Theoretical Explanation for the Variability in Platelet Activation through the GPVI Receptor

Cover Page

Cite item

Full Text

Open Access Open Access
Restricted Access Access granted
Restricted Access Subscription Access

Abstract

One of the key receptors on the surface of platelets, non-nuclear cells responsible for preventing blood loss when blood vessels are damaged, is the receptor for the extracellular matrix protein collagen, glycoprotein VI (GPVI). GPVI triggers tyrosine kinase signaling in platelets, simultaneously initiating calcium signaling via phospholipase Cγ2 (PLCγ2) and phosphoinositide signaling via phosphoinositide-3-kinase (PI3K). Previously, our group demonstrated that among healthy donors there is more than a twofold variability in calcium response to activation through the GPVI receptor. Here, a computer model of platelet activation through the GPVI receptor is proposed to explain this phenomenon. This model is a system of ordinary differential equations integrable by the LSODA method. The model equations were derived from a previously published model of platelet activation via the CLEC-2 receptor. Using the developed model, a monotonic dependence of the degree of platelet activation on the number of GPVI receptors was predicted. An analysis of the sensitivity of the model to its parameters showed that the platelet response to activation through GPVI is determined by the number of GPVI receptors, as well as the catalytic parameters of tyrosine kinases, while a twofold change in the number of receptors is sufficient to explain the observed phenomenon. Thus, it was theoretically predicted that the variability of calcium responses of platelets to their stimulation through the GPVI receptor could be determined by the variability in the number of GPVI receptors on the platelet surface of healthy donors.

About the authors

A. A. Martyanov

Center for Theoretical Problems of Physico-chemical Pharmacology, Russian Academy of Sciences; Dmitry Rogachev National Research Center of Pediatric Hematology, Oncology and Immunology

Email: a.sveshnikova@physics.msu.ru
Russia, 109029, Moscow; Russia, 117997, Moscow

M. G. Stepanyan

Center for Theoretical Problems of Physico-chemical Pharmacology, Russian Academy of Sciences

Email: a.sveshnikova@physics.msu.ru
Russia, 109029, Moscow

A. N. Sveshnikova

Center for Theoretical Problems of Physico-chemical Pharmacology, Russian Academy of Sciences; Dmitry Rogachev National Research Center of Pediatric Hematology, Oncology and Immunology; Moscow Lomonosov State University, Faculty of Basic Physico-Chemical Engineering

Author for correspondence.
Email: a.sveshnikova@physics.msu.ru
Russia, 109029, Moscow; Russia, 117997, Moscow; Russia, 119991, Moscow

