Clocks on steroids: how glucocorticoid receptors tell cells the time

Glucocorticoid (GC) steroid hormone signalling via the glucocorticoid receptor (GR) underlies most daily physiological rhythms in mammals by synchronising cellular circadian rhythms throughout the body. Impaired circadian synchrony is associated with many non-communicable diseases, such as cardiovascular disease, diabetes and cancer. The functions and daily regulation of systemic GC levels are relatively well understood, yet a clearly defined mechanism for GC/GR-mediated circadian synchronisation is lacking. Historically, mechanistic studies of GR action have focused on its role as a transcription factor, sufficient to explain many, but not all, consequences of GC/GR signalling. Recently, several non-canonical modes of GR action have been described and proposed as a basis for understanding rapid cellular responses to GCs that cannot be explained by relatively slow changes in transcription. Here, we review the current state of knowledge on the cellular mechanism of GR signalling in the context of GR-mediated circadian synchronisation, outline gaps in current understanding and suggest new avenues for investigation.