Figure 7

Effects of the modulation of the negative feedback on Pde1 (reaction constant c ₂₆ ). The figure shows the simulated dynamics of cAMP (top left), Ras2-GTP (top right), phosphorylated Ira2 (bottom left) and phosphorylated Pde1 (bottom right) resulting from a PSA-1D on the value of the reaction constant that modulates the phosphorylation of Pde1 by means of active PKA. The varied parameter is constant c₂₆ (see Table 1), within the interval [1.0×10⁻⁹, 1.0×10⁻³], being 1.0×10⁻⁶ the reference value (represented with the black thick line). For values of the constant lower than the reference value, stable oscillations still occur. On the contrary, by increasing the value of the reaction constant, that is, if we simulate a marked promotion of the activity of Pde1, after an initial transient increase the amount of cAMP gets almost completely degraded and no oscillations occur anymore (cAMP reaches a noisy steady state around 5,000 molecules, top left). Under the same condition, the amount of Ras2-GTP tends to a high steady state level (around 10,000 molecules, top right), which would intuitively induce a promotion of the cyclase activity and thus an expectable increase in the cAMP amount, which is instead counterbalanced by two concurrent processes: (i) the reduced activity of Ira2 proteins, whereby only a few copies of phosphorylated Ira2 are present inside the system (around 5 molecules, bottom left), and (ii) the strong phosphodiesterase activity taking place in this condition, that is also confirmed by the high level of phosphorylated Pde1 (around 1,200 molecules, bottom right).