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Review
. Sep-Oct 2011;29(5 Suppl 68):S32-41.
Epub 2011 Oct 21.

Glucocorticoid Receptor: Implications for Rheumatic Diseases

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Free PMC article
Review

Glucocorticoid Receptor: Implications for Rheumatic Diseases

T Kino et al. Clin Exp Rheumatol. .
Free PMC article

Abstract

The glucocorticoid receptor (GR), a member of the nuclear receptor superfamily, mediates most of the known biologic effects of glucocorticoids. The human GR gene consists of 9 exons and expresses 2 alternative splicing isoforms, the GRα and GRβ. GRα is the classic receptor that binds to glucocorticoids and mediates most of the known actions of glucocorticoids, while GRβ does not bind to these hormones and exerts a dominant negative effect upon the GRα-induced transcriptional activity. Each of the two GR splice isoforms has 8 translational variants with specific transcriptional activity and tissue distribution. GRα consists of three subdomains, translocates from the cytoplasm into the nucleus upon binding to glucocorticoids, and regulates the transcriptional activity of numerous glucocorticoid-responsive genes either by binding to its cognate DNA sequences or by interacting with other transcription factors. In addition to these genomic actions, the GR also exerts rapid, non-genomic effects, which are possibly mediated by membrane-localised receptors or by translocation into the mitochondria. All these actions of the GR appear to play an important role in the regulation of the immune system. Specifically, the splicing variant GRβ may be involved in the pathogenesis of rheumatic diseases, while the circadian regulation of the GR activity via acetylation by the Clock transcription factor may have therapeutic implications for the preferential timing of glucocorticoid administration in autoimmune inflammatory disorders.

Figures

Figure 1
Figure 1
Genomic and complementary DNA, and protein structures of the human (h) GR, functional distribution of the GRα, and the isoforms produced through alternative splicing. The hGR gene consists of 9 exons. Exon 1 is untranslated region, exon 2 codes for the immunogenic domain (A/B), exon 3 and 4 for the DNA-binding domain (C), and exons 5–9 for the hinge region (D) and the ligand-binding domain (E). The GR gene contains two terminal exon 9s (exon 9α and 9β) alternatively spliced to produce the classic GRα and the non-ligand-binding GRβ. C-terminal gray colored domains in GRα and GRβ show their specific portions. Locations of several functional domains are also indicated. (modified from [97]) AF-1 and -2: activation function 1 and 2; DBD; DNA-binding domain; HD: hinge region; LBD: Ligand-binding domain; NTD: N-terminal domain, NL1 and 2: Nuclear translocation signal -1 and -2.
Figure 2
Figure 2
GR isoforms produced through alternative splicing or use of different translational initiation sites. Using at least 8 different translation initiation sites located in N-terminal domain, the GR gene produces multiple GRα isoforms termed A through D (A, B, C1–C3 and D1–D3) with distinct transcriptional activities on glucocorticoid-responsive genes. Since GRα and GRβ share a common mRNA domain that contains the same translation initiation sites, the GRβ variant mRNA appears to be also translated through the same initiation sites and to produce 8 β isoforms with different lengths N-terminal domain (modified from [21, 98]) AF-1 and -2: activation function 1 and 2; DBD; DNA-binding domain; HD: hinge region; LBD: Ligand-binding domain.
Figure 3
Figure 3
Intracellular circulation of the GR. Circulation of GRα between the cytoplasm and the nucleus, and its transactivation or transrepressive activities (from [67]). GR: glucocorticoid receptor; GRE: glucocorticoid responsive element; TFREs: transcription factor responsive elements; HSPs: heat shock proteins; TF: transcription factor
Figure 4
Figure 4
Circadian fluctuation of serum cortisol and target tissue sensitivity to glucocorticoids, as well as levels of IL-6 in patients with rheumatoid arthritis. Schematic diurnal changes of serum levels of cortisol (A) and target tissue glucocorticoid sensitivity (B) as well as of IL-6 (C) are shown [90]. Note that night-directed glucocorticoid treatment (grey areas) targets the period with high sensitivity to glucocorticoids in target tissues, which may explain the pronounced effect of these hormones administered in the evening.
Figure 5
Figure 5
Acetylation sites of the GR and regulation of GR transcriptional activity by Clock. A: Multiple lysines acetylated by Clock in the human GR. The human GR has 4 acetylation sites in its hinge region; lysines, 480, 492, 494 and 495, acetylated by Clock. Clock physically interacts with GR ligand-binding domain through the domain enclosed in its C-terminal part and acetylates GR at all lysine residues located in a lysine cluster of the hinge region. (modified from [95]) B: A heuristic model of the physiologic implications of this study. Clock/Bmal1 acetylates GR via its intrinsic histone acetyltransferase activity through physical interaction with GR ligand-binding domain, reduces affinity of GR to its cognate DNA GREs and ultimately suppresses GR-induced transcriptional activity. (modified from [95]) A: acetylation, Bmal1: brain-muscle-arnt-like protein 1, Clock: circadian locomotor output cycle kaput, DBD: DNA-binding domain, GR: glucocorticoid receptor, GRE: glucocorticoid response element, HD: hinge region, LBD: ligand-binding domain, NTD: N-terminal domain

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