Korean Circulation Journal

The Korean Society of Cardiology (대한심장학회)
권호 표지
DOI QR코드

DOI QR Code

Mechanisms of Platelet Activation and Integrin ${\alpha}II{\beta}3$

  • Joo, Seung-Jae (Cardiology Division, Department of Internal Medicine, Jeju National University Hospital)
  • Published : 2012.05.31
⟨ Previous Next ⟩

Abstract

Platelet aggregation is not only an essential part of hemostasis, but also initiates acute coronary syndrome or ischemic stroke. The precise understanding of the activation mechanism of platelet aggregation is fundamental for the development of more effective agents against platelet aggregation. Adenosine diphosphate, thrombin, and thromboxane $A_2$ activate platelet integrin ${\alpha}II{\beta}3$ through G protein-coupled receptors. G protein-mediated signaling pathways, which are initiated by $G_q$, $G_{12}/G_{13}$ or $G_i$, include phospholipase C with calcium signaling, Rho signaling, protein kinase C and phosphatidylinositol 3-kinase. Rap1b, $Ca^{2+}$ and diacylglycerol-regulated guanine nucleotide exchange factor I, Rap1-GTP-interacting adaptor molecule, and Akt are important proteins involved in G protein-mediated activation of integrin ${\alpha}IIb{\beta}3$. Binding of talin-1 and kindlin-3 to cytoplasmic domains of ${\beta}3$-integrin triggers a conformational change in the extracellular domains that increases its affinity for ligands, such as fibrinogen or von Willebrand factor. Fibrinogens act as bridges between adjacent platelets to generate a platelet aggregate.

