title: 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.
abstract: Blood platelet activation is required to allow their participation in hemostasis and thrombosis. It is regulated by a complicated signaling network, whose functioning has been recently attracting attention for basic research and pharmacological purposes. Phospholipase С (PLC) is an enzyme playing an important role in platelet calcium signaling and responsible for release of inositol triphosphate (IP3) into platelet cytoplasm thus controlling intracellular calcium concentration. Using a comprehensive computational model of platelet calcium signaling, we studied the influence of the positive feedback executed by cytosolic calcium on the PLC isoform β2 during platelet activation. With the positive feedback, the model predicted hyperintensive response to platelet activation by thrombin, where non-physiologically high calcium concentrations arose. However, if one took into account a negative feedback determined by IP3 3-kinase (IP3K), combination of the feedback resulted in the formation of a stepped response (with a stable oscillation amplitude and activation-dependent duration). Stochastic simulations confirmed that PLC and IP3K should act in pair to ensure platelet's "all-or-none" response to activation, when the activation level sets the probability of platelet activation, but not its intensity.
authors.affiliation: Faculty of Physics, M.V. Lomonosov Moscow State University, 1-2 Leninskie gory, GSP-1, Moscow 119991, Russia.
authors.forename: Fedor A
authors.initials: FA
authors.lastname: Balabin
authors.affiliation: Faculty of Physics, M.V. Lomonosov Moscow State University, 1-2 Leninskie gory, GSP-1, Moscow 119991, Russia; Center for Theoretical Problems of Physicochemical Pharmacology, Russian Academy of Sciences, 4 Kosygina St, Moscow 119991, Russia; Federal Research and Clinical Center of Pediatric Hematology, Oncology and Immunology, 1 Samory Mashela St, Moscow 117198, Russia. Electronic address: agolomy@gmail.com.
authors.forename: Anastasia N
authors.initials: AN
authors.lastname: Sveshnikova
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000201:enzymology*; D020013:Calcium Signaling / Q000502:physiology*; D019295:Computational Biology / Q000379:methods*; D025461:Feedback, Physiological / Q000502:physiology*; D006801:Humans; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D010738:Type C Phospholipases / Q000378:metabolism*
chemical_list: D017853:Phosphotransferases (Alcohol Group Acceptor); C051038:Inositol 1,4,5-trisphosphate 3-kinase; D010738:Type C Phospholipases
keywords: Blood platelet; Calcium signaling; Negative feedback; Positive feedback