References

  1. Пантелеев М.А., Свешникова А.Н. 2014. Тромбоциты и гемостаз. Онкогематология. 9 (2), 65–73.
  2. Sveshnikova A., Stepanyan M., Panteleev M., Sveshnikova A., Stepanyan M., Panteleev M. 2021. Platelet functional responses and signalling: the molecular relationship. Part 1: Responses. Syst. Biol. Physiol. Reports. 1 (1), 20.
  3. Bergmeier W., Stefanini L. 2009. Novel molecules in calcium signaling in platelets. J. Thromb. Haemost. 7, 187–190.
  4. Martyanov A., Panteleev M. 2021. Platelet functional responses and signalling: The molecular relationship. Part 2: Receptors. Syst. Biol. Physiol. Reports. 1 (3), 13–30.
  5. Gear A.R. 1994. Platelet adhesion, shape change, and aggregation: rapid initiation and signal transduction events. Can. J. Physiol. Pharmacol. 72 (3), 285–294.
  6. Канева В.Н., Мартьянов А.А., Морозова Д.С., Пантелеев М.А., Свешникова А.Н. 2019. Тромбоцитарные интегрины αIIBβ3. Биол. мембраны. 36 (1), 15–31.
  7. Podoplelova N.A., Sveshnikova A.N., Kotova Y.N., Eckly A., Receveur N., Nechipurenko D.Yu., Obydennyi S.I., Kireev I.I., Gachet C., Ataullakhanov F.I., Mangin P.H., Panteleev M.A. 2016. Coagulation factors bound to procoagulant platelets concentrate in cap structures to promote clotting. Blood. 128 (13), 1745–1755.
  8. Bryckaert M., Rosa J.-P., Denis C.V., Lenting P.J. 2015. Of von Willebrand factor and platelets. Cell Mol. Life Sci. 72 (2), 307–326.
  9. Poulter N.S., Pollitt A.Y., Owen D.M., Gardiner E.E., Andrews R.K., Shimizu H., Ishikawa D., Bihan D., Farndale R.W., Moroi M., Watson S.P., Jung S.M. 2017. Clustering of glycoprotein VI (GPVI) dimers upon adhesion to collagen as a mechanism to regulate GPVI signaling in platelets. J. Thromb. Haemost. 15 (3), 549–564.
  10. Степанян М.Г., Филькова А.А., Гарсон Дасгупта А.К., Мартьянов А.А., Свешникова А.Н. 2020. Активация тромбоцитов через рецептор GPVI: вариабельность ответа. Биол. мембраны. 37 (6), 442–452.
  11. Johnson E.N., Brass L.F., Funk C.D. 1998. Increased platelet sensitivity to ADP in mice lacking platelet-type 12-lipoxygenase. Proc. Natl. Acad. Sci. USA. 95 (6), 3100–3105.
  12. Pollitt A.Y., Poulter N.S., Gitz E., Navarro-Nuñez L., Wang Y.-J., Hughes C.E., Thomas S.G., Nieswandt B., Douglas M.R., Owen D.M., Jackson D.G., Dustin M.L., Watson S.P. 2014. Syk and Src family kinases regulate C-type lectin receptor 2 (CLEC-2)-mediated clustering of podoplanin and platelet adhesion to lymphatic endothelial cells. J. Biol. Chem. 289 (52), 35 695–35 710.
  13. Garzon Dasgupta A.K., Martyanov A.A., Filkova A.A., Panteleev M.A., Sveshnikova A.N. 2020. Development of a simple kinetic mathematical model of aggregation of particles or clustering of receptors. Life. 10 (6), 97.
  14. Watson S.P., Herbert J.M.J., Pollitt A.Y. 2010. GPVI and CLEC-2 in hemostasis and vascular integrity. J. Thromb. Haemost. 8 (7), 1456–1467.
  15. Rayes J., Watson S.P., Nieswandt B. 2019. Functional significance of the platelet immune receptors GPVI and CLEC-2. J. Clin. Invest. 129 (1), 12–23.
  16. Balabin F.A., Sveshnikova A.N. 2016. Computational biology analysis of platelet signaling reveals roles of feedbacks through phospholipase C and inositol 1,4,5-trisphosphate 3-kinase in controlling amplitude and duration of calcium oscillations. Math Biosci. 276, 67–74.
  17. Sveshnikova A.N., Balatskiy A.V., Demianova A.S., Shepelyuk T.O., Shakhidzhanov S.S., Balatskaya M.N., Pichugin A.V., Ataullakhanov F.I., Panteleev M.A. 2016. Systems biology insights into the meaning of the platelet’s dual-receptor thrombin signaling. J. Thromb. Haemost. 14 (10), 2045–2057.
  18. Jackson S.P., Schoenwaelder S.M. 2010. Procoagulant platelets: Are they necrotic? Blood. 116 (12), 2011–2018.
