Identification of the key parameters in a mathematical model of PAR1-mediated signaling in endothelial cells

TL;DR

This study performs sensitivity analyses on a PAR1-mediated signaling model in endothelial cells, identifying key parameters that influence receptor activation and signaling outcomes, thus assessing model robustness and biological relevance.

Contribution

It applies local and global sensitivity methods to a previously developed model, highlighting the most influential parameters and demonstrating the model's robustness.

Findings

Binding rate of PAR1 to Galpha_12/13 is crucial for RhoGTP response

Deactivation rate of PAR1 significantly impacts signaling dynamics

Model is robust across parameter variations

Abstract

Biophysical models are often populated by a large number of input parameters that are difficult to predict or measure experimentally. The validity and robustness of a given model can be evaluated by a sensitivity test to its input parameters. In this study, we performed local (based on a Taylor-like method) and global sensitivity (based on Monte Carlo filtering techniques) analyses of a previously derived PAR1-mediated activation model of endothelial cells. This activation model previously demonstrated that peptide-activated PAR1 has a different receptor/G-protein binding affinity that favors Galpha_q activation over Galpha_12/13 by approximately 800-fold. Interestingly, the present study shows that the parameter regulating the binding rate of activated PAR1 to Galpha_12/13 is indeed important to obtain the expected RhoGTP response. Moreover, we show that the parameters representing the rate of PAR1 deactivation and the rate of PAR1 binding to G_q, are the most important parameters in the system. Finally, we illustrate that the kinetic model considered in this study is robust and we provide complementary insights into the biological meaning and importance of its kinetic parameters.