The Cellular Mechanism of Orcadian Rhythms–A View on Evidence, Hypotheses and Problems

Abstract

A stable period length is a characteristic property of circadian oscillations. The question about whether higher frequency oscillators (0.5-8 hr) contribute to or establish the stable circadian periodicity cannot be answered at present. A sequential coupling of quantal subcycles appears possible on the basis of known "ultradian" oscillations. There is, however, no supporting evidence for such a concept. Phase response curves of the circadian clock derived from various perturbing pulses allow qualitative conclusions concerning the perturbed clock process. Deductions from computer simulations also allow conclusions about the phase of this oscillatory process. The distinction between processes (a) essential to the clock mechanism, (b) maintaining and controlling the clock (inputs) and (c) depending on the clock (outputs) on the basis of "oscillatory" and "change of psi or tau after perturbation" seems to be useful but not stringent. Protein synthesis may be an essential or input process. Oscillatory changes of this process may be due to periodic translational control or RNA-supply. Circadian changes in protein concentration and/or activity may depend on periodic synthesis, proteolysis, covalent modifications or aggregations. Specific essential proteins have not been identified conclusively. The large overlap between the group of agents and treatments that phase shift the clock and the group that induces stress proteins suggest that the latter may play a role in the controlling (input) or essential domain. The role of membranes in the clock mechanism is not clear: concepts assuming an essential function are based on circumstantial evidence. The membrane potential as well as Ca2+ may be involved in either input or essential function. Ca(2+)-calmodulin may also be important as concluded from inhibitor experiments. It is tempting to assume that a calmodulin-dependent kinase is part of a periodic protein phosphorylation process, yet it is not clear whether the periodic protein phosphorylation that has been observed is essential or is just another output process.

Ultradian Rhythm of Activity in Japanese Quail Groups under Semi-Natural Conditions during Ontogeny: Functional Aspects and Relation to Circadian Rhythm

“…A link between the clarity of circadian and ultradian rhythms has already been demonstrated in the golden hamster; the ultradian periodicity of animals with stronger circadian rhythmicities tended to be clearer (Refinetti, 1994). All authors, reporting similar relationships, discussed the possibility that circadian rhythms may in some way be composed of ultradian sub-cycles by a simple counting mechanism (Kippert, 1992); an alternative explanation was that circadian rhythms might be the result of interactions between higher frequency oscillations (Rensing & Hardeland, 1990). However, possible structural relationships between different levels of rhythms have, until now, been studied mainly from the viewpoint of period and using reduction models, rather than from the viewpoint of the clarity of rhythms as in the investigation presented here.…”

Tansley Review No. 37 Circadian rhythms: their origin and control

“…Biochemical and molecular biological studies are beginning to probe the mechanisms that generate circadian rhythms, although the problem of distinguishing reactions that are actually involved in the generation of the oscillation, as opposed to those which are controlled by it, must not be underestimated. This problem has been well reviewed recently by Rensing & Hardeland (1990).…”

Differential Effects of Light and Heat on the Drosophila Circadian Clock Proteins PER and TIM

“…For example, thermally denatured proteins are prime targets for proteolysis by the ubiquitin-proteasome system (reviewed in references 19 and 22). Indeed, a possible link between the heat or stress response and the regulation of circadian timing systems has been suggested previously (38,39). This suggestion was based on several lines of evidence demonstrating that numerous agents that elicit the heat or stress response also perturb the phases of a variety of circadian rhythms.…”