Expression Profiles of Glucocorticoid Receptor α- and β-Isoforms in Diverse Physiological and Pathological Conditions

Through alternative splicing, two isoforms of the glucocorticoid receptor (GR) gene are generated, termed GRα and GRβ. GRα is predominantly expressed and shows steroid binding activity, whereas GRβ is thought to be inactive as a result of its truncated ligand-binding domain. GRβ may only act as a dominant negative inhibitor when co-expressed with GRα. GRβ specifically binds RU486 and also exhibits intrinsic transcriptional activities to directly regulate the expression of a large number of genes via both GRα-dependent and GRα-independent mechanisms. Hypercortisolemia and hypocortisolemia show different effects on the expression profiles of GR isoforms. Inflammatory cytokines induce GRβ expression and lead to an increased GRβ/GRα ratio, which may be related to glucocorticoid resistance during inflammatory diseases. Because GRβ inhibits the activity of GRα, it has the potential to ameliorate glucocorticoid-induced abnormal metabolism, muscle loss or be used to treat tumors. While elevated GRβ expression has been found in some inflammatory diseases and may be relevant to glucocorticoid unresponsiveness, whether GRβ modulates glucocorticoid sensitivity in vivo is under debate because of its extremely low expression levels under physiological situations.