Pulsatile signaling of bistable switches reveal the distinct nature of pulse processing by mutual activation and mutual inhibition loop

Abstract

Cells often encounter various external and internal signals in a non-sustained pulsatile manner with varying amplitude, duration and residual value. However, the effect of signal pulse on the regulatory networks is poorly understood. In order gain a quantitative understating of pulse processing by bistable switches, we investigated pulse induced population inversion kinetics in bistable switches generated either by mutual activation or by mutual inhibition motifs. We show that a transient intense pulse or a prolonged weak pulse both can induce population inversion, however by distinct mechanisms. An intense pulse facilitates the population inversion by reducing the inversion time, while a weak prolonged pulse allows more late responders to flip their steady state causing increased average transition time. Although the inversion is controlled by the pulse amplitude and duration, however the fate of the inverted state is dictated by the residual signal that determines the mean residence at the flipped state. Therefore, population inversion and its maintenance require a proper tuning of all three signal parameters. Bistable system of mutual activation motif is more prone to make a transient response to the pulse however it is less susceptible to flip its steady state. While the bistability of mutual inhibition motif does not make a transient response yet it is more prone to switch its steady state. By comparing the pulse parameters and statistical properties of associated times scales, we conclude that a bistable switch originating from mutual activation loop is less susceptible to spurious signals as compared to the mutual inhibition loop.