PDF herunterladen
Semin Thromb Hemost 2004; 30(4): 411-418
DOI: 10.1055/s-2004-833476
Copyright © 2004 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Platelet Receptors for Adenine Nucleotides and Thromboxane A2

Swaminathan Murugappan1 , 3 , Haripriya Shankar1 , Satya P. Kunapuli1 , 2 , 3 , 4
  • 1Department of Physiology, Temple University School of Medicine, Philadelphia, Pennsylvania
  • 2Department of Pharmacology, Temple University School of Medicine, Philadelphia, Pennsylvania
  • 3The Sol Sherry Thrombosis Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania
  • 4Associate Professor, Temple University School of Medicine, Philadelphia, Pennsylvania
Weitere Informationen

Publikationsverlauf

Publikationsdatum:
08. September 2004 (online)

    Lizenzen und Reprints

Adenosine diphosphate (ADP) and thromboxane A2 (TXA2) are important physiological activators of platelets and exert their effects by acting on cell surface receptors. Platelet nucleotide receptors can be distinguished as three separate subtypes of the P2 receptor family. The P2X1 receptor is a ligand-gated adenosine triphosphate (ATP) receptor that was originally mistaken for an ADP receptor. This calcium-influx-causing receptor mediates platelet shape change and plays an important role in thrombus formation in small arterioles. The P2Y1 receptor, through activation of Gq and phospholipase C, is required for ADP-induced platelet shape change, fibrinogen receptor activation, and TXA2 generation. The Gi-coupled P2Y12 receptor plays an important role in platelet aggregation, potentiation of dense granule release, and TXA2 generation. Both the P2Y receptors are crucial for in vivo thrombus formation. TXA2 stimulates two subtypes of G protein-coupled TP receptor, TPα and TPβ, but its effects in platelets are mediated predominantly through the α isoform. Although interference with the activation of G protein-coupled ADP or TP receptors results in increased bleeding times and protection from thromboembolism, TP receptor antagonists did not translate into effective antiplatelet drugs. Blockade of ADP receptor is a mode of newer classes of antithrombotic drugs in the coming era. This review focuses on the contribution of different nucleotide receptors and TP receptors to platelet function and their potential as antithrombotic agents.