  19. Podoplelova N.A., Nechipurenko D.Y., Ignatova A.A., Sveshnikova A.N., Panteleev M.A. 2021. Procoagulant platelets: Mechanisms of generation and action. Hämostaseologie. 41 (02), 146–153.
  20. Martyanov A.A., Balabin F.A., Dunster J.L., Panteleev M.A., Gibbins J.M., Sveshnikova A.N. 2020. Control of platelet CLEC-2-mediated activation by receptor clustering and tyrosine kinase signaling. Biophys. J. 118 (11), 2641–2655.
  21. Moroi M., Jung S.M. 2004. Platelet glycoprotein VI: Its structure and function. Thromb. Res. 114 (4), 221–233.
  22. Furihata K., Clemetson K.J., Deguchi H., Kunicki T.J. 2001. Variation in human platelet glycoprotein VI content modulates glycoprotein VI-specific prothrombinase activity. Arterioscler. Thromb. Vasc. Biol. 21 (11), 1857–1863.
  23. Best D., Senis Y.A., Jarvis G.E., Eagleton H.J., Roberts D.J., Saito T., Jung S.M., Moroi M., Harrison P., Green F.R., Watson S.P. 2003. GPVI levels in platelets: Relationship to platelet function at high shear. Blood. 102 (8), 2811–2818.
  24. Hoops S., Sahle S., Gauges R., Lee C., Pahle J., Simus N., Singhal M., Xu L., Mendes P., Kummer U. 2006. COPASI – a COmplex PAthway SImulator. Bioinformatics. 22 (24), 3067–3074.
  25. Petzold L., Hindmarsh A. 1997. LSODA (Livermore solver of ordinary differential equations). Computing and Mathematics Research Division, Lawrence Livermore National Laboratory, Livermore, CA, 24.
  26. Burkhart J.M., Vaudel M., Gambaryan S., Radau S., Walter U., Martens L., Geiger J., Sickmann A., Zahedi R.P. 2012. The first comprehensive and quantitative analysis of human platelet protein composition allows the comparative analysis of structural and functional pathways. Blood. 120 (15), e73–82.
  27. Back T. 1996. Evolutionary algorithms in theory and practice: Evolution strategies, evolutionary programming, genetic algorithms. Oxford: Oxford university press.
  28. Saltelli A., Ratto M., Tarantola S., Campolongo F. 2005. Sensitivity analysis for chemical models. Chem. Rev. 105 (7), 2811–2828.
  29. Мартьянов А.А., Балабин Ф.А., Майоров А.С., Шамова Е.В., Пантелеев М.А., Свешникова А.Н. 2018. Компьютерное моделирование внутриклеточной сигнализации при активации тромбоцитов крови фукоиданом. Биол. мембраны. 35 (5), 364–375.
  30. Dunster J.L., Mazet F., Fry M.J., Gibbins J.M., Tindall M.J. 2015. Regulation of early steps of GPVI signal transduction by phosphatases: A systems biology approach. PLoS Comput. Biol. 11 (11), e1004589.
  31. Rayes J., Watson S.P., Nieswandt B. 2019. Functional significance of the platelet immune receptors GPVI and CLEC-2. J. Clin. Invest. 129 (1), 12–23.
  32. Senis Y.A., Mazharian A., Mori J. 2014. Src family kinases: At the forefront of platelet activation. Blood. 124 (13), 2013–2024.
  33. Séverin S., Pollitt A.Y., Navarro-Nuñez L., Nash C.A., Mourão-Sá D., Eble J.A., Senis Y.A., Watson S.P. 2011. Syk-dependent phosphorylation of CLEC-2. J. Biol. Chem. 286 (6), 4107–4116.
  34. Burkhart J.M., Vaudel M., Gambaryan S., Radau S., Walter U., Martens L., Geiger J., Sickmann A., Zahedi R.P. 2012. The first comprehensive and quantitative analysis of human platelet protein composition allows the comparative analysis of structural and functional pathways. Blood. 120 (15), e73–82.
  35. Quinter P.G., Quinton T.M., Dangelmaier C.A., Kunapuli S.P., Daniel J.L. 2005. Role of lipid rafts in GPVI agonist-induced platelet signaling. Blood. 106 (11), 3576.
  36. Miura Y., Takahashi T., Jung S.M., Moroi M. 2002. Analysis of the interaction of platelet collagen receptor glycoprotein VI (GPVI) with collagen. A dimeric form of GPVI, but not the monomeric form, shows affinity to fibrous collagen. J. Biol. Chem. 277 (48), 46 197–46 204.
