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

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Biochemistry (Moscow), Supplement Series A: Membrane and Cell Biology Aims and scope

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 integrated with the LSODA method. The model equations were derived from our 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.

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Funding

This work was supported by the Russian Foundation for Basic Research and London Royal Community (project no. 21-51-10005).

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Authors and Affiliations

  1. Center for Theoretical Problems of Physico-Chemical Pharmacology, Russian Academy of Sciences, 109029, Moscow, Russia

    A. A. Martyanov, M. G. Stepanyan & A. N. Sveshnikova

  2. Dmitry Rogachev National Research Center of Pediatric Hematology, Oncology and Immunology, 117997, Moscow, Russia

    A. A. Martyanov & A. N. Sveshnikova

  3. Faculty of Basic Physico-Chemical Engineering, Lomonosov Moscow State University, 119991, Moscow, Russia

    A. N. Sveshnikova

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  1. A. A. Martyanov
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  2. M. G. Stepanyan
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  3. A. N. Sveshnikova
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Correspondence to A. N. Sveshnikova.

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Translated by A. Martyanov

   Abbreviations: CRP, collagen related peptide; DTS, dense tubular system; ER, endoplasmic reticulum; GPVI, glycoprotein VI; IP3, inositol-1,4,5-triphosphate; IP3R, IP3 receptor; LAT, linker adapter T-cell protein; PLCγ2, phospholipase Cγ2; PMCA, plasma membrane calcium ATPase; PRP, platelet rich plasma; SERCA, sarcoplasmic/endoplasmic reticulum calcium ATPase; VWF, von Willebrand factor.

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Martyanov, A.A., Stepanyan, M.G. & Sveshnikova, A.N. Theoretical Explanation for the Variability in Platelet Activation through the GPVI Receptor. Biochem. Moscow Suppl. Ser. A 17, 83–91 (2023). https://doi.org/10.1134/S1990747823020046

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  • DOI: https://doi.org/10.1134/S1990747823020046

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