Compartmentalized calcium signaling triggers subpopulation formation upon platelet activation through PAR1статья
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Дата последнего поиска статьи во внешних источниках: 19 сентября 2015 г.
Аннотация:Blood platelets need to undergo activation to carry out their function of stopping bleeding. Different
activation degrees lead to a stepped hierarchy of responses: ability to aggregate, granule release, and, in a
fraction of platelets, phosphatidylserine (PS) exposure. This suggests the existence of decision-making
mechanisms in the platelet intracellular signaling network. To identify and investigate them, we developed a
computational model of PAR1-stimulated platelet signal transduction that included a minimal set of major
players in the calcium signaling network. The model comprised three intracellular compartments: cytosol,
dense tubular system (DTS) and mitochondria and extracellular space. Computer simulations showed that
the stable resting state of platelets is maintained via a balance between calcium pumps and leaks through
the DTS and plasma membranes. Stimulation of PAR1 induced oscillations in the cytosolic calcium
concentrations, in good agreement with experimental observations. Further increase in the agonist level
activated the mitochondrial uniporter leading to calcium uptake by mitochondria, which caused the
collapse of mitochondrial membrane potential in a fraction of platelets leading to the PS exposure. The
formation of this subpopulation was shown to be a stochastic process determined by the small number of
activated PAR1 receptors and by heterogeneity in the number of ion pumps. These results demonstrate
how a gradual increase of the activation degree can be converted into a stepped response hierarchy
ultimately leading to formation of two distinct subpopulations from an initially homogeneous population.