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Thromb Haemost 2001; 85(02): 341-348
DOI: 10.1055/s-0037-1615690
DOI: 10.1055/s-0037-1615690
Review Article
Potentiation of Thromboxane A2-induced Platelet Secretion by Gi Signaling through the Phosphoinositide-3 Kinase Pathway
Authors
Further Information
Publication History
Received
05 April 2000
Accepted after resubmission
11 August 2000
Publication Date:
08 December 2017 (online)
Summary
Platelet activation results in shape change, aggregation, generation of thromboxane A2, and release of granule contents. We have recently demonstrated that secreted ADP is essential for thromboxane A2-induced platelet aggregation (J. Biol. Chem. 274: 29108-29114, 1999). The aim of this study was to investigate the role of secreted ADP interacting at P2 receptor subtypes in platelet secretion. Platelet secretion induced by the thromboxane A2 mimetic U46619 was unaffected by adenosine-3’phosphate-5’-phosphate, a P2Y1 receptor selective antagonist. However, AR-C66096, a selective antagonist of the P2T AC receptor, inhibited U46619-induced platelet secretion, indicating an important role for Gi signaling in platelet secretion. Selective activation of either the P2T AC receptor or the α2A adrenergic receptor did not cause platelet secretion, but potentiated U46619-induced platelet secretion. SC57101, a fibrinogen receptor antagonist, failed to inhibit platelet secretion, demonstrating that outside-in signaling was not required for platelet secretion. Since Gi signaling results in reduction of basal cAMP levels through inhibition of adenylyl cyclase, we investigated whether this is the signaling event that potentiates platelet secretion. SQ22536 or dideoxyadenosine, inhibitors of adenylyl cyclase, failed to potentiate U46619-induced primary platelet secretion, indicating that reduction in cAMP levels does not directly contribute to platelet secretion. Wortmannin, a selective inhibitor of PI-3 kinase, minimally inhibited U46619-induced platelet secretion when it was solely mediated by Gq, but dramatically ablated the potentiation of Gi signaling. We conclude that signaling through the P2TAC receptor by secreted ADP causes positive feedback on platelet secretion through a PI-3 kinase pathway.
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References
- 1 Holmsen H. 1994. in Hemostasis and Thrombosis: Basic Principles and Clincal Practice. Colman, R. W., Hirsh, J., Marder, V. J., and Salzman, E. W., eds Vol. Third Edition, pp. 524-45 J. B. Lippincott Company; Philadelphia.:
- 2 Mills DCB. ADP receptor in platelets. Thromb Haemost 1996; 76: 835-856.
- 3 Escolar G, White JG. The platelet open canalicular system: a final common pathway. Blood Cells 1991; 17: 467-85.
- 4 White JG, Rao GH. Effects of a microtubule stabilizing agent on the response of platelets to vincristine. Blood 1982; 60: 474-83.
- 5 Lefebvre P, White JG, Krumwiede MD, Cohen I. Role of actin in platelet function. Eur J, Cell Biol 1993; 62: 194-204.
- 6 Rasmussen UB, Gachet C, Schlesinger Y, Hanau D, Ohlmann P, Van Obberghen-Schilling E, Pouyssegur J, Cazenave JP, Pavirani A. A peptide ligand of the human thrombin receptor antagonizes alpha- thrombin and partially activates platelets. J Biol Chem 1993; 268: 14322-8.
- 7 Wheeler-Jones CP, Saermark T, Kakkar VV, Authi KS. Mastoparan promotes exocytosis and increases intracellular cyclic AMP in human platelets. Evidence for the existence of a Ge-like mechanism of secretion. Biochem J 1992; 281: 465-72.
- 8 Paul BZS, Jin J, Kunapuli SP. Molecular mechanism of thromboxane A2- induced platelet aggregation: Essential role for P2TAC and 2A receptors. J Biol Chem 1999; 274: 29108-29114.
- 9 Brass LF, Manning DR, Cichowski K, Abrams CS. Signaling through G proteins in platelets: to the integrins and beyond. Thromb Haemost 1997; 78: 581-9.
