Physiology and molecular mechanism of glucocorticoid action

Endogenous glucocorticoids (GCs) are secreted into the systemic circulation from the adrenal cortex. This release is under the control of the circadian clock and can be enhanced at any time in response to a stressor. The levels of circulating GC are regulated systemically by the hypothalamo-pituitary-adrenal axis and locally by access to target cells and pre-receptor metabolism by 11 beta-hydroxysteroids dehydrogenase enzymes. GCs mediate their genomic action by binding to two different ligand-inducible transcription factors: high-affinity mineralocorticoid receptor (MR) and 10-fold lower affinity glucocorticoid receptor (GR). Responses to GCs vary among individuals, cells, and tissues. The diversity and specificity in the steroid hormone's response in the cell is controlled at different levels, including receptor translocation, interaction with specific transcription factors and coregulators, and the regulation of receptor protein levels by microRNA. Moreover, multiple GR isoforms are generated from one single GR gene by alternative splicing and alternative translation initiation. These isoforms all have unique tissue distribution patterns and transcriptional regulatory profiles. Furthermore, each is subjected to various post-translational modifications that affect receptor function. Deciphering the molecular mechanisms of GC action is further complicated by the realization that GCs can induce rapid, non-genomic effects within the cytoplasm. A tight regulation of GC secretion and their cell-specific activity is essential for proper organism function. This is particularly seen under conditions of GC deficiency or excess, as in Addison's disease and Cushing's syndrome, respectively.