KEYWORDS

P2Y1 receptor - P2Y12 receptor - P2X1 receptor - platelet function

REFERENCES

  • 1 Packham M A. Role of platelets in thrombosis and hemostasis.  Can J Physiol Pharmacol. 1994;  72 278-284
    PubMedGoogle Scholar
  • 2 Cattaneo M, Gachet C. ADP receptors and clinical bleeding disorders.  Arterioscler Thromb Vasc Biol. 1999;  19 2281-2285
    PubMedGoogle Scholar
  • 3 Bennett J S. Novel platelet inhibitors.  Annu Rev Med. 2001;  52 161-184
    CrossrefPubMedGoogle Scholar
  • 4 FitzGerald G A, Mayo G, Price P, Takahara K. Aspirin in cardiovascular disease; biochemical pharmacology and clinical trials.  Prog Clin Biol Res. 1989;  301 97-106
    PubMedGoogle Scholar
  • 5 Kunapuli S P, Dorsam R T, Kim S, Quinton T M. Platelet purinergic receptors.  Curr Opin Pharmacol. 2003;  3 175-180
    CrossrefPubMedGoogle Scholar
  • 6 MacKenzie A B, Mahaut-Smith M P, Sage S O. Activation of receptor-operated cation channels via P2X1 not P2T purinoceptors in human platelets.  J Biol Chem. 1996;  271 2879-2881
    CrossrefPubMedGoogle Scholar
  • 7 Vial C, Hechler B, Leon C, Cazenave J P, Gachet C. Presence of P2X1 purinoceptors in human platelets and megakaryoblastic cell lines.  Thromb Haemost. 1997;  78 1500-1504
    PubMedGoogle Scholar
  • 8 Sun B, Li J, Okahara K, Kambayashi J. P2X1 purinoceptor in human platelets. Molecular cloning and functional characterization after heterologous expression.  J Biol Chem. 1998;  273 11544-11547
    CrossrefPubMedGoogle Scholar
  • 9 Mahaut-Smith M P, Ennion S J, Rolf M G, Evans R J. ADP is not an agonist at P2X(1) receptors: evidence for separate receptors stimulated by ATP and ADP on human platelets.  Br J Pharmacol. 2000;  131 108-114
    CrossrefPubMedGoogle Scholar
  • 10 Jacobson K A, Kim Y C, Wildman S S et al.. A pyridoxine cyclic phosphate and its 6-azoaryl derivative selectively potentiate and antagonize activation of P2X1 receptors.  J Med Chem. 1998;  41 2201-2206
    CrossrefPubMedGoogle Scholar
  • 11 Vial C, Rolf M G, Mahaut-Smith M P, Evans R J. A study of P2X1 receptor function in murine megakaryocytes and human platelets reveals synergy with P2Y receptors.  Br J Pharmacol. 2002;  135 363-372
    CrossrefPubMedGoogle Scholar
  • 12 Takano S, Kimura J, Matsuoka I, Ono T. No requirement of P2X1 purinoceptors for platelet aggregation.  Eur J Pharmacol. 1999;  372 305-309
    CrossrefPubMedGoogle Scholar
  • 13 Rolf M G, Brearley C A, Mahaut-Smith M P. Platelet shape change evoked by selective activation of P2X1 purinoceptors with alpha,beta-methylene ATP.  Thromb Haemost. 2001;  85 303-308
    PubMedGoogle Scholar
  • 14 Rolf M G, Mahaut-Smith M P. Effects of enhanced P2X1 receptor Ca2+ influx on functional responses in human platelets.  Thromb Haemost. 2002;  88 495-502
    PubMedGoogle Scholar
  • 15 Oury C, Toth-Zsamboki E, Thys C et al.. The ATP-gated P2X1 ion channel acts as a positive regulator of platelet responses to collagen.  Thromb Haemost. 2001;  86 1264-1271
    PubMedGoogle Scholar
  • 16 Oury C, Toth-Zsamboki E, Vermylen J, Hoylaerts M F. P2X(1)-mediated activation of extracellular signal-regulated kinase 2 contributes to platelet secretion and aggregation induced by collagen.  Blood. 2002;  100 2499-2505
    CrossrefPubMedGoogle Scholar
  • 17 Toth-Zsamboki E, Oury C, Cornelissen H, De Vos R, Vermylen J, Hoylaerts M F. P2X1 mediated ERK2 activation amplifies the collagen induced platelet secretion by enhancing myosin light chain kinase activation.  J Biol Chem. 2003;  278 46661-46667
    CrossrefPubMedGoogle Scholar
  • 18 Hechler B, Lenain N, Marchese P et al.. A role of the fast ATP-gated P2X1 cation channel in thrombosis of small arteries in vivo.  J Exp Med. 2003;  198 661-667
    CrossrefPubMedGoogle Scholar
  • 19 Oury C, Kuijpers M J, Toth-Zsamboki E et al.. Overexpression of the platelet P2X1 ion channel in transgenic mice generates a novel prothrombotic phenotype.  Blood. 2003;  101 3969-3976
    CrossrefPubMedGoogle Scholar
  • 20 Ayyanathan K, Webbs T E, Sandhu A K et al.. Cloning and chromosomal localization of the human P2Y1 purinoceptor.  Biochem Biophys Res Commun. 1996;  218 783-788
    CrossrefPubMedGoogle Scholar
  • 21 Leon C, Vial C, Cazenave J P, Gachet C. Cloning and sequencing of a human cDNA encoding endothelial P2Y1 purinoceptor.  Gene. 1996;  171 295-297
    CrossrefPubMedGoogle Scholar
  • 22 Jin J, Daniel J L, Kunapuli S P. 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 2030-2034
    CrossrefPubMedGoogle Scholar
  • 23 Offermanns S, Toombs C F, Hu Y H, Simon M I. Defective platelet activation in G alpha(q)-deficient mice.  Nature. 1997;  389 183-186
    CrossrefPubMedGoogle Scholar
  • 24 Jin J, Kunapuli S P. Coactivation of two different G protein-coupled receptors is essential for ADP-induced platelet aggregation.  Proc Natl Acad Sci USA. 1998;  95 8070-8074
    CrossrefPubMedGoogle Scholar
  • 25 Dangelmaier C, Jin J, Daniel J L, Smith J B, Kunapuli S P. The P2Y1 receptor mediates ADP-induced p38 kinase-activating factor generation in human platelets.  Eur J Biochem. 2000;  267 2283-2289
    CrossrefPubMedGoogle Scholar
  • 26 Jin J, Quinton T M, Zhang J, Rittenhouse S E, Kunapuli S P. Adenosine diphosphate (ADP)-induced thromboxane A(2) generation in human platelets requires coordinated signaling through integrin alpha(IIb)beta(3) and ADP receptors.  Blood. 2002;  99 193-198
    CrossrefPubMedGoogle Scholar
  • 27 Storey R F, Newby L J, Heptinstall S. Effects of P2Y(1) and P2Y(12) receptor antagonists on platelet aggregation induced by different agonists in human whole blood.  Platelets. 2001;  12 443-447
    CrossrefPubMedGoogle Scholar
  • 28 Turner N A, Moake J L, McIntire L V. Blockade of adenosine diphosphate receptors P2Y(12) and P2Y(1) is required to inhibit platelet aggregation in whole blood under flow.  Blood. 2001;  98 3340-3345
    CrossrefPubMedGoogle Scholar
  • 29 Remijn J A, Wu Y P, Jeninga E H et al.. Role of ADP receptor P2Y(12) in platelet adhesion and thrombus formation in flowing blood.  Arterioscler Thromb Vasc Biol. 2002;  22 686-691
    CrossrefPubMedGoogle Scholar
  • 30 Leon C, Hechler B, Freund M et al.. Defective platelet aggregation and increased resistance to thrombosis in purinergic P2Y(1) receptor-null mice.  J Clin Invest. 1999;  104 1731-1737
    PubMedGoogle Scholar
  • 31 Fabre J E, Nguyen M, Latour A et al.. Decreased platelet aggregation, increased bleeding time and resistance to thromboembolism in P2Y1-deficient mice.  Nat Med. 1999;  5 1199-1202
    PubMedGoogle Scholar
  • 32 Hechler B, Zhang Y, Eckly A et al.. Lineage-specific overexpression of the P2Y1 receptor induces platelet hyper-reactivity in transgenic mice.  J Thromb Haemost. 2003;  1 155-163
    CrossrefPubMedGoogle Scholar
  • 33 Leon C, Freund M, Ravanat C et al.. Key role of the P2Y(1) receptor in tissue factor-induced thrombin- dependent acute thromboembolism: studies in P2Y(1)-knockout mice and mice treated with a P2Y(1) antagonist.  Circulation. 2001;  103 718-723
    PubMedGoogle Scholar
  • 34 Lenain N, Freund M, Leon C, Cazenave J P, Gachet C. Inhibition of localized thrombosis in P2Y1-deficient mice and rodents treated with MRS2179, a P2Y1 receptor antagonist.  J Thromb Haemost. 2003;  1 1144-1149