- 10 Gabbeta J, Yang X, Kowalska MA, Sun L, Dhanasekaran N, Rao AK. Platelet signal transduction defect with Galpha subunit dysfunction and diminished Galphaq in a patient with abnormal platelet responses. Proc Natl Acad Sci USA 1997; 94: 8750-5.
- 11 Werner MH, Senzel L, Bielawska A, Khan W, Hannun YA. Diacylglycerol overcomes aspirin inhibition of platelets: evidence for a necessary role for diacylglycerol accumulation in platelet activation. Mol Pharmacol 1991; 39: 547-56.
- 12 Walker TR, Watson SP. Synergy between Ca2+ and protein kinase C is the major factor in determining the level of secretion from human platelets. Biochem J 1993; 289: 277-82.
- 13 Offermanns S, Toombs CF, Hu Y-H, Simon MI. Defective platelet activation in Gaq-deficient mice. Nature 1997; 389: 183-6.
- 14 Habib A, FitzGerald GA, Maclouf J. Phosphorylation of the thromboxane receptor alpha, the predominant isoform expressed in human platelets. J Biol Chem 1999; 274: 2645-51.
- 15 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 1999; 103: 879-87.
- 16 Kunapuli SP. Multiple P2 receptor subtypes on platelets: a new interpretation of their function Trends. Pharmacol Sci 1998; 19: 391-4.
- 17 Jin J, Daniel JL, Kunapuli SP. Molecular basis for ADP-induced platelet activation II: The P2Y1 receptor mediates ADP-induced intracellular calcium mobilization and shape change in platelets. J Biol Chem 1998; 273: 2030-4.
- 18 Jin J, Kunapuli SP. Co-activation of two different G protein-coupled receptors is essential for ADP-induced platelet aggregation. Proc Natl Acad Sci USA 1998; 95: 8070-4.
- 19 Zablocki JA, Miyano M, Garland RB, Pireh D, Schretzman L, Rao SN, Lindmark RJ, Panzer-Knodle SG, Nicholson NS, Taite BB. et al. Potent in vitro and in vivo inhibitors of platelet aggregation based upon the ArgGly-Asp-Phe sequence of fibrinogen. A proposal on the nature of the binding interaction between the Arg-guanidine of RGDX mimetics and the platelet GP IIb-IIIa receptor. J Med Chem 1993; 36: 1811-9.
- 20 Costa JL, Murphy DL. Platelet 5-HT uptake and release stopped rapidly by formaldehyde. Nature 1975; 255: 407-8.
- 21 Daniel JL, Dangelmaier C, Jin J, Ashby B, Smith JB, Kunapuli SP. Molecular basis for ADP-induced platelet activation I: Evidence for three distinct ADP receptors on platelets. J Biol Chem 1998; 273: 2024-9.
- 22 Boyer JL, Romero-Avila T, Schachter JB, Harden TK. Identification of competitive antagonists of the P2Y1 receptor. Molecular Pharmacology 1996; 50: 1323-9.
- 23 Humphries RG, Robertson MJ, Leff P. A novel series of P2T purinoceptor antagonists: definition of the role of ADP in arterial thrombosis. Trends in Pharmacol Sci 1995; 16: 179-81.
- 24 Hourani SMO, Cusack NJ. Pharmacological receptors on blood platelets. Pharmacol Rev 1991; 43: 243-98.
- 25 Huang TF, Holt JC, Lukasiewicz H, Niewiarowski S. Trigramin. A low molecular weight peptide inhibiting fibrinogen interaction with platelet receptors expressed on glycoprotein IIb-IIIa complex. J Biol Chem 1987; 262: 16157-63.
- 26 Savage B, Marzec UM, Chao BH, Harker LA, Maraganore JM, Ruggeri ZM. Binding of the snake venom-derived proteins applaggin and echistatin to the arginine-glycine-aspartic acid recognition site(s) on platelet glycoprotein IIb. IIIa complex inhibits receptor function. J Biol Chem 1990; 265: 11766-72.
