Most of the known effects of the glucocorticoids are mediated by widely distributed intracellular glucocorticoid receptors. These proteins are members of the superfamily of nuclear receptors, which includes steroid, sterol (vitamin D), thyroid, retinoic acid, and many other receptors with unknown or nonexistent ligands (orphan receptors). All these receptors interact with the promoters of—and regulate the transcription of—target genes (Figure 39–4). In the absence of the hormonal ligand, glucocorticoid receptors are primarily cytoplasmic, in oligomeric complexes with chaperone heat-shock proteins (hsp). The most important of these are two molecules of hsp90, although other proteins (eg, hsp40, hsp70, FKBP5) are also involved. Free hormone from the plasma and interstitial fluid enters the cell and binds to the receptor, inducing conformational changes that allow it to dissociate from the heat shock proteins and dimerize. The dimeric ligand-bound receptor complex then is actively transported into the nucleus, where it interacts with DNA and nuclear proteins. As a homodimer, it binds to glucocorticoid receptor elements (GREs) in the promoters of responsive genes. The GRE is composed of two palindromic sequences that bind to the hormone receptor dimer.
In addition to binding to GREs, the ligand-bound receptor also forms complexes with and influences the function of other transcription factors, such as AP1 and nuclear factor kappa-B (NF-κB), which act on non-GRE-containing promoters, to contribute to the regulation of transcription of their responsive genes. These transcription factors have broad actions on the regulation of growth factors, proinflammatory cytokines, etc, and to a great extent mediate the anti-growth, anti-inflammatory, and immunosuppressive effects of glucocorticoids.
Two genes for the corticoid receptor have been identified: one encoding the classic glucocorticoid receptor (GR) and the other encoding the mineralocorticoid receptor (MR). Alternative splicing of human glucocorticoid receptor pre-mRNA generates two highly homologous isoforms, termed hGRα and hGRβ. Human GRα is the classic ligand-activated glucocorticoid receptor, which, in the hormone-bound state, modulates the expression of glucocorticoid-responsive genes. In contrast, hGRβ does not bind glucocorticoids and is transcriptionally inactive. However, hGRβ is able to inhibit the effects of hormone-activated hGRα on glucocorticoid-responsive genes, playing the role of a physiologically relevant endogenous inhibitor of glucocorticoid action. It was recently shown that the two hGR alternative transcripts have eight distinct translation initiation sites—ie, in a human cell there may be up to 16 GRα and GRβ isoforms, which may form up to 256 homodimers and heterodimers with different transcriptional and possibly nontranscriptional activities. This variability suggests that this important class of steroid receptors has complex
FIGURE 39–3 Chemical structures of several glucocorticoids. The acetonide-substituted derivatives (eg, triamcinolone acetonide) have increased surface activity and are useful in dermatology. Dexamethasone is identical to betamethasone except for the configuration of the methyl group at C16: in betamethasone it is beta (projecting up from the plane of the rings); in dexamethasone it is alpha.
stochastic activities. In addition, rare mutations in hGR may result in partial glucocorticoid resistance. Affected individuals have increased ACTH secretion because of reduced pituitary feedback and additional endocrine abnormalities (see below).