Exploring the molecular mechanisms of glucocorticoid receptor action from sensitivity to resistance

Abstract

Glucocorticoids regulate a variety of physiological processes, and are commonly used to treat disorders of inflammation, autoimmune diseases, and cancer. Glucocorticoid action is predominantly mediated through the classic glucocorticoid receptor (GR), but sensitivity to glucocorticoids varies among individuals, and even within different tissues from the same individual. The molecular basis of this phenomenon can be partially explained through understanding the process of generating bioavailable ligand and the molecular heterogeneity of the GR. The molecular mechanisms that regulate glucocorticoid action highlight the dynamic nature of hormone signaling and provide novel insights into genomic glucocorticoid actions and glucocorticoid sensitivity. Although glucocorticoids are highly effective for therapeutic purposes, long-term and/or high-dose glucocorticoid administration often leads to reduced glucocorticoid sensitivity or resistance. Here, we summarize our current understanding of the mechanisms that modulate glucocorticoid sensitivity and resistance with a focus on GR-mediated signaling.

Fig. 1

Genomic location and organization of the human GR. a Alternative splicing and translation initiation of hGR primary transcript. The hGR gene (NR3C1) is one locus on chromosome 5q31–32. 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 by 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. 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. 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.

Fig. 2

Genomic action of GR. Upon binding glucocorticoids, cytoplasmic GR undergoes a conformation change (activation), becomes hyper-phosphorylated (P), dissociates from heterocomplex, 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.