- 27 Carroll RC, Wang XF, Lanza F, Steiner B, Kouns WC. Blocking platelet aggregation inhibits thromboxane A2 formation by low dose agonists but does not inhibit phosphorylation and activation of cytosolic phospholipase A2. Thromb Res 1997; 88: 109-125.
- 28 Jin J, Zhang J, Rittenhouse SE, Kunapuli SP. ADP-induced thromboxane A2 generation in human platelets requires coordinated signaling through integrinαIIbβ3 and ADP receptors. Blood 1999; 94: 962a (abstract).
- 29 Daniel JL, Dangelmaier C, Jin J, Kim YB, Kunapuli SP. Role of Intracellular signaling events in ADP-induced platelet aggregation. Thromb Haemost 1999; 82: 1322-6.
- 30 Salzman EW. Cyclic AMP in platelet function. New Engl J Med 1972; 286: 358-63.
- 31 Rao AK, Koike K, Willis J, Daniel JL, Beckett C, Hassel B, Day HJ, Smith JB, Holmsen H. Platelet secretion defect associated with impaired liberation of arachidonic acid and normal myosin light chain phosphorylation. Blood 1984; 64: 914-21.
- 32 Rao AK, Kowalska MA, Disa J. Impaired cytoplasmic ionized calcium mobilization in inherited platelet secretion defects. Blood 1989; 74: 664-72.
- 33
Lee SB,
Rao AK,
Lee KH,
Yang X,
Bae YS,
Rhee SG.
Decreased expression of phospholipase C-beta 2 isozyme in human platelets with impaired
function. Blood 1996; 88: 1684-91.
Reference Ris Wihthout Link
- 34 Klages B, Brandt U, Simon MI, Schultz G, Offermanns S. Activation of G12/G13 results in shape change and Rho/Rho-kinase- mediated myosin light chain phosphorylation in mouse platelets. J Cell Biol 1999; 144: 745-54.
- 35 Bauer M, Retzer M, Wilde JI, Maschberger P, Essler M, Aepfelbacher M, Watson SP, Siess W. Dichotomous regulation of myosin phosphorylation and shape change by Rho-kinase and calcium in intact human platelets. Blood 1999; 94: 1665-72.
- 36 Paul BZS, Daniel JL, Kunapuli SP. Platelet shape change is mediated by both calcium-dependent and -independent signaling pathways: Role of p160ROCK in platelet shape change. J Biol Chem 1999; 274: 28293-300.
- 37 Sloan DC, Haslam RJ. Protein kinase C-dependent and Ca2+-dependent mechanisms of secretion from streptolysin O-permeabilized platelets: effects of leakage of cytosolic proteins. Biochem J 1997; 328: 13-21.
- 38 Pulcinelli FM, Ashby B, Gazzaniga PP, Daniel JL. Protein kinase C activation is not a key step in ADP-mediated exposure of fibrinogen receptors on human platelets. FEBS Lett 1995; 364: 87-90.
- 39 Hirata T, Ushikubi F, Kakizuka A, Okuma M, Narumiya S. Two thromboxane A2 receptor isoforms in human platelets. Opposite coupling to adenylyl cyclase with different sensitivity to Arg60 to Leu mutation. J Clin Invest 1996; 97: 949-56.
- 40 Cattaneo M, Lombardi R, Zighetti ML, Gachet C, Ohlmann P, Cazenave JP, Mannucci PM. Deficiency Of (P-33)2mes-Adp Binding Sites On Platelets With Secretion Defect, Normal Granule Stores and Normal Thromboxane a(2) Production - Evidence That Adp Potentiates Platelet Secretion Independently Of the Formation Of Large Platelet Aggregates and Thromboxane a(2) Production. Thromb Haemost 1997; 77: 986-90.
- 41 Cattaneo M, Lecchi A, Randi AM, McGregor JL, Mannucci PM. Identification of a new congenital defect of platelet aggregation characterized by severe impairment of platelet responses to adenosine 5′-diphosphate. Blood 1992; 80: 2787-96.
