Contribution of membrane-associated oscillators to biological timing at different timescales

Abstract

Environmental rhythms have selected for endogenous clocks that predict regular environmental changes like the daily light-dark cycle. Endogenous clocks are based on positive feedforward and negative feedback loops that generate rhythms even under constant conditions. Autonomous coupling of oscillators is the basis of self-organized timing that determines the repetitive sequence of events of physiology and behavior while mechanisms of homeostatic plasticity serve to maintain and stabilize physiological and behavioral homeostasis. The best studied biological clocks are circadian clock neurons of insects and mammals. Their molecular clockwork in the nucleus consists of transcriptional and translational feedback loops (TTFLs). This clockwork generates ~24 h rhythms in clock gene expression entrained to the light-dark cycle. It is assumed to drive all circadian oscillations in clock neurons such as rhythms in membrane potential, second messenger levels, and neurotransmitter release, thereby controlling circadian rhythms in physiology and behavior. It is not discerned yet whether the membrane-bound rhythms are mere outputs of the TTFL clockwork or whether instead they are driven by an autonomous posttranscriptional feedback loop (PTFL) clockwork in the plasma membrane. Furthermore, next to circadian rhythms the plasma membrane generates rhythms on much faster or slower timescales. It is not understood whether and how these multiscale rhythms are linked. Based on our work in peripheral and central insect multiscale clock neurons, we hypothesize that the excitable plasma membrane constitutes an adaptive endogenous PTFL clockwork at multiple timescales. Multiscale membrane-associated rhythms are suggested to be coupled to, but not driven by, the TTFL clockwork in the nucleus. Furthermore, we suggest that negative feedback loops via protein kinases and phosphatases on the one hand provide for mechanisms of homeostatic plasticity that maintain physiological homeostasis, keeping the period of cellular clocks stable. On the other hand, they also serve as coupling factors and links between cellular oscillators and clocks at multiple time scales controlling the temporal sequence and/or synchronization of physiological and behavioral processes. Our novel hypothesis is up for challenge in future experiments in different species.