Figure 1 Intracellular regulation of the glucocorticoid receptor Figure 1 | Intracellular regulation of the glucocorticoid receptor. Corticosterone and mineralocorticoids are released from the adrenal glands into circulation. As lipid-soluble molecules, they can freely cross the cellular membrane. Membrane-bound glucocorticoid receptors (GRs) and mineralocorticoid receptors (MRs) are expressed throughout the brain and can act rapidly, following ligand binding, to modulate glutamate release, N-methyl-d-aspartate (NMDA) receptor activity and dendritic spine dynamics. Oestradiol (E2) competes with corticosterone to inhibit GR signalling. When corticosterone binds to cytosolic GR, this leads to the release of inhibitory complexes, such as HSP90, FKBP5 and BAG1, followed by GR dimerization and translocation to the nucleus. Corticosterone and progesterone can increase FKBP5 levels and inhibit GR translocation. This is accomplished through an ultra-short feedback loop in which the hormone binds to its receptor and acts on intronic hormone response elements that lead to increased Fkpb5 mRNA and protein levels. Binding of dimerized GRs to a glucocorticoid response element (GRE) leads to recruitment of RNA polymerase and other transcription factors such as NCoA1. E2 and testosterone increase NCoA1 expression, which positively modulates GR-dependent gene expression. BAG1 facilitates the conjugation of GRs to the proteasome for degradation. GRs can also negatively affect gene expression without directly binding to DNA via tethering to other transcription factors such as nuclear factor NF-kappa-B (NF-κB) or AP1. Gray, J. D. et al. (2017) Genomic and epigenomic mechanisms of glucocorticoids in the brain