computerized analysis of ligand binding data Methods Enzymol 92:543,1983

6. Kampner ES, Schlegel W: Size determination of enzymes by radiation inactivation. Anal Biochem 92:2, 1979

7. Harmon JT, Jamieson GA: Thrombin binds to a high-affinity -900,000 dalton site on human platelets. Biochemistry 24:58,1985

8. Vu T-KH, Hung DT, Wheaton VI, Coughlin SR: Molecular cloning of a functional thrombin receptor reveals a novel proteolytic mechanism of receptor activation. Cell 64:1057,1991

9. Leong L, Henriksen RA, Ketmode JC, Rittenhouse SE, Tracy PB: The thrombin high-affinity binding site on platelets is a negative regulator of thrombin-induced platelet activation. Structure-function studies using two mutant thrombins, Quick I and Quick II. Biochemistry 31:2567,1992

10. Hayes KL, Leong L, Henriksen RA, Bouchard BA, Ouellette L, Church WR, Tracy B: o-Thrombin-induced human platelet activation results solely from formation of a specific enzyme-substrate complex. J Biol Chem 269:28606,1994

11. Hourani SMO, CusackNJ: Pharmacological receptors on blood platelets. Pharma Rev 43:243,1991

12. Greco NJ, Tenner Jr,T.E., Tandon NN, Jamieson GA: PPACK-thrombin inhibits thrombin-induced platelet aggregation and cytoplasmic acidification but does not inhibit platelet shape change. Blood 75:1983,1990

13. Greco NJ, Tandon NN, Jameson GA: Thrombin binding to platelets defines functional receptors: Inhibition of thrombin-induced platelet activation by catalytically-inactivated thrombin. Platelets 6:270,1995

14. Tandon NN, Harmon JT, Rodbard D, Jamieson GA: Thrombin receptors define responsiveness of cholesterol-modified platelets. J Biol Chem 258:11840,1983

15. Harmon JT, Tandon NN, Hoeg JM, Jamieson GA: Thrombin binding and response in platelets from patients with dysiipoproteinemias: increased stimulus-response coupling in type II hyperlipoproteinemia Blood 68:498,1986

Tandon NN, Hoeg JM, Jamieson GA: Perfusion studies on the formation of mural thrombi with cholesterol-modified and hyperdiolesterolemic platelets. J Lab Clin Med 105:157,1985

Jamieson GA: Hie activation of platelets by thrombin: A model for activation by high and moderate affinity receptor pathways, in Jamieson GA: (ed): Platelet Membrane Receptors: Molecular Biology, Immunology, Biochemistry, and Pathology, New York, Alan R. Liss, Inc., 1988, p 137

Greco NJ, Jamieson GA: High and moderate affinity pathways for a-thrombin-induced platelet activation. Proc Soc Exp Biol Med 198:792,1991

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 386:502,1997

Scase TJ, Heath MF, Evans RJ: Cloning of PAR3 cDNA from human platelets and human erthroleukemic and human promonocytic cell lines. Blood 90:2113,1997

Rasmussen UB, Vouret-Craviari V, Jallat S, Sdileanger Y, Pages G, Pavirani A, Lecocq JP, Pouyssegur J, Van Obberghen-Sdiilling E: cDNA cloning and expression of a hamster a-thrombin receptor coupled to Ca2* mobilization. FEBS Lett 288:123,1991

Verrall S, Ishii M, Chen M, Wang L, Tram T, Coughlin SR: The thrombin receptor second cytoplasmic loop confers coupling to G^-like G proteins in chimeric receptors. J Biol Chem 272:6898,1997

Seiler SM, Midiel IM, Fenton JW: Involvement of the "tethered-ligand" receptor in thrombin inhibition of platelet adenylate cyclase. Biochem Biophys Res Commun 182:1296,1992

Baffy G, Yang L, Raj S, Manning DR, Williamson JR: G protein coupling to the thrombin receptor in Chinese hamster lung fibroblasts. J Biol Chem 269:8483,1994

Ishii K, Hein L, Kobilka B, Coughlin SR: Kinetics of thrombin receptor cleavage on intact cells. J Biol Chem 268:9780,1993

Parry MAA, Myles t, Tschopp J, Stone SR: Cleavage of the thrombin receptor: dentification of potential activators and inactivators. Biochem J 320:335,1996

Greco NJ, Tandon NN, Jones GD, Komhauser R, Jackson B, Yamamoto N, Tanoue K, Jamieson GA: Contributions of glycoprotein lb and the seven transmembrane domain receptor to increases in platelet cytoplasmic [Ca2*]^ induced by a-thrombin. Biochemistry 35:906,19%

