Figure 5

Sensitivity of AP-1 to perturbations in network parameters. (A) Upper Panel: Simulated response of Total AP-1 DNA binding activity as well as its constituent dimers to Ang II stimulus. Note that these profiles are repeated from Figure 3 to facilitate direct interpretation of the AP-1 activity time series in the context of sensitivity analysis. The composition of Total AP-1 activity has been highlighted by the rectangles at three time points of interest. Lower Panel: Dynamic profiles of total-effects sensitivity indices of Total AP-1 for the top seven most sensitive model parameters (1: ppc-Fos:ppc-Jun dephosphorylation, 2: FRK dynamics, 3: c-Jun pre-mRNA synthesis, 4: ppc-Jun:ppc-Jun dephosphorylation, 5: c-Jun translation, 6: pc-Jun phosphorylation, 7: JNK dynamics). (B-D) Contribution of first-order effects (white inset) to the AP-1 activity total effects sensitivities calculated at (B) 20, (C) 40, and (D) 60 minutes after Ang II treatment. Gray and black bars correspond to Fos:Jun and Jun:Jun arms of the network, respectively. Parameter index matches the ordering in (A). Bar coloring corresponds to mechanisms relating to activation of ppc-Fos:ppc-Jun (light grey) or ppc-Jun:ppc-Jun (black) as shown in Figure 2. (E-G) DyNSIM representation of global sensitivity analysis results in network context at (E) 20, (F) 40, and (G) 60 minutes after Ang II treatment. Total AP-1 activity is indicated in the purple rectangle, while line thickness indicates sensitivity of Total AP-1 activity to the reaction mechanisms index of (A). A detailed description of network nodes is presented in Figure 2. Sensitivity analysis of Total AP-1 was performed during 15-60 minutes of Ang II treatment when the variance of simulated Total AP-1 activity levels was greater than 1% of the maximum variance to avoid numerical oddities affecting the sensitivity calculations.