Modeling platelet P2Y(1/12) pathway to integrin activation.

Through experimental studies, many details of the pathway of integrin α(IIb)β(3) activation by ADP during the platelet aggregation process have been mapped out. ADP binds to two separate G protein-coupled receptors on platelet surfaces, leading to alterations in the regulation of the small GTPase RAP1. We seek to 1) gain insights into the relative contributions of both pathways to RAP1-mediated integrin activation and to 2) predict wild-type and mutated cell behavior in response to a continuous range of external agonist concentrations. To this end, we develop a dynamical systems model detailing the action of each protein in the two pathways up to the regulation of RAP1. We perform a parameter estimation using flow-cytometry data to determine a number of unknown rate constants. We then validate with already-published data; in particular, the model confirmed the effect of impaired P2Y(1) receptor desensitization or reduced RASA3 expression on RAP1 activation. We then predict the effect of protein expression levels on integrin activation and show that components of the P2Y(12) pathway are critical to the regulation of integrin. This model aids in our understanding of interindividual variability in platelet response to ADP and therapeutic P2Y(12) inhibition. It also provides a more detailed view of platelet activation in the ongoing mathematical study of platelet aggregation.