- 42 Macfarlane DE, Srivastava PC, Mills DCB. 2-Methylthioadenosine [32P]diphosphate. An agonist and radioligand for the receptor that inhbits the accumulation of cyclic AMP in intact blood platelets. J Clin Invest 1983; 71: 420-8.
- 43 Shattil SJ, Haimovich B, Cunningham M, Lipfert L, Parsons JT, Ginsberg MH, Brugge JS. Tyrosine phosphorylation of pp125FAK in platelets requires coordinated signaling through integrin and agonist receptors. J Biol Chem 1994; 269: 14738-14745.
- 44 Banga HS, Simons ER, Brass LF, Rittenhouse SE. Activation of phospholipases A and C in human platelets exposed to epinephrine: role of glycoproteins IIb/IIIa and dual role of epinephrine. Proc Natl Acad Sci USA 1986; 83: 9197-201.
- 45 Sweatt JD, Johnson SL, Cragoe EJ, Limbird LE. Inhibitors of Na+/H+ exchange block stimulus-provoked arachidonic acid release in human platelets. Selective effects on platelet activation by epinephrine, ADP and lower concentrations of thrombin. J Biol Chem 1985; 260: 12910-9.
- 46 Sweatt JD, Connolly TM, Cragoe EJ, Limbird LE. Evidence that Na+/H+ exchange regulates receptor-mediated phospholipase A2 activation in human platelets. J Biol Chem 1986; 261: 8667-73.
- 47 Kulkarni S, Saido TC, Suzuki K, Fox JE. Calpain mediates integrin-induced signaling at a point upstream of Rho family members. J Biol Chem 1999; 274: 21265-75.
- 48 Kovacsovics TJ, Bachelot C, Toker A, Vlahos CJ, Duckworth B, Cantley LC, Hartwig JH. Phosphoinositide 3-kinase inhibition spares actin assembly in activating platelets but reverses platelet aggregation. J Biol Chem 1995; 270: 11358-66.
- 49 Abrams CS, Zhang J, Downes CP, Tang X, Zhao W, Rittenhouse SE. Phosphopleckstrin inhibits gbetagamma-activable platelet phosphatidylinositol-4,5-bisphosphate 3-kinase. J Biol Chem 1996; 271: 25192-7.
- 50 Stephens L, Smrcka A, Cooke FT, Jackson TR, Sternweis PC, Hawkins PT. A novel phosphoinositide 3 kinase activity in myeloid-derived cells is activated by G protein beta gamma subunits. Cell 1994; 77: 83-93.
- 51 Zhang J, Shattil SJ, Cunningham MC, Rittenhouse SE. Phosphoinositide 3-kinase gamma and p85/phosphoinositide 3-kinase in platelets. Relative activation by thrombin receptor or beta-phorbol myristate acetate and roles in promoting the ligand-binding function of alphaIIbbeta3 integrin. J Biol Chem 1996; 271: 6265-72.
- 52 Trumel C, Payrastre B, Plantavid M, Hechler B, Viala C, Presek P, Martinson EA, Cazenave JP, Chap H, Gachet C. A key role of adenosine diphosphate in the irreversible platelet aggregation induced by the PAR1-activating peptide through the late activation of phosphoinositide 3-kinase. Blood 1999; 94: 4156-65.
- 53 Zhang J, Banfic H, Straforini F, Tosi L, Volinia S, Rittenhouse SE. A type II phosphoinositide 3-kinase is stimulated via activated integrin in platelets. A source of phosphatidylinositol 3-phosphate. J Biol Chem 1998; 273: 14081-4.
- 54 Elzagallaai A, Rose SD, Trifaro JM. Platelet secretion induced by phorbol esters stimulation is mediated through phosphorylation of MARCKS: a MARCKS-derived peptide blocks MARCKS phosphorylation and serotonin release without affecting pleckstrin phosphorylation. Blood 2000; 95: 894-902.