Key result
Dynamical modelling of the platelet cAMP pathway revealed that the EP3 receptor exhibits greater signalling strength than the P2Y12 receptor, with implications for antithrombotic treatment.
This computational model reveals the individual quantitative contributions of prostaglandin receptors in platelets, highlighting the strong inhibitory signaling of EP3 with potential implications for antithrombotic therapy.
EP3 may exceed P2Y12 in platelet cAMP inhibition; hypothesis-generating for antithrombotic targets pending human data.
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.
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Mischnik et al. (2013) studied Platelet function. Dynamical modelling of the platelet cAMP pathway was evaluated on Quantitative role of each receptor in elevating or decreasing pathway activity. Dynamical modelling of the platelet cAMP pathway revealed that the EP3 receptor exhibits greater signalling strength than the P2Y12 receptor, with implications for antithrombotic treatment.
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