    CrossrefPubMedGoogle Scholar
  • 35 Kunapuli S P, Ding Z, Dorsam R T et al.. ADP receptors-targets for developing antithrombotic agents.  Curr Pharm Des. 2003;  9 2303-2316
    CrossrefPubMedGoogle Scholar
  • 36 Ohlmann P, Laugwitz K L, Nurnberg B et al.. The human platelet ADP receptor activates Gi2 proteins.  Biochem J. 1995;  312(pt 3) 775-779
    PubMedGoogle Scholar
  • 37 Takasaki J, Kamohara M, Saito T et al.. Molecular cloning of the platelet P2T(AC) ADP receptor: pharmacological comparison with another ADP receptor, the P2Y(1) receptor.  Mol Pharmacol. 2001;  60 432-439
    PubMedGoogle Scholar
  • 38 Zhang F L, Luo L, Gustafson E et al.. ADP is the cognate ligand for the orphan G protein-coupled receptor SP1999.  J Biol Chem. 2001;  276 8608-8615
    CrossrefPubMedGoogle Scholar
  • 39 Hollopeter G, Jantzen H M, Vincent D et al.. Identification of the platelet ADP receptor targeted by antithrombotic drugs.  Nature. 2001;  409 202-207
    CrossrefPubMedGoogle Scholar
  • 40 Savi P, Labouret C, Delesque N et al.. P2y(12), a new platelet ADP receptor, target of clopidogrel.  Biochem Biophys Res Commun. 2001;  283 379-383
    CrossrefPubMedGoogle Scholar
  • 41 Daniel J L, Dangelmaier C, Jin J et al.. Molecular basis for ADP-induced platelet activation. I. Evidence for three distinct ADP receptors on human platelets.  J Biol Chem. 1998;  273 2024-2029
    CrossrefPubMedGoogle Scholar
  • 42 Daniel J L, Dangelmaier C, Jin J, Kim Y B, Kunapuli S P. Role of intracellular signaling events in ADP-induced platelet aggregation.  Thromb Haemost. 1999;  82 1322-1326
    PubMedGoogle Scholar
  • 43 Dangelmaier C, Jin J, Smith J B, Kunapuli S P. Potentiation of thromboxane A2-induced platelet secretion by Gi signaling through the phosphoinositide-3 kinase pathway.  Thromb Haemost. 2001;  85 341-348
    PubMedGoogle Scholar
  • 44 Paul B Z, Jin J, Kunapuli S P. Molecular mechanism of thromboxane A(2)-induced platelet aggregation. Essential role for p2t(ac) and alpha(2a) receptors.  J Biol Chem. 1999;  274 29108-29114
    CrossrefPubMedGoogle Scholar
  • 45 Cattaneo M, Lecchi A, Randi A M, McGregor J L, Mannucci P M. Identification of a new congenital defect of platelet function characterized by severe impairment of platelet responses to adenosine diphosphate.  Blood. 1992;  80 2787-2796
    PubMedGoogle Scholar
  • 46 Jung S M, Moroi M. Activation of the platelet collagen receptor integrin alpha(2)beta(1): its mechanism and participation in the physiological functions of platelets.  Trends Cardiovasc Med. 2000;  10 285-292
    CrossrefPubMedGoogle Scholar
  • 47 Storey R F, Sanderson H M, White A E et al.. The central role of the P(2T) receptor in amplification of human platelet activation, aggregation, secretion and procoagulant activity.  Br J Haematol. 2000;  110 925-934
    CrossrefPubMedGoogle Scholar
  • 48 Ohlmann P, Eckly A, Freund M et al.. ADP induces partial platelet aggregation without shape change and potentiates collagen-induced aggregation in the absence of Galphaq.  Blood. 2000;  96 2134-2139
    PubMedGoogle Scholar
  • 49 Quinton T M, Kim S, Dangelmaier C et al.. Protein kinase C- and calcium-regulated pathways independently synergize with Gi pathways in agonist-induced fibrinogen receptor activation.  Biochem J. 2002;  368 535-543
    CrossrefPubMedGoogle Scholar
  • 50 Wagner W R, Hubbell J A. ADP receptor antagonists and converting enzyme systems reduce platelet deposition onto collagen.  Thromb Haemost. 1992;  67 461-467
    PubMedGoogle Scholar
