Kasper Astrup Eriksen
Robustness in filter designs. Implications for receptor internalization.

A common signaling processing step is to filter the signal. In biology there are amble examples where the physiological response depends on the duration of the signal. A simple way to obtain such a filter effect is with the help of a delay circuitry. There are at least two principally different ways to obtain the delay: activate an activator or by inhibiting an inhibitor. Previously a model based on the first option has been proposed in connection with the early signaling events in the mammalian response to Insulin. Here we consider the equivalent model based on the second option. We demonstrate that although the two options are able to obtain the exact same filter characteristics, the robustness to external perturbations are very different. In particular is the inhibitory version insensitive to variations in the concentration of the inhibitor, while the cross-over frequency in the activator case depends linearly on the concentration of the activator. The cross-over frequency determines the timescale that separates the two different physiological responses metabolic versus mitogenic. This kind of robustness is thus very important in the design of drugs that interfere with the signaling pathway (Insulin sensitizers). However one can not generally conclude that the inhibitor version is the most robust as in transcriptional feed forward loops the activate an activator version is the most robust. Furthermore we point out that receptor internalization effectively implement a robust delay circuitry, and this raises the intriguing possibility that receptor internalization quite generally is involved in filtering of the external signal.

LU TP 04-14