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Hamostaseologie 2025; 45(01): 049-062
DOI: 10.1055/a-2486-6758
Review Article

Signal Transduction and Transformation by the Platelet Activation Cascade: Systems Biology Insights

Anastasia N. Sveshnikova
1   Cell Biology, Dmitry Rogachev National Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russian Federation
2   Molecular Hemostasis, Center for Theoretical Problems of Physicochemical Pharmacology, Moscow, Russian Federation
3   Physics Faculty, M. V. Lomonosov Moscow State University, Moscow, Russian Federation
,
Mikhail Aleksandrovich Panteleev
1   Cell Biology, Dmitry Rogachev National Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russian Federation
2   Molecular Hemostasis, Center for Theoretical Problems of Physicochemical Pharmacology, Moscow, Russian Federation
3   Physics Faculty, M. V. Lomonosov Moscow State University, Moscow, Russian Federation
› Author Affiliations Funding Russian Science Foundation. 23-45-10039
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Abstract

Binding of platelet activators to their receptors initiates a signal transduction network, where intracellular signal is filtered, amplified, and transformed. Computational systems biology methods could be a powerful tool to address and analyze dynamics and regulation of the crucial steps in this cascade. Here we review these approaches and show the logic of their use for a relatively simple case of SFLLRN-induced procoagulant activity. Use of a typical model is employed to track signaling events along the main axis, from the binding of the peptide to PAR1 receptor down to the mPTP opening. Temporal dynamics, concentration dependence, formation of calcium oscillations and their deciphering, and role of stochasticity are quantified for all essential signaling molecules and their complexes. The initial step-wise activation stimulus is transformed to a peak at the early stages, then to oscillation calcium spikes, and then back to a peak shape. The model can show how both amplitude and width of the peak encode the information about the activation level, and show the principle of decoding calcium oscillations via integration of the calcium signal by the mitochondria. Use of stochastic algorithms can reveal that the complexes of Gq, in particular the complex of phospholipase C with Gq, which are the limiting steps in the cascade with their numbers not exceeding several molecules per platelet at any given time; it is them that cause stochastic appearance of the signals downstream. Application of reduction techniques to simplify the system is demonstrated.

Keywords

signal transduction - mathematical models - computational systems biology - secondary messengers - reduction


Publication History

Received: 22 October 2024

Accepted: 22 November 2024

Article published online:
19 February 2025

© 2025. Thieme. All rights reserved.

Georg Thieme Verlag KG
Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

 

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