  • 51 Storey R F, Wilcox R G, Heptinstall S. Comparison of the pharmacodynamic effects of the platelet ADP receptor antagonists clopidogrel and AR-C69931MX in patients with ischaemic heart disease.  Platelets. 2002;  13 407-413
    CrossrefPubMedGoogle Scholar
  • 52 Larson M K, Chen H, Kahn M L et al.. Identification of P2Y12-dependent and -independent mechanisms of glycoprotein VI-mediated Rap1 activation in platelets.  Blood. 2003;  101 1409-1415
    CrossrefPubMedGoogle Scholar
  • 53 Atkinson B T, Stafford M J, Pears C J, Watson S P. Signalling events underlying platelet aggregation induced by the glycoprotein VI agonist convulxin.  Eur J Biochem. 2001;  268 5242-5248
    CrossrefPubMedGoogle Scholar
  • 54 Dorsam R T, Kim S, Jin J, Kunapuli S P. Coordinated signaling through both G12/13 and G(i) pathways is sufficient to activate GPIIb/IIIa in human platelets.  J Biol Chem. 2002;  277 47588-47595
    CrossrefPubMedGoogle Scholar
  • 55 Nieswandt B, Schulte V, Zywietz A, Gratacap M P, Offermanns S. Costimulation of Gi- and G12/G13-mediated signaling pathways induces integrin alpha IIbbeta 3 activation in platelets.  J Biol Chem. 2002;  277 39493-39498
    CrossrefPubMedGoogle Scholar
  • 56 Goto S, Tamura N, Eto K, Ikeda Y, Handa S. Functional significance of adenosine 5′-diphosphate receptor (P2Y(12)) in platelet activation initiated by binding of von Willebrand factor to platelet GP Ibalpha induced by conditions of high shear rate.  Circulation. 2002;  105 2531-2536
    CrossrefPubMedGoogle Scholar
  • 57 van Gestel M A, Heemskerk J W, Slaaf D W et al.. In vivo blockade of platelet ADP receptor P2Y12 reduces embolus and thrombus formation but not thrombus stability.  Arterioscler Thromb Vasc Biol. 2003;  23 518-523
    PubMedGoogle Scholar
  • 58 Dorsam R T, Murugappan S, Ding Z, Kunapuli S P. Clopidogrel: interactions with the P2Y12 receptor and clinical relevance.  Hematology (Am Soc Hematol Educ Program). 2003;  8 359-365
    CrossrefPubMedGoogle Scholar
  • 59 Leon C, Ravanat C, Freund M, Cazenave J P, Gachet C. Differential involvement of the P2Y1 and P2Y12 receptors in platelet procoagulant activity.  Arterioscler Thromb Vasc Biol. 2003;  23 1941-1947
    PubMedGoogle Scholar
  • 60 Leon C, Alex M, Klocke A et al.. Platelet ADP receptors contribute to the initiation of intravascular coagulation.  Blood. 2003;  103 594-600
    PubMedGoogle Scholar
  • 61 Jantzen H M, Milstone D S, Gousset L, Conley P B, Mortensen R M. Impaired activation of murine platelets lacking G alpha(i2).  J Clin Invest. 2001;  108 477-483
    CrossrefPubMedGoogle Scholar
  • 62 Kauffenstein G, Bergmeier W, Eckly A et al.. The P2Y(12) receptor induces platelet aggregation through weak activation of the alpha(IIb)beta(3) integrin-a phosphoinositide 3-kinase-dependent mechanism.  FEBS Lett. 2001;  505 281-290
    CrossrefPubMedGoogle Scholar
  • 63 Hirsch E, Bosco O, Tropel P et al.. Resistance to thromboembolism in PI3Kgamma-deficient mice.  FASEB J. 2001;  15 2019-2021
    PubMedGoogle Scholar
  • 64 Foster C J, Prosser D M, Agans J M et al.. Molecular identification and characterization of the platelet ADP receptor targeted by thienopyridine antithrombotic drugs.  J Clin Invest. 2001;  107 1591-1598
    CrossrefPubMedGoogle Scholar
  • 65 Andre P, Delaney S M, LaRocca T et al.. P2Y12 regulates platelet adhesion/activation, thrombus growth, and thrombus stability in injured arteries.  J Clin Invest. 2003;  112 398-406
    CrossrefPubMedGoogle Scholar
  • 66 Samuelsson B, Goldyne M, Granstrom E et al.. Prostaglandins and thromboxanes.  Annu Rev Biochem. 1978;  47 997-1029
