The ultradian rhythm of the glucocorticoid secretion and the time course of target gene regulation

Abstract

Glucocorticoid hormones (cortisol in humans and corticosterone in rodents) are secreted in discrete pulses during the day with a periodicity of approximately 1 h (ultradian rhythm), and this pattern is maintained in plasma and extracellular fluid. However, the vast majority of studies on gene regulation by glucocorticoids assess gene responses disregarding the ultradian rhythm. These experiments usually involve long-term stimulation with synthetic hormones (dexamethasone and triamcinolone), whose complexes with the glucocorticoid receptor (GR) are more stable, by an order of magnitude, than the complexes of natural hormones. This review summarizes the current scarce information obtained in experiments mimicking the ultradian mode of natural hormone secretion in the cultured cells and adrenalectomized animals. The results of these experiments clearly demonstrate that ultradian stimulation with natural hormones induces rapid GR association–dissociation with glucocorticoid response elements (GREs) and leads to cyclic GR-mediated transcriptional regulation (gene pulsing) at the level of nascent RNA in cell cultures and in various organs of the experimental animals. In contrast, no pulsing occurs in the experiments with the cyclic application of the synthetic glucocorticoid dexamethasone or with the constant presence of natural or synthetic glucocorticoids. In addition, the levels of mature mRNAs of the genes under study are much lower in the case of cyclic treatment with natural glucocorticoids than with the cyclic application of dexamethasone or the constant presence of the natural hormones. The scientists hypothesize that gene pulsing is of great significance for the formation of the proper response to glucocorticoid hormones and that constant hormonal stimulation may distort the transcriptomes of the target cells and thereby cause adverse physiological consequences.