Figure 3

(A) Schematic model of PKA and MAPK signaling pathways. 5-HT regulates the PKA and MAPK cascades via multiple pathways. Red, blue, green dashed lines represent newly added pathways. Blue denotes the ERK/RSK/p38 MAPK feedback loop, green denotes the NT-dependent pathways. Each number represents a signaling pathway (not equation numbers). Arrowheads indicate activation, circular ends indicate repression. (B–D) Simulated dynamics of kinases after one pulse of 5-HT. (B) Control simulations (black solid curves). Empirical data points (red circles) are from this study (PKAc and pRSK) and from Zhang et al.¹¹ (pERK and p-p38 MAPK). Numbers “1”, “2” in B2 represent two waves of increases in pRSK. The “1” in B3 represents the transient decrease of p-p38 MAPK. The “2” in B3 represents the delayed increase of p-p38 MAPK. (C) Dynamics of kinases with a simulated inhibition of downstream effects of PKA, ended 45 min post-onset of 5-HT. The slow increases of pERK (C1), pRSK (C2) and p-p38 MAPK (C3) were blocked. Blue curves are simulations with inhibitors, black dashed curves are control simulation. This inhibition suppressed the delayed activation of pERK as observed empirically in Fig. 2A, and pRSK and p-p38 MAPK subsequently decreased (black arrows). Control simulation curves added in this and following panels and figures, are for the convenience of comparison with the curves in the presence of inhibitors. Dashed curves are used to make overlapped curves visible. (D) Dynamics of kinases with simulated inhibition of RSK ending 60 min post-onset of 5-HT. The delayed increase of p-p38 MAPK (D3) was blocked by RSK inhibition, but pERK (D1) and pRSK (D2) remained elevated for 60 min. Green curves are simulations with inhibitors, black dashed curves are control simulation. This RSK inhibition suppressed the delayed activation of p-p38 MAPK (D3, black arrow) as observed empirically (Fig. 2F). Reduced p-p38 MAPK activity disinhibited MEK. The disinhibition led to a sustained increase of pERK and pRSK at 1 h (D1-2, red arrows).