  37. Kemble D.J., Wang Y.H., Sun G. 2006. Bacterial expression and characterization of catalytic loop mutants of Src protein tyrosine kinase. Biochemistry. 45 (49), 14 749–14 754.
  38. Bradshaw J.M. 2010. The Src, Syk, and Tec family kinases: Distinct types of molecular switches. Cell. Signal. 22 (8), 1175–1184.
  39. Ren L., Chen X., Luechapanichkul R., Selner N.G., Meyer T.M., Wavreille A.-S., Chan R., Iorio C., Zhou X., Neel B.G., Pei D. 2011. Substrate specificity of protein tyrosine phosphatases 1B, RPTPα, SHP-1, and SHP-2. Biochemistry. 50 (12), 2339–2356.
  40. Lin X., Lee S., Sun G. 2003. Functions of the activation loop in Csk protein-tyrosine kinase. J. Biol. Chem. 278 (26), 24 072–24 077.
  41. Park M.J., Sheng R., Silkov A., Jung D.J., Wang Z.G., Xin Y., Kim H., Thiagarajan-Rosenkranz P., Song S., Yoon Y., Nam W., Kim I., Kim E., Lee D.G., Chen Y., Singaram I., Wang L., Jang M.H., Hwang C.S., Honig B., Ryu S., Lorieau J., Kim Y.M., Cho W. 2016. SH2 domains serve as lipid-binding modules for pTyr-signaling proteins. Mol. Cell. 62 (1), 7–20.
  42. Tsang E., Giannetti A.M., Shaw D., Dinh M., Tse J.K.Y., Gandhi S., Ho A., Wang S., Papp E., Bradshaw J.M. 2008. Molecular mechanism of the Syk activation switch. J. Biol. Chem. 283 (47), 32650–32659.
  43. Hughes C.E., Sinha U., Pandey A., Eble J.A., O’Callaghan C.A., Watson S.P. 2013. Critical role for an acidic amino acid region in platelet signaling by the HemITAM (hemi-immunoreceptor tyrosine-based activation motif) containing receptor CLEC-2 (C-type lectin receptor-2). J. Biol. Chem. 288 (7), 5127–5135.
  44. Sveshnikova A.N., Balatskiy A.V., Demianova A.S., Shepelyuk T.O., Shakhidzhanov S.S., Balatskaya M.N., Pichugin A.V., Ataullakhanov F.I., Panteleev M.A. 2016. Systems biology insights into the meaning of the platelet’s dual-receptor thrombin signaling. J. Thromb. Haemost. 14 (10), 2045–2057.
  45. Ahmed M.U., Kaneva V., Loyau S., Nechipurenko D., Receveur N., Le Bris M., Janus-Bell E., Didelot M., Rauch A., Susen S., Chakfé N., Lanza F., Gardiner E.E., Andrews R.K., Panteleev M., Gachet C., Jandrot-Perrus M., Mangin P.H. 2020. Pharmacological blockade of glycoprotein VI promotes thrombus disaggregation in the absence of thrombin. Arterioscler. Thromb. Vasc. Biol. 40 (9), 2127–2142.
  46. Montague S.J., Delierneux C., Lecut C., Layios N., Dinsdale R.J., Lee C.S.-M., Poulter N.S., Andrews R.K., Hampson P., Wearn C.M., Maes N., Bishop J., Bamford A., Gardiner C., Lee W.M., Iqbal T., Moiemen N., Watson S.P., Oury C., Harrison P., Gardiner E.E. 2018. Soluble GPVI is elevated in injured patients: Shedding is mediated by fibrin activation of GPVI. Blood Adv. 2 (3), 240–251.
  47. Montague S.J., Andrews R.K., Gardiner E.E. 2018. Mechanisms of receptor shedding in platelets. Blood. 132 (24), 2535–2545.
  48. Al-Tamimi M., Tan C.W., Qiao J., Pennings G.J., Javadzadegan A., Yong A.S.C., Arthur J.F., Davis A.K., Jing J., Mu F.-T., Hamilton J.R., Jackson S.P., Ludwig A., Berndt M.C., Ward C.M., Kritharides L., Andrews R.K., Gardiner E.E. 2012. Pathologic shear triggers shedding of vascular receptors: a novel mechanism for down-regulation of platelet glycoprotein VI in stenosed coronary vessels. Blood. 119 (18), 4311–4320.
  49. Yakusheva A.A., Butov K.R., Bykov G.A., Závodszky G., Eckly A., Ataullakhanov F.I., Gachet C., Panteleev M.A., Mangin P.H. 2022. Traumatic vessel injuries initiating hemostasis generate high shear conditions. Blood Adv. 6 (16), 4834–4846.

Supplementary files

Supplementary Files
Action
1. JATS XML
Download
2.

Download (1MB)
Indexing metadata
3.

Download (224KB)
Indexing metadata
4.

Download (60KB)
Indexing metadata

Copyright (c) 2023 The Russian Academy of Sciences

This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies