An ultradian oscillation of protein synthesis was detected by synchronization of metabolic activity in rat hepatocyte cultures. This oscillation occurs in dense cultures in fresh medium, but not in sparse ones. Metabolic synchronization of sparse cultures, however, was initiated by conditioned medium or addition of 0.3-0.5 microm of a mixture of bovine brain gangliosides to fresh culture medium along with either 0.06-0.2 microm GM1 or 0.1-0.2 microm GDIa. GTIb and GDIb did not produce oscillations, nor did human liver ganglioside GM3. High expression of GM1 ganglioside determinants in hepatocytes maintained in the conditioned medium purified polyclonal antibodies to GM1 was coupled with protein synthetic oscillatory activity, i.e. metabolic synchronization. Incubation of dense cultures with GM1-antibodies for 24 h decreased the amplitude of these oscillations. In sparse cultures maintained in fresh medium where protein synthesis showed no oscillatory pattern, GM1 expression was low.

This review presents data concerning metabolic rhythms with periods close to one hour (20 to 120 min): their occurrence, biochemical organization, nature, and significance for adaptations and age-related changes of cells and organs. Circahoralian (ultradian) rhythms have been detected for cell mass and size, protein synthesis, enzyme activities, concentration of ATP and hormones, cell respiration, and cytoplasm pH. Rhythms have been observed in bacteria, yeasts, and protozoa, as well as in many cells of metazoans, including mammals, in vivo and in cell cultures. In cell populations, the rhythms are organized by direct cell-cell communication. The biochemical mechanism involves membrane signal factors and cytoplasmic processes resulting in synchronization of individual oscillations to a common rhythm. Phosphorylation of proteins is the key process of coordination of protein synthesis and enzyme activity kinetics. The fractal nature of circahoralian rhythms is discussed as well as the involvement of these rhythms in adaptations of the cells and organs. Senescent decrease in rhythm amplitudes and correspondingly in cell-cell communication has been observed. The possibility of remodeling these changes through the intercellular medium has been predicted and experimentally shown. Perspectives for studies of the organizers and disorganizers of cell-cell communication in the intercellular medium along with appropriate receptors are discussed with special emphasis on aging and pathology. One perspective can be more precise definition of the range of normal biochemical and physiological state with the goal of correction of cellular functions.

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Recent data concerning ultradian (circahoralian) intracellular rhythms are used to assess the biochemical mechanisms of direct cell-cell communication. New results and theoretical considerations suggest a fractal nature of ultradian rhythms and their self-organisation. The fundamental and innate nature of these rhythms relates to their self-similarity at different levels of cell and tissue organisation. They can be detected in cell-free systems as well as in cells and organs in vivo. Such rhythms are a means of finding an optimal state of cell function rather than achieving a state of absolute stability. As a consequence, oscillations, being irregular and numerous by the set of periods, are resilient to functional overload and injury. Recent data on the maintenance of their fractal structure and, especially on the selection of optimal periods are discussed. The positive role of chaotic dynamics is stressed. The ultradian rhythm of protein synthesis in hepatocytes in vitro was used as a marker of direct cell-cell communication. The system demonstrates cell cooperation and synchronisation throughout the cell population, and suggests that the ultradian rhythms are self-organised. These observations also led to the detection of mechanisms of direct cell-cell communication in which extracellular factors have an essential role. Experimental evidence indicated the involvement of gangliosides and/or catecholamines in this large-scale synchronisation of protein synthesis. The response of all, or a major part, of the cell population is important; after the initial trigger effect, a periodic pattern is retained for some time. The influence of Ca2+-dependent protein kinases on protein phosphorylation can be a final step in the phase modulation of rhythms during cell-cell synchronisation. The intercellular medium plays an important role in self-synchronisation of ultradian rhythms between individual cells. Low cooperative activity of hepatocytes of old rats resulted from altered composition of the intercellular medium rather than direct effects of animal and cellular ageing. Similarly, in the whole body, changes in levels of gangliosides and catecholamines in the blood serum, a natural intercellular medium, can be critical events in age-dependent changes of the serum and accordingly cell-cell synchronisation. Hepatocytes of old rats exhibit some of the properties of young cells following an increase in blood serum ganglioside level, as well as, in in vitro conditions, after the addition of gangliosides to the culture medium. Together with data on ultradian functional and metabolic rhythms, all the material reviewed here allows us to propose a mechanism of direct cell-cell cooperation via the medium in which the cells exist, that supplements the nervous and hormonal central regulation of organ functions. Ultradian intracellular rhythms may thus provide a finer framework within which the integrated dynamics of respiration, heart rate, brain activity, and even behavioural patterns, are brought to an optimal functional pattern. I...

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