The Glucocorticoid Receptor: Isoforms, Functions, and Contribution to Glucocorticoid Sensitivity

Abstract

Glucocorticoids exert pleiotropic effects on all tissues to regulate cellular and metabolic homeostasis. Synthetic forms are used therapeutically in a wide range of conditions for their anti-inflammatory benefits, at the cost of dose and duration-dependent side effects. Significant variability occurs between tissues, disease states, and individuals with regard to both the beneficial and deleterious effects. The glucocorticoid receptor (GR) is the site of action for these hormones and a vast body of work has been conducted understanding its function. Traditionally, it was thought that the anti-inflammatory benefits of glucocorticoids were mediated by transrepression of pro-inflammatory transcription factors, while the adverse metabolic effects resulted from direct transactivation. This canonical understanding of the GR function has been brought into question over the past 2 decades with advances in the resolution of scientific techniques, and the discovery of multiple isoforms of the receptor present in most tissues. Here we review the structure and function of the GR, the nature of the receptor isoforms, and the contribution of the receptor to glucocorticoid sensitivity, or resistance in health and disease.

Keywords: glucocorticoid receptor; glucocorticoid receptor isoforms; glucocorticoid sensitivity; glucocorticoids; hypothalamic-pituitary-adrenal axis.

Graphical Abstract

Figure 1.

Hypothalamic-pituitary-adrenal axis. The hypothalamus secretes CRH with a circadian rhythm, which acts on anterior pituitary corticotrope cells, stimulating secretion of ACTH (among other hormones). This induces cortisol secretion from the adrenal gland. Cortisol circulates predominantly bound to CBG and induces pleiotropic effects in almost all tissues. Several external inputs modulate this system and negative feedback loops constrain the secretion at each level, ultimately maintaining normal serum cortisol levels. (+) indicates stimulates; (−) indicates inhibits. Abbreviations: ACTH, adrenocorticotropic hormone; AVP, arginine vasopressin; CBG, corticosteroid-binding globulin; CRH, corticotropin-releasing hormone; GABA, gamma-aminobutyric acid; IL-1β, interleukin 1β; IL-6, interleukin 6; LIF, leukemia inhibitory factor; TNF-α, tumor necrosis factor α. Created with Biorender.com.

Figure 2.

Mechanisms of glucocorticoid receptor (GR) action. GR is maintained in the cytoplasm by an anchoring complex [1] which modifies the conformation of GR to allow high affinity for glucocorticoids [2]. Glucocorticoids cross the membrane where they can be activated/inactivated by 11β-ΗSD isoforms [3]. Binding of active glucocorticoid to GR leads to dissociation of the complex [4]. GR can have a series of nongenomic effects in the cytoplasm (see text for details), or predominantly enters the nucleus. GR binds to open chromatin (determined by pioneering transcription factors) [5] where it can: directly activate or repress transcription at canonical GREs, direction of regulation determined by cofactors, gene, other transcription factors [6]; repress transcription at nGREs [7]; interact with other transcription factors either as a monomer or dimer at shared binding sites to enhance/repress transcription [8, 9], whether this can occur without direct DNA binding (tethering) [8] has been brought into question; or compete for binding sites with other transcription factors [10]. Unliganded GR is bound throughout open chromatin [11] and dissociates in favor of glucocorticoid-bound dimers upon exposure. Created with Biorender.com.

Figure 3.

Splice and translation initiation isoforms of the glucocorticoid receptor. NR3C1 gene is composed of 9 exons, exon 1 contains 11 untranslated promoter variants, while exons 2 to 9 encode the GR, which occurs as a number of splice, and translational initiation isoforms, see text for details. Abbreviations: AF-1, transcriptional activation function 1; DBD, DNA-binding domain; GR, glucocorticoid receptor; H, hinger region; LBD, ligand-binding domain; NTD, N-terminal domain. Created with Biorender.com.