Gralnick HR, Williams S, McKeown LP, Hananann K, Fenton JW,III, Krutzsch H: High-affinity a-thrombin binding to platelet glycoprotein Iba: Identification of two binding domains. Proc Natl Acad Sci USA 91:6334,1994

Brass LF, Vassallo RR,Jr., Belmonte E, Ahuja M, Cichowski K, Hoxie JA: Structure and function of the human platelet thrombin receptor. J Biol Chem 267:13795,1992

Lau L-F, 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 303:391,1994

Kramer RM, Robots EF, Hyslop PA, Utterback BG, Hui KY, Jakubowski JA: Differential activation of cytosolic phospholipase A2 (cPLAj) by thrombin and thrombin receptor agonist peptide in human platelets. J Biol Chem 270:14816,1995

Goodwin CA, Wheeler-Jones CPD, Kakkar W, Deadman JJ, Authi KS, Scully MF: Thrombin receptor activating peptide does not stimulate platelet procoagulant activity. Biochem Biophys Res Commun 202:321,1994

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 74:1323,1995

Sugama Y, Tiruppathi CM, Janakidevi K, Andersen TT, Fenton II,J.W., Main AB: Thrombin-induced expression of endothelial P-Selectin and intercellular adhesion molecule-1: A mechanism for stabilizing neutrophil adhesion. J Cell Biol 119:935,1992

Lum H, Andersen TT, Siflinger-Bimboim A, Tiruppathi C, Goligorsky MS, Fenton II,J.W„ Main AB: Thrombin receptor peptide inhibits thrombin-induced increase in endothelial permeability by receptor desensitization. J Cell Biol 120:1491,1993

Lenormand P, Sardet C, Pages G, L'Alleman G, Brunei A, Pouyssegur J: Growth factors induce nuclear translocation of MAP kinases (p42"** and p44"**) but not of their activator MAP kinase kinase (p45™***) in fibroblasts. J Cell Biol 122:1079,1993

Vouret-Craviari V, Van Obberghoi-Schilling E, Scimeca JC, Van Obberghen E, Pouyssegur J: Differential activation ofp44""'* (ERK1) by a-thrombin and thrombin-receptor peptide agonist. Biochem J 289:209, 1993

Jenkins AL, Bootman MD, Derridge MJ, Stone SR: Differences in intracellular calcium signaling after activation of the thrombin receptor by thrombin and agonist peptide in osteoblast-like cells. J Biol Chem 269:17104,1994

Vouret-Craviari V, Van Obberghen-Schilling E, Rasmussen UB, Pavirani A, Lecocq J-P, Pouyssegur J: Synthetic a-thrombin receptor peptides activate G protein-coupled signaling pathways but are unable to induce mitogenesis. Mol Biol Cell 3:95,1992

Trejo J, Connolly AJ, Coughlin SR: The cloned thrombin receptor is necessary and sufficient for activation of mitogen-activated protein kinase and mitogenesis in mouse lung fibroblasts. Loss of responses in fibroblasts from receptor knockout mice. J Biol Chem 271:21536,1996

Connolly AJ, Ishihara H, Kahn ML, Farese Jr,R.V., Coughlin SR: Role of the thrombin receptor in development and evidence for a second receptor. Nature 381:516,19%

Darrow AL, Fung-Leung W-P, Ye RD, Santulli RJ, Cheung W-M, Derian CK, Burns CL, Damiano BP, Zhou L, Keenan CM, Peterson PA, Andrade-Gordon P: Biological consequences of thrombin receptor deficiency in mice. Thromb Haemost 76:860, 19%

Ware J: Molecular analyses of the platelet glycoprotein Ib-IX-V receptor. Thromb Haemost 79:466,1998

Lopez JA: The platelet glycoprotein Ib-IX complex. Blood Coagul Fibrinolysis 5:97,1994

De Marco L, Mazzucato M, Masotti A, Ruggeri ZM: Localization and characterization of an a-thrombin-binding site on platelet glycoprotein Iba. J Biol Chem 269:6478,1994

Mazurov AV, Vinogradov DV, Vlasik TN, Repin VS, Booth WJ, Berndt MC: Characterization of an antiglycoprotein lb monoclonal antibody that specifically inhibits platelet-thrombin interaction. Thromb Res 62:673,1991

Peng M Emig FA, Mao A, Lu W, Kirby EP, Niewiarowski S, Kowalska MA: Interaction of echicetin with a high affinity thrombin binding site on platelet glycoprotein GPIb. Thromb Haemost 74:954,1995

Chang M-C, Lin H-K, Peng H-C, Huang T-F: Antithrombotic effect of crotalin, a platelet membrane glycoprotein lb antagonist from venom of crotaius atrox. Blood 91:1582, 1998

Bradford HN, Dela Cadena RA, Kunapuli SP, Dong J-F, Lopez JA, Colman RW: Human kininogens regulate thrombin binding to platelets through the glycoprotein Ib-IX-V complex. Blood 90:1508,1997

