Corticosteroids: Mechanisms of Action in Health and Disease

Abstract

Glucocorticoids are primary stress hormones that regulate a variety of physiologic processes and are essential for life. The actions of glucocorticoids are predominantly mediated through the classic glucocorticoid receptor (GR). GRs are expressed throughout the body, but there is considerable heterogeneity in glucocorticoid sensitivity and biologic responses across tissues. The conventional belief that glucocorticoids act through a single GR protein has changed dramatically with the discovery of a diverse collection of receptor isoforms. This article provides an overview of the molecular mechanisms that regulate glucocorticoid actions, highlights the dynamic nature of hormone signaling, and discusses the molecular properties of the GR isoforms.

Keywords: Glucocorticoid; Glucocorticoid receptor; Glucocorticoid signaling; Hypothalamic-pituitary-adrenal axis; Isoforms; Phosphorylation; Polymorphism.

FIG 1

A. Regulation of glucocorticoid secretion by the hypothalamic-pituitary-adrenal (HPA) axis. Stress induces the release of CRF from the hypothalamus, which is transported to the anterior pituitary, where it triggers the release of ACTH into the blood stream. ACTH stimulates the adrenal cortex to synthesize and release the glucocorticoids (cortisol in humans or corticosterone in rodents). Subsequently, the glucocorticoids act on the hypothalamus and pituitary to dampen excess activation of the HPA axis (“negative feedback system”). CRH, Corticotrophin-releasing hormone, ACTH, Adrenocorticotropic hormone. B. Domain structure of hGR-α. GR contains three major functional regions, the N-terminal transactivation domain (NTD), the central DBD and the C-terminal LBD. The region located between the DBD and LBD is known as the hinge region (H). Regions involved in transcriptional activation (AF1 and AF2), dimerization, nuclear localization and chaperone hsp90 binding are indicated. Adapted from Ramamoorthy S, Cidlowski JA (2013) Exploring the molecular mechanisms of glucocorticoid receptor action from sensitivity to resistance. Endocr Dev 24:41–56. doi: 10.1159/000342502; with permission.

FIG 1

A. Regulation of glucocorticoid secretion by the hypothalamic-pituitary-adrenal (HPA) axis. Stress induces the release of CRF from the hypothalamus, which is transported to the anterior pituitary, where it triggers the release of ACTH into the blood stream. ACTH stimulates the adrenal cortex to synthesize and release the glucocorticoids (cortisol in humans or corticosterone in rodents). Subsequently, the glucocorticoids act on the hypothalamus and pituitary to dampen excess activation of the HPA axis (“negative feedback system”). CRH, Corticotrophin-releasing hormone, ACTH, Adrenocorticotropic hormone. B. Domain structure of hGR-α. GR contains three major functional regions, the N-terminal transactivation domain (NTD), the central DBD and the C-terminal LBD. The region located between the DBD and LBD is known as the hinge region (H). Regions involved in transcriptional activation (AF1 and AF2), dimerization, nuclear localization and chaperone hsp90 binding are indicated. Adapted from Ramamoorthy S, Cidlowski JA (2013) Exploring the molecular mechanisms of glucocorticoid receptor action from sensitivity to resistance. Endocr Dev 24:41–56. doi: 10.1159/000342502; with permission.

FIG 2. Genomic action of GR

Upon binding glucocorticoids, cytoplasmic GR undergoes a conformation change (activation), becomes hyper-phosphorylated (P), dissociates from multi-protein complex, and translocates into the nucleus, where it regulates gene expression. GR activates or represses transcription of target genes by direct GRE binding, by tethering itself to other transcription factors apart from DNA binding, or in a composite manner by both direct GRE binding and interactions with transcription factors bound to neighboring sites. NPC = Nuclear pore complex; BTM = basal transcription machinery; TBP = TATA-binding protein; nGRE = negative GRE; RE = response element. Adated modified from

FIG 3

A. Alternative splicing and translation initiation of hGR primary transcript. The hGR primary transcript is composed of 9 exons, with exon 2 encoding most of the N- terminal domain (NTD), exons 3 and 4 encoding the DBD, and exons 5–9 encoding the hinge region (H) and LBD. GR splice variant isoform: The classic GRα protein results from splicing of exon 8 to the beginning of exon 9. GRβ is produced from an alternative splice acceptor site that links the end of exon 8 to downstream sequences in exon 9, encoding a variant with a unique 15 amino acid at C terminus (positions 728–742). GRγ is generated from an alternative splice donor site in the intronic sequence separating exons 3 and 4, resulting in a protein with an arginine insertion (Arg-452) between the two zinc fingers of the DBD. GR-A is produced from alternative splicing that joins exon 4 to exon 8, deleting the proximal 185 amino acids of the LBD (Ala-490-Ser-674) encoded by exons 5–7. GR-P is formed by a failure to splice exon 7 to exon 8. The retained intronic sequence introduces a stop codon, resulting in a truncated receptor mutant missing the distal half of the LBD. GRα translational isoforms: Domain organization of the GRα translational isoforms. Initiation of translation from eight different AUG start codons in a single GR-mRNA generates receptor isoforms with progressively shorter N-terminal domains. This generates the GRα translational isoforms GRα-A, B, C1, C2, C3, D1, D2 and D3. B. Domain structure and posttranslational modifications of hGR-α. Sites of posttranslational modifications like phosphorylation (P), sumoylation (S), ubiquitination (U) and acetylation (A) are indicated. C. hGR polymorphisms. Arrows indicate polymorphisms that result in amino acid changes and A3669G which leads to GR stability. Adopted and modified from