A N Sveshnikova1,2,3,4, A V Balatskiy5,6, A S Demianova3, T O Shepelyuk2,3,6, S S Shakhidzhanov1,2, M N Balatskaya6, A V Pichugin7, F I Ataullakhanov1,2,3,8, M A Panteleev9,10,11,12. 1. Faculty of Physics, Lomonosov Moscow State University, Moscow, Russia. 2. Center for Theoretical Problems of Physicochemical Pharmacology, Russian Academy of Sciences, Moscow, Russia. 3. Federal Research and Clinical Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia. 4. Therapeutic Faculty, Pirogov Russian National Research Medical University, Moscow, Russia. 5. Medical Scientific and Educational Center, Lomonosov Moscow State University, Moscow, Russia. 6. Faculty of Basic Medicine, Lomonosov Moscow State University, Moscow, Russia. 7. Institute of Immunology FMBA of Russia, Moscow, Russia. 8. Faculty of Biological and Medical Physics, Moscow Institute of Physics and Technology, Dolgoprudnyi, Russia. 9. Faculty of Physics, Lomonosov Moscow State University, Moscow, Russia. mapanteleev@yandex.ru. 10. Center for Theoretical Problems of Physicochemical Pharmacology, Russian Academy of Sciences, Moscow, Russia. mapanteleev@yandex.ru. 11. Federal Research and Clinical Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia. mapanteleev@yandex.ru. 12. Faculty of Biological and Medical Physics, Moscow Institute of Physics and Technology, Dolgoprudnyi, Russia. mapanteleev@yandex.ru.
Abstract
Essentials Roles of the two thrombin receptors in platelet signaling are poorly understood. Computational systems biology modeling was used together with continuous flow cytometry. Dual-receptor system has wide-range sensitivity to thrombin and optimal response dynamics. Procoagulant platelet formation is determined by donor-specific activities of the two receptors. SUMMARY: Background Activation of human platelets with thrombin proceeds via two protease-activated receptors (PARs), PAR1 and PAR4, that have identical main intracellular signaling responses. Although there is evidence that they have different cleavage/inactivation kinetics (and some secondary variations in signaling), the reason for such redundancy is not clear. Methods We developed a multicompartmental stochastic computational systems biology model of dual-receptor thrombin signaling in platelets to gain insight into the mechanisms and roles of PAR1 and PAR4 functioning. Experiments employing continuous flow cytometry of washed human platelets were used to validate the model and test its predictions. Activity of PAR receptors in donors was evaluated by mRNA measurement and by polymorphism sequencing. Results Although PAR1 activation produced rapid and short-lived response, signaling via PAR4 developed slowly and propagated in time. Response of the dual-receptor system was both rapid and prolonged in time. Inclusion of PAR1/PAR4 heterodimer formation promoted PAR4 signaling in the medium range of thrombin concentration (about 10 nm), with little contribution at high and low thrombin. Different dynamics and dose-dependence of procoagulant platelet formation in healthy donors was associated with individual variations in PAR1 and PAR4 activities and particularly by the Ala120Thr polymorphism in the F2RL3 gene encoding PAR4. Conclusions The dual-receptor combination is critical to produce a response combining three critical advantages: sensitivity to thrombin concentration, rapid onset and steady propagation; specific features of the protease-activated receptors do not allow combination of all three in a single receptor.
Essentials Roles of the two thrombin receptors in platelet signaling are poorly understood. Computational systems biology modeling was used together with continuous flow cytometry. Dual-receptor system has wide-range sensitivity to thrombin and optimal response dynamics. Procoagulant platelet formation is determined by donor-specific activities of the two receptors. SUMMARY: Background Activation of human platelets with thrombin proceeds via two protease-activated receptors (PARs), PAR1 and PAR4, that have identical main intracellular signaling responses. Although there is evidence that they have different cleavage/inactivation kinetics (and some secondary variations in signaling), the reason for such redundancy is not clear. Methods We developed a multicompartmental stochastic computational systems biology model of dual-receptor thrombin signaling in platelets to gain insight into the mechanisms and roles of PAR1 and PAR4 functioning. Experiments employing continuous flow cytometry of washed human platelets were used to validate the model and test its predictions. Activity of PAR receptors in donors was evaluated by mRNA measurement and by polymorphism sequencing. Results Although PAR1 activation produced rapid and short-lived response, signaling via PAR4 developed slowly and propagated in time. Response of the dual-receptor system was both rapid and prolonged in time. Inclusion of PAR1/PAR4 heterodimer formation promoted PAR4 signaling in the medium range of thrombin concentration (about 10 nm), with little contribution at high and low thrombin. Different dynamics and dose-dependence of procoagulant platelet formation in healthy donors was associated with individual variations in PAR1 and PAR4 activities and particularly by the Ala120Thr polymorphism in the F2RL3 gene encoding PAR4. Conclusions The dual-receptor combination is critical to produce a response combining three critical advantages: sensitivity to thrombin concentration, rapid onset and steady propagation; specific features of the protease-activated receptors do not allow combination of all three in a single receptor.
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