The biology of the glucocorticoid receptor: new signaling mechanisms in health and disease

Abstract

Glucocorticoids are primary stress hormones necessary for life that regulate numerous physiologic processes in an effort to maintain homeostasis. Synthetic derivatives of these hormones have been mainstays in the clinic for treating inflammatory diseases, autoimmune disorders, and hematologic cancers. The physiologic and pharmacologic actions of glucocorticoids are mediated by the glucocorticoid receptor (GR), a member of the nuclear receptor superfamily of ligand-dependent transcription factors. Ligand-occupied GR induces or represses the transcription of thousands of genes through direct binding to DNA response elements, physically associating with other transcription factors, or both. The traditional view that glucocorticoids act through a single GR protein has changed dramatically with the discovery of a large cohort of receptor isoforms with unique expression, gene-regulatory, and functional profiles. These GR subtypes are derived from a single gene by means of alternative splicing and alternative translation initiation mechanisms. Posttranslational modification of these GR isoforms further expands the diversity of glucocorticoid responses. Here we discuss the origin and molecular properties of the GR isoforms and their contribution to the specificity and sensitivity of glucocorticoid signaling in healthy and diseased tissues.

Keywords: ACTH; AF; AP1; Activation function; Activator protein 1; Adrenocorticotropic hormone; CBG; Corticosteroid-binding globulin; DBD; DNA-binding domain; G protein–coupled receptor; GPCR; GR; GRE; Glucocorticoid receptor; Glucocorticoid-responsive element; LBD; Ligand-binding domain; MAPK; Mitogen-activated protein kinase; N-terminal transactivation domain; NF-κB; NTD; Negative glucocorticoid-responsive element; Nuclear factor κB; SEGRA; Selective glucocorticoid receptor agonist; glucocorticoid; glucocorticoid signaling; isoforms; nGRE; β(2)-Adrenergic receptor; β2AR.

Published by Mosby, Inc.

Figures

Figure 1

Regulation of glucocorticoid hormone secretion by the hypothalamic-pituitary-adrenal (HPA) axis.

Figure 2

GR domain structure and sites of post-translational modification. Shown are the domains of GR and regions of the receptor involved in transactivation (AF1 and AF2), dimerization, nuclear localization, and hsp90 binding. Also depicted are the amino acid residues modified by phosphorylation (P), sumoylation (S), ubiquitination (U), and acetylation (A). Numbers are for human GR.

Figure 3

GR signaling pathways. Glucocorticoid-activated GR regulates gene expression in 3 primary ways: binding directly to DNA (A), tethering itself to other DNA-bound transcription factors (B), or binding directly to DNA and interacting with neighboring DNA-bound transcription factors (C). GR can also signal in a non-genomic manner through alterations in the activity of various kinases.

Figure 4

GR splice variants. The GR primary transcript is composed of 9 exons. Exon 2 encodes the NTD, exons 3-4 encode the DBD, and exons 5-9 encode the hinge region (H) and LBD. GRα results from splicing exon 8 to the beginning of exon 9. GRβ, GRγ, GR-A, and GR-P are generated by the depicted alternative splicing events.

Figure 5

GR translational isoforms. Translation initiation from 8 different AUG start codons in the single GRα mRNA (location of the AUG start codons indicated by an asterisk) produces 8 receptor isoforms with progressively shorter amino NTDs. The numbers for the initiator methionines and AF1 region (amino acids 77-262) are for the human GRα protein.