Review
Molecular dynamics of ultradian glucocorticoid receptor action

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Abstract

In recent years it has become evident that glucocorticoid receptor (GR) action in the nucleus is highly dynamic, characterized by a rapid exchange at the chromatin template. This stochastic mode of GR action couples perfectly with a deterministic pulsatile availability of endogenous ligand in vivo. The endogenous glucocorticoid hormone (cortisol in man and corticosterone in rodent) is secreted from the adrenal gland with an ultradian rhythm made up of pulses at approximately hourly intervals. These two components – the rapidly fluctuating ligand and the rapidly exchanging receptor – appear to have evolved to establish and maintain a system that is exquisitely responsive to the physiological demands of the organism. In this review, we discuss recent and innovative work that questions the idea of steady state, static hormone receptor responses, and replaces them with new concepts of stochastic mechanisms and oscillatory activity essential for optimal function in molecular and cellular systems.

Highlights

► This review focuses on the highly dynamic mode of GR action at the chromatin template. ► Stochastic GR action is discussed in light of the glucocorticoid ultradian rhythm. ► GR slow cycling on chromatin is directed by the pulsatile ligand. ► GR slow cycling directs a novel gene pulsing effect. ► Cyclical activity of cofactors and histone acetylation at a GR regulated gene.

Section snippets

Characterization of the ultradian rhythm

Pulsatile glucocorticoid secretion has been detected in all mammalian species studied so far, from rodent to man (Atkinson et al., 2006, Carnes et al., 1990, Carnes et al., 1992, Cudd et al., 1995, Tapp et al., 1984, Henley et al., 2009, Windle et al., 1998, Hellman et al., 1970, Russell et al., 2010, Loudon et al., 1994, Holaday et al., 1977). This pulsatile secretory profile is characterized by discrete pulses at approximately hourly intervals, with very low nadir levels between each pulse.

Structure/function

Glucocorticoids act via intracellular receptors. The glucocorticoid receptor (GR) is a member of the nuclear receptor superfamily (Mangelsdorf et al., 1995), acting as a latent transcription factor. In the absence of ligand GR is sequestered in the cytoplasm in a large multiprotein complex made up of the chaperone molecules including HSP90 and p23 (Pratt et al., 2004). The lipophilic hormone ligand can readily pass through the plasma membrane of target cells to activate GR. Molecular chaperones

The gene pulsing effect

Does the phenomenon of GR slow cycling at glucocorticoid regulatory sites in the chromatin template have any functional output for target cells? A significant functional output in the form of transcriptional gene pulsing has been elucidated (Stavreva et al., 2009). RNA FISH technology has allowed the direct visualization of newly transcribed RNA from the MMTV promoter in the 3617 cell line (Stavreva et al., 2004). Adding physiological significance, several endogenous genes were also found to be

Physiological and clinical significance

The implications of our experimental data is that ultradian glucocorticoid secretion has evolved to interact with the stochastic regulation of glucocorticoid receptor signalling to achieve a remarkably versatile and sensitive response mechanism that can readily adapt to both long term epigenetic programming, and to short term changes in environmental conditions. The other side to this coin of course is that loss of ultradian rhythmicity should result in dysregulation of normal glucocorticoid

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