title: Dynamical modelling of prostaglandin signalling in platelets reveals individual receptor contributions and feedback properties.
abstract: Prostaglandins are the key-players in diminishing platelet function. They exert their effects via a variety of surface receptors that are linked to the cAMP/PKA-signalling cascade. However, less is known about the quantitative impact of the individual receptors on the underlying pathway. We present here a comprehensive ordinary differential equation-based model of the platelet cAMP pathway, including the four prostaglandin receptors IP, DP1, EP3 and EP4, the ADP receptor P2Y12, a detailed PKA-module as well as downstream-targets. Parameter estimation along with a comprehensive combination of time-course and dose-response measurements revealed the individual quantitative role of each receptor in elevating or decreasing pathway activity. A comparison of the two inhibiting receptors EP3 and P2Y12 exhibited a greater signalling strength of the EP3 receptor with implications for antithrombotic treatment. Furthermore, analysis of different model topologies revealed a direct influence of PKA on adenylate cyclase, reducing its maximum catalytic speed. Finally, we show here for the first time the dynamic behaviour of VASP-phosphorylation, which is commonly used as a marker for platelet-inhibition. We validate our model by comparing it to further experimental data.
authors.affiliation: Institute of physics, Hermann-herder-strasse 3a, 79104 Freiburg, Germany. marcel.mischnik@fdm.uni-freiburg.de jeti@fdm.uni-freiburg.de.
authors.forename: Marcel
authors.initials: M
authors.lastname: Mischnik
authors.forename: Katharina
authors.initials: K
authors.lastname: Hubertus
authors.forename: Jörg
authors.initials: J
authors.lastname: Geiger
authors.forename: Thomas
authors.initials: T
authors.lastname: Dandekar
authors.forename: Jens
authors.initials: J
authors.lastname: Timmer
mesh_terms: D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008954:Models, Biological; D011453:Prostaglandins / Q000378:metabolism* / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000378:metabolism*; D015203:Reproducibility of Results; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D011453:Prostaglandins; D011956:Receptors, Cell Surface; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases