Oscillatory signaling processes: the how, the why and the where

Abstract

Oscillatory processes in biological signal transduction have come under progressively increasing scrutiny in terms of their functional significance and mechanisms of emergence and regulation. Since oscillatory processes can be a by-product of rapid adaptation and can also easily emerge if the feedback underlying adaptive processes is inadvertently artificially enhanced, one needs to exercise caution in both claiming the existence of in vivo oscillations and seeking to assign to them a specific functional significance. Nevertheless, oscillations can be a powerful means of encoding and transferring information both in time and in space, thus possessing important potential advantages for evolutionary selection and stabilization. Thus periodicity in the cell responses to diverse persistent external stimuli might become a more recognized and even expected feature of signaling processes.

Figure 1

(A) Schematic demonstrating that increased negative feedback, whether naturally or artificially induced, increases the propensity of oscillations. Plots show the response to a step input of a linear proportional-integral feedback system, thought to be commonly present in signaling pathways. In each case, the response eventually settles on the target steady state shown by the red line. As the strength of negative feedback is increased, the steady state is reached more rapidly, but at the cost of overshoot and oscillations. (B) Schematic showing how synchronous and asynchronous oscillations, though leading to similar average responses, may be distinguished experimentally. The response dynamics of individual cells are shown by the light red and light gray traces, leading to the same population-average dynamics as shown in red and black. However, when the population is sampled at a single time point(s) during the steady phase of the response (indicated by the green rectangle), the variance of the asynchronous population tends to be much larger than that of a synchronous population, enabling these possibilities to be distinguished by single-cell resolution experimental techniques not relying on live cell probes.

Figure 2

Extraction of information from an oscillatory input. An example oscillatory input is shown at the top. (Lower left) When the input impinges on a response element with slow kinetics, only the amplitude of the input is extracted. This effect is revealed by the varying the amplitude and frequency of the input. The response amplitude differs when the input amplitude is varied (compare high vs. low amp.), but not when the input frequency is varied (compare high vs. low freq.); (Lower right) When the input impinges on a response element with rapid kinetics, especially with thresholding capability, the frequency is primarily extracted. The resulting response amplitude is mostly held fixed, but the response tends to oscillate at a frequency similar to that of the input.