Keywords

References

  1. Joo SJ, Lee JW, Park YS. Increased activation of platelet glycoprotein IIb/IIIa in hypercholesterolemic patients. Korean Circ J 1998;28:2030-41. https://doi.org/10.4070/kcj.1998.28.12.2030
  2. Ruggeir ZM. Platelets in atherothrombosis. Nat Med 2002;8:1227-34. https://doi.org/10.1038/nm1102-1227
  3. Di Virgilio F, Solini A. P2 receptors: new potential players in atherosclerosis. Br J Pharmacol 2002;135:831-42. https://doi.org/10.1038/sj.bjp.0704524
  4. Dorsam RT, Kunapuli SP. Central role of the P2Y12 receptor in platelet activation. J Clin Invest 2004;113:340-5. https://doi.org/10.1172/JCI20986
  5. Gachet C, Leon C, Hechler B. The platelet P2 receptors in arterial thrombosis. Blood Cells Mol Dis 2006;36:223-7. https://doi.org/10.1016/j.bcmd.2005.12.024
  6. Oury C, Toth-Zsamboki E, Vermylen J, Hoylaerts MF. The platelet ATP and ADP receptors. Curr Pharm Des 2006;12:859-75. https://doi.org/10.2174/138161206776056029
  7. Nguyen TA, Diodati JG, Pharand C. Resistance to clopidogrel: a review of the evidence. J Am Coll Cardiol 2005;45:1157-64. https://doi.org/10.1016/j.jacc.2005.01.034
  8. Brass S. Cardiovascular biology: platelets and proteases. Nature 2001; 413:26-7. https://doi.org/10.1038/35092647
  9. Offermanns S. Activation of platelet function through G protein-coupled receptors. Circ Res 2006;99:1293-304. https://doi.org/10.1161/01.RES.0000251742.71301.16
  10. Smyth SS, Woulfe DS, Weitz JI, et al. G-protein-coupled receptors as signaling targets for antiplatelet therapy. Arterioscler Thromb Vasc Biol 2009;29:449-57. https://doi.org/10.1161/ATVBAHA.108.176388
  11. Becker RC, Moliterno DJ, Jennings LK, et al. Safety and tolerability of SCH 530348 in patients undergoing non-urgent percutaneous coronary intervention: a randomised, double-blind, placebo-controlled phase II study. Lancet 2009;373:919-28. https://doi.org/10.1016/S0140-6736(09)60230-0
  12. Tricoci P, Huang Z, Held C, et al. Thrombin-receptor antagonist vorapaxar in acute coronary syndromes. N Engl J Med 2012;366:20-33. https://doi.org/10.1056/NEJMoa1109719
  13. Giannarelli C, Zafar MU, Badimon JJ. Prostanoid and TP-receptors in atherothrombosis: is there a role for their antagonism? Thromb Haemost 2010;104:949-54. https://doi.org/10.1160/TH10-03-0195
  14. Offermanns S, Laugwitz KL, 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 U S A 1994;91:504-8. https://doi.org/10.1073/pnas.91.2.504
  15. Lefkovits J, Plow EF, Topol EJ. Platelet glycoprotein IIb/IIIa receptors in cardiovascular medicine. N Engl J Med 1995;332:1553-9. https://doi.org/10.1056/NEJM199506083322306
  16. Nieswandt B, Varga-Szabo D, Elvers M. Integrins in platelet activation. J Thromb Haemost 2009;7(Suppl 1):206-9.
  17. Topol EJ, Byzova TV, Plow EF. Platelet GPIIb-IIIa blockers. Lancet 1999; 353:227-31. https://doi.org/10.1016/S0140-6736(98)11086-3
  18. Quinn MJ, Byzova TV, Qin J, Topol EJ, Plow EF. Integrin alphaIIbbeta3 and its antagonism. Arterioscler Thromb Vasc Biol 2003;23:945-52. https://doi.org/10.1161/01.ATV.0000066686.46338.F1
  19. Banno A, Ginsberg MH. Integrin activation. Biochem Soc Trans 2008; 36(Pt 2):229-34. https://doi.org/10.1042/BST0360229
  20. Chrzanowska-Wodnicka M, Smyth SS, Schoenwaelder SM, Fischer TH, White GC 2nd. Rap1b is required for normal platelet function and hemostasis in mice. J Clin Invest 2005;115:680-7. https://doi.org/10.1172/JCI22973
  21. Cifuni SM, Wagner DD, Bergmeier W. CalDAG-GEFI and protein kinase C represent alternative pathways leading to activation of integrin alphaIIbbeta3 in platelets. Blood 2008;112:1696-703. https://doi.org/10.1182/blood-2008-02-139733
  22. Crittenden JR, Bergmeier W, Zhang Y, et al. CalDAG-GEFI integrates signaling for platelet aggregation and thrombus formation. Nat Med 2004;10:982-6. https://doi.org/10.1038/nm1098
  23. Berridge MJ, Bootman MD, Roderick HL. Calcium signalling: dynamics, homeostasis and remodelling. Nat Rev Mol Cell Biol 2003;4:517-29. https://doi.org/10.1038/nrm1155
  24. Varga-Szabo D, Braun A, Kleinschnitz C, et al. The calcium sensor STIM1 is an essential mediator of arterial thrombosis and ischemic brain infarction. J Exp Med 2008;205:1583-91. https://doi.org/10.1084/jem.20080302
  25. Braun A, Varga-Szabo D, Kleinschnitz C, et al. Orai1 (CRACM1) is the platelet SOC channel and essential for pathological thrombus formation. Blood 2009;113:2056-63. https://doi.org/10.1182/blood-2008-07-171611
  26. Lafuente EM, van Puijenbroek AA, Krause M, et al. RIAM, an Ena/VASP and Profilin ligand, interacts with Rap1-GTP and mediates Rap1-induced adhesion. Dev Cell 2004;7:585-95. https://doi.org/10.1016/j.devcel.2004.07.021
  27. Lee HS, Lim CJ, Puzon-McLaughlin W, Shattil SJ, Ginsberg MH. RIAM activates integrins by linking talin to ras GTPase membrane-targeting sequences. J Biol Chem 2009;284:5119-27. https://doi.org/10.1074/jbc.M807117200
  28. Watanabe N, Bodin L, Pandey M, et al. Mechanisms and consequences of agonist-induced talin recruitment to platelet integrin alphaIIbbeta3. J Cell Biol 2008;181:1211-22. https://doi.org/10.1083/jcb.200803094
  29. Han J, Lim CJ, Watanabe N, et al. Reconstructing and deconstructing agonist-induced activation of integrin alphaIIbbeta3. Curr Biol 2006; 16:1796-806. https://doi.org/10.1016/j.cub.2006.08.035
  30. Woulfe D, Jiang H, Morgans A, Monks R, Birnbaum M, Brass LF. Defects in secretion, aggregation, and thrombus formation in platelets from mice lacking Akt2. J Clin Invest 2004;113:441-50.
  31. Chen J, De S, Damron DS, Chen WS, Hay N, Byzova TV. Impaired platelet responses to thrombin and collagen in AKT-1-deficient mice. Blood 2004;104:1703-10. https://doi.org/10.1182/blood-2003-10-3428
  32. Li D, August S, Woulfe DS. GSK3beta is a negative regulator of platelet function and thrombosis. Blood 2008;111:3522-30. https://doi.org/10.1182/blood-2007-09-111518
  33. Stojanovic A, Marjanovic JA, Brovkovych VM, et al. A phosphoinositide 3-kinase-AKT-nitric oxide-cGMP signaling pathway in stimulating platelet secretion and aggregation. J Biol Chem 2006;281:16333-9. https://doi.org/10.1074/jbc.M512378200
  34. Zhang W, Colman RW. Thrombin regulates intracellular cyclic AMP concentration in human platelets through phosphorylation/activation of phosphodiesterase 3A. Blood 2007;110:1475-82. https://doi.org/10.1182/blood-2006-10-052522
  35. Bennett JS, Berger BW, Billings PC. The structure and function of platelet integrins. J Thromb Haemost 2009;7(Suppl 1):200-5. https://doi.org/10.1111/j.1538-7836.2009.03378.x
  36. Critchley DR, Gingras AR. Talin at a glance. J Cell Sci 2008;121(Pt 9): 1345-7. https://doi.org/10.1242/jcs.018085
  37. Li R, Babu CR, Valentine K, et al. Characterization of the monomeric form of the transmembrane and cytoplasmic domains of the integrin beta 3 subunit by NMR spectroscopy. Biochemistry 2002;41:15618-24. https://doi.org/10.1021/bi026822l
  38. Lau TL, Partridge AW, Ginsberg MH, Ulmer TS. Structure of the integrin beta3 transmembrane segment in phospholipid bicelles and detergent micelles. Biochemistry 2008;47:4008-16. https://doi.org/10.1021/bi800107a
  39. Petrich BG, Marchese P, Ruggeri ZM, et al. Talin is required for integrinmediated platelet function in hemostasis and thrombosis. J Exp Med 2007;204:3103-11. https://doi.org/10.1084/jem.20071800
  40. Nieswandt B, Moser M, Pleines I, et al. Loss of talin1 in platelets abrogates integrin activation, platelet aggregation, and thrombus formation in vitro and in vivo. J Exp Med 2007;204:3113-8. https://doi.org/10.1084/jem.20071827
  41. Larjava H, Plow EF, Wu C. Kindlins: essential regulators of integrin signalling and cell-matrix adhesion. EMBO Rep 2008;9:1203-8. https://doi.org/10.1038/embor.2008.202
  42. Moser M, Nieswandt B, Ussar S, Pozgajova M, Fässler R. Kindlin-3 is essential for integrin activation and platelet aggregation. Nat Med 2008;14:325-30. https://doi.org/10.1038/nm1722