Pedicord DL, Greco NJ, Jamieson GA, Dicker IB: GPIb mediates thrombin-induced platelet procoagulant activity. Thromb Haemost 475,1997(abstr)

McNiool A, Sutherland M, Zou r, Drouin J: Defective thrombin-induced calcium changes and aggregation of Bernard-Soulier platelets are not associated with deficient moderate-affinity receptors. Arterioscler Thromb & Vascular Biol 16:628,19%

52. Harmon JT, Jamieson GA: Activation of platelets by alpha-thrombin is a receptor-mediated event J Biol Chem 261:15928,1986

53. Brower MS, Levin RI, Garry K: Human neutrophil elastase modulates platelet function by limited proteolysis of membrane glycoproteins J Clin Invest 75:657,1985

54. Greco NJ, Jones GD, Tandon NN, Kornhauser R, Jackson B, Jamieson GA: Differentiation of the two forms of GPIb functioning as receptors for a-thrombin and von Willebrand factor: Ca2* responses of protease-treated human platelets activated with a-thrombin and the tethered ligand peptide. Biochemistry 35:915,1996

55. Lozano ML, Rivera J, Gonzalez-Conejero R, Moraleda JM, Vicente V: Loss of high-affinity thrombin receptors during platelet concentrate storage impairs the reactivity of platelets to thrombin. Transfusion 37:368, 1997

56. Mazzucato M, DeMarco L, Masotti A, Pradella P, Bahou WF, Ruggeri ZM: Characterization of the initial a-thrombin interaction with glycoprotein Iba in relation to platelet activation. J Biol Chem 273:1880, 1998

57. Msrchese P, MurataM, Mazzucato M, Pradella P, DeMarco L, Ware J, Ruggeri ZM: Identification of three tyrosine residues of glycoprotein Iba with distinct roles in von Willebrand facto- and a-thrombin binding. J Biol Chem 16:9571,1995

58. Harmon JT, Jamieson GA: The glycocalicin portion of platelet glycoprotein lb expresses both high and moderate affinity receptor sites in thrombin. J Biol Chem 261:13224,1986

59. Liu L, Freedman J, Homstein A, Fenton JW.II, Song Y, Ofosu FA: Binding of thrombin to the G-protein-linked receptor, and not to glycoprotein lb, precedes thrombin-mediated platelet activation. J Biol Chem 272:1997,1997

60. Parry MAA, Stone SR, Hofsteenge J, Jackman MP: Evidence for common structural changes in thrombin induced by active-site or exosite binding. Biochem J 290:665,1993

61. Wu Q, Sheehan JP, Tsiang M, Lentz SR, Birktoft JJ, Sadler JE: Single amino acid substitutions dissociate fibrinogen-clotting and thrombomodulin-binding activities of human thrombin. Proc Natl Acad Sci USA 88:6775,1991

62. Okumura T, Jamieson G A: A single receptor for platelet aggregation induced by thrombin or ristocetin. Thromb Res 8:701,1976

63. Parker RI, Gralnidc HR: Fibrin monomer induces binding of endogenous platelet von Willebrand Factor to the glycocalicin portion of platelet glycoprotein IB. Blood 70:1589,1987

64. Ward CM, Andrews RK, Smith AI, Berndt MC: Mocarhagin, a novel cobra venom metalloproteinase, cleaves the platelet von Willebrand factor receptor glycoprotein Iba. Identification of the sulfated tyrosine/anionic sequence Tyr-276 —Glu-282 of glycoprotein Iba as a binding site for von Willebrand factor and a-thrombin Biochemistry 35:4929,1996

65. Dong J-F, Li CQ, Lopez JA: Tyrosine sulfation of the glycoprotein Ib-IX complex: Identification of sulfated residues and effect on ligand binding. Biochemistry 33:13946,1994

66. Wyler B, Bienz D, Clemetson KJ, Luscher EF: Glycoprotein Iba is the only phosphorylated major membrane glycoprotein in human platelets. Biochem J 234:373,1986

67. Huang R, Sorisky A, Church WR, Simons ER, Rittenhouse SE: "Thrombin" receptor-directed ligand accounts for activation by thrombin of platelet phospholipase C and accumulation of 3-phosphorylated phosphoinositides. J Biol Chan 266:18435,1991

68. Offermanns S, Toombs CF, Hu Y-H, Simon MI: Defective platelet activation in Gaq-deficient mice. Nature 389:183, 1997

69. Du X Hanis SJ, Tetaz TJ, Ginsberg MH, Berndt MC: Association of a phospholipase A2 (14-3-3 protein) with the platelet glycoprotein Ib-IX complex. J Biol Chem 269:18287,1994

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