    CrossrefPubMedGoogle Scholar
  • 67 Kobayashi T, Narumiya S. Function of prostanoid receptors: studies on knockout mice.  Prostaglandins Other Lipid Mediat. 2002;  68-69 557-573
    PubMedGoogle Scholar
  • 68 Ushikubi F, Nakajima M, Hirata M et al.. Purification of the thromboxane A2/prostaglandin H2 receptor from human blood platelets.  J Biol Chem. 1989;  264 16496-16501
    PubMedGoogle Scholar
  • 69 Arita H, Nakano T, Hanasaki K. Thromboxane A2: its generation and role in platelet activation.  Prog Lipid Res. 1989;  28 273-301
    PubMedGoogle Scholar
  • 70 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;  97 949-956
    PubMedGoogle Scholar
  • 71 Habib A, FitzGerald G A, Maclouf J. Phosphorylation of the thromboxane receptor alpha, the predominant isoform expressed in human platelets.  J Biol Chem. 1999;  274 2645-2651
    CrossrefPubMedGoogle Scholar
  • 72 Miggin S M, Kinsella B T. Expression and tissue distribution of the mRNAs encoding the human thromboxane A2 receptor (TP) alpha and beta isoforms.  Biochim Biophys Acta. 1998;  1425 543-559
    PubMedGoogle Scholar
  • 73 Shenker A, Goldsmith P, Unson C G, Spiegel A M. The G protein coupled to the thromboxane A2 receptor in human platelets is a member of the novel Gq family.  J Biol Chem. 1991;  266 9309-9313
    PubMedGoogle Scholar
  • 74 Knezevic I, Borg C, Le Breton G C. Identification of Gq as one of the G-proteins which copurify with human platelet thromboxane A2/prostaglandin H2 receptors.  J Biol Chem. 1993;  268 26011-26017
    PubMedGoogle Scholar
  • 75 Kinsella B T, O'Mahony D J, Fitzgerald G A. The human thromboxane A2 receptor alpha isoform (TP alpha) functionally couples to the G proteins Gq and G11 in vivo and is activated by the isoprostane 8-epi prostaglandin F2 alpha.  J Pharmacol Exp Ther. 1997;  281 957-964
    PubMedGoogle Scholar
  • 76 Offermanns S, Laugwitz K L, Spicher K, Schultz G. G proteins of the G12 family are activated via thromboxane A2 and thrombin receptors in human platelets.  Proc Natl Acad Sci USA. 1994;  91 504-508
    PubMedGoogle Scholar
  • 77 FitzGerald G A. Mechanisms of platelet activation: thromboxane A2 as an amplifying signal for other agonists.  Am J Cardiol. 1991;  68 11B-15B
    CrossrefPubMedGoogle Scholar
  • 78 Takahara K, Murray R, FitzGerald G A, Fitzgerald D J. The response to thromboxane A2 analogues in human platelets. Discrimination of two binding sites linked to distinct effector systems.  J Biol Chem. 1990;  265 6836-6844
    PubMedGoogle Scholar
  • 79 Thomas D W, Mannon R B, Mannon P J et al.. Coagulation defects and altered hemodynamic responses in mice lacking receptors for thromboxane A2.  J Clin Invest. 1998;  102 1994-2001
    PubMedGoogle Scholar
  • 80 Patrono C, Coller B, Dalen J E et al.. Platelet-active drugs: the relationships among dose, effectiveness, and side effects.  Chest. 2001;  119 39S-63S
    CrossrefPubMedGoogle Scholar
  • 81 Cairns J A, Theroux P, Lewis Jr H D, Ezekowitz M, Meade T W. Antithrombotic agents in coronary artery disease.  Chest. 2001;  119 228S-252S
    CrossrefPubMedGoogle Scholar
  • 82 Rolin S, Petein M, Tchana-Sato V et al.. BM-573, a dual thromboxane synthase inhibitor and thromboxane receptor antagonist, prevents pig myocardial infarction induced by coronary thrombosis.  J Pharmacol Exp Ther. 2003;  306 59-65
    CrossrefPubMedGoogle Scholar

Satya P KunapuliPh.D. 

Department of Physiology, Temple University, Department of Physiology

Rm. 224, OMS, 3420 N. Broad Street

Philadelphia, PA 19140

eMail: spk@temple.edu