Human glucocorticoid receptor isoform β: recent understanding of its potential implications in physiology and pathophysiology

The human glucocorticoid receptor (GR) gene expresses two splicing isoforms alpha and beta through alternative use of specific exons 9 alpha and 9 beta. In contrast to the classic receptor GR alpha, which mediates most of the known actions of glucocorticoids, the functions of GR beta have been largely unexplored. Owing to newly developed methods, for example microarrays and the jellyfish fluorescence proteins, we and others have recently revealed novel functions of GR beta. Indeed, this enigmatic GR isoform influences positively and negatively the transcriptional activity of large subsets of genes, most of which are not responsive to glucocorticoids, in addition to its well-known dominant negative effect against GR alpha-mediated transcriptional activity. A recent report suggested that the ligand-binding domain of GR beta is active, forming a functional ligand-binding pocket associated with the synthetic compound RU 486. In this review, we discuss the functions of GR beta, its mechanisms of action, and its pathologic implications.