Cited by

  1. New Anticoagulants and Antiplatelet Agents: A Primer for the Clinical Gastroenterologist vol.109, pp.1, 2012, https://doi.org/10.1038/ajg.2013.228
  2. Antiplatelet activity of nifedipine is mediated by inhibition of NF-κB activation caused by enhancement of PPAR-β/-γ activity : Nifedipine inhibits NF-κB activation in platelets vol.171, pp.6, 2012, https://doi.org/10.1111/bph.12523
  3. The Marine-Derived Kinase Inhibitor Fascaplysin Exerts Anti-Thrombotic Activity vol.13, pp.11, 2012, https://doi.org/10.3390/md13116774
  4. rLj-RGD3, a Novel Recombinant Toxin Protein from Lampetra japonica , Protects against Cerebral Reperfusion Injury Following Middle Cerebral Artery Occlusion Involving the Integrin-PI3K/Akt Pathway in vol.11, pp.10, 2012, https://doi.org/10.1371/journal.pone.0165093
  5. Antiplatelet mechanism of an herbal mixture prepared from the extracts of Phyllostachys pubescens leaves and Prunus mume fruits vol.17, pp.None, 2012, https://doi.org/10.1186/s12906-017-2032-5
  6. GAS6/TAM Pathway Signaling in Hemostasis and Thrombosis vol.5, pp.None, 2012, https://doi.org/10.3389/fmed.2018.00137
  7. Interaction of Treponema pallidum , the syphilis spirochete, with human platelets vol.14, pp.1, 2019, https://doi.org/10.1371/journal.pone.0210902
  8. Signaling Pathways of Receptors Involved in Platelet Activation and Shedding of These Receptors in Stored Platelets vol.9, pp.1, 2012, https://doi.org/10.15171/apb.2019.005
  9. The Role of Serum Calcium Level in Intracerebral Hemorrhage Hematoma Expansion: Is There Any? vol.31, pp.1, 2012, https://doi.org/10.1007/s12028-018-0564-2
  10. Platelets and platelet extracellular vesicles in hemostasis and sepsis vol.68, pp.4, 2012, https://doi.org/10.1136/jim-2019-001195
  11. Role of thrombospondin-1 and thrombospondin-2 in cardiovascular diseases (Review) vol.45, pp.5, 2012, https://doi.org/10.3892/ijmm.2020.4507
  12. Extracellular creatine kinase may modulate purinergic signalling vol.16, pp.3, 2012, https://doi.org/10.1007/s11302-020-09707-0
  13. Creatine kinase is associated with bleeding after myocardial infarction vol.7, pp.2, 2012, https://doi.org/10.1136/openhrt-2020-001261
  14. Fibrinogen-mimicking, multiarm nanovesicles for human thrombus-specific delivery of tissue plasminogen activator and targeted thrombolytic therapy vol.7, pp.23, 2012, https://doi.org/10.1126/sciadv.abf9033
  15. Extracellular Vesicles in Skin Wound Healing vol.14, pp.8, 2012, https://doi.org/10.3390/ph14080811