Molecular mechanisms of glucocorticoid action

Glucocorticoids act on target cells via two isoforms of intracellular glucocorticoid receptors (GRs) called GRalpha (hormone-binding form) and GRbeta which does not bind any glucocorticoids. A cycle of Hsp90 chaperone and co-chaperones maintains the functional status of GRs and their recycling. The binding of a glucocorticoid hormone to GRa leads to its activation and translocation from the cytoplasm to nucleus. Glucocorticoids influence activities of genes of target cells using two different types of mechanism. In type-1 mechanism, the hormone-bound GRa undergoes homo-dimerization (GRalpha/GRalpha) or heterodimerization (GRalpha/GRbeta). A homodimer binds directly to a glucocorticoid response element (GRE) and activates gene transcription. Binding of a heterodimer (GRalpha/GRbeta) to GRE induces only partial transactivation, because GRbeta inhibits the hormone-induced, GRalpha-mediated stimulation of gene expression by specifically inhibiting GRE-mediated transcription. In some cases, a hormone-GRalpha complex binds to a negative-GRalpha (nGRE) and suppresses transcription (transrepression). In type-2 mechanism, a hormone-GRalpha complex binds to other transcription factors (TFs),and inhibits the transcription of target genes stimulated by the TFs. GRalpha-induced transactivation and transrepression of genes may also involve several transcription co-activators and dominant negative inhibitors respectively. The present article provides critical information on structure and types of GRs, GR gene, chaperone cycle, and details of different types of mechanism of glucocorticoid actions.