PMC

Role of glucocorticoids in health and disease. This schematic represents the roles of glucocorticoids in major organ systems of the human body (black text), beneficial roles of glucocorticoids in the clinic (green text) and adverse outcomes in patients with elevated glucocorticoid levels (blue text).

Glucocorticoid Receptor Signaling. Upon binding glucocorticoids, cytoplasmic GR undergoes a confirmational change, becomes hyperphosphorylated (P), dissociates from accessory proteins, and translocates into the nucleus, where it can exert its actions through genomic mechanisms. Activated cytoplasmic GR is also known to exert its actions via non-genomic mechanisms. In the nucleus, GR enhances or represses transcription of target genes by direct binding to simple or negative GREs respectively, by tethering itself to other transcription factors, or in a composite manner by direct binding to GRE and interacting with other transcription factors. One of the mechanisms by which GR suppresses inflammation is by inducing TTP expression, which in turn binds to mRNA of pro-inflammatory gene expression and destabilizes them. GR modulates the gene expression of arrestins 1 & 2 to alter GPCR signaling.

Schematic representation of the regulation of glucocorticoid levels by the hypothalamic pituitary adrenal (HPA) axis. The synthesis and release of glucocorticoids is under the dynamic circadian and ultradian regulation by the periventricular nucleus of the hypothalamus. Corticotropin-releasing hormone (CRH) secreted by the hypothalamus stimulates the release of adrenocorticotropic hormone (ACTH) from the anterior pituitary gland. In turn, ACTH induces the synthesis and secretion of cortisol from the cortex of the adrenal glands into the blood stream. In the blood, majority of the cortisol remains bound to corticosteroid-binding globulins in the blood. The biologically active form of the glucocorticoid is the unbound cortisol that can be converted to the inactive form, cortisone by type 2 11β-hydroxysteroid dehydrogenase. Type 1 11β-hydroxysteroid dehydrogenase converts the cortisone to cortisol. Homeostasis in glucocorticoid levels in maintained by the negative feedback loop suppressing ACTH levels in the anterior pituitary and CRH levels in the hypothalamus.

Genomic location and organization of the human glucocorticoid receptor. The human glucocorticoid receptor is located on chromosome 5q31–32 locus. (A) GR undergoes alternative processing to yield multiple functionally distinct subtypes of GR. GR contains 9 exons with the protein coding region formed by exons 2–9. Exon 1 forms the 5’-untranslated region. Alternative splicing of GR generates hGRα and hGRβ isoforms, which differ in their C-termini. (B) The GRα isoform undergoes alternative translation initiation in exon 2, generating eight additional isoforms of GR with truncated N-termini (GRα-A, GRα-B, GRα-C1, GRα-C2, GRα-C3, GRα-D1, GRα-D2, and GRα-D3). GR β is predicted to also generate eight β isoforms similar to hGRα. (C) GR is a modular protein containing an N-terminal transactivation domain (NTD), a central DNA-binding domain (DBD), a C-terminal ligand-binding domain (LBD), and a flexible “hinge region” separating the DBD and the LBD. The NTD has strong transcriptional activation function (AF1), which allows for the recruitment of coregulators and transcription machinery. Glucocorticoids bind the hydrophobic pocket of the LBD causing the second activation function (AF2), located in the LBD itself, to interact with coregulators. The DBD/hinge region junction and the LBD, each contain a nuclear localization signal that allows translocation to the nucleus. (D) GR undergoes multiple posttranslational modifications including phosphorylation (P), SUMOylation (S), ubiquitination (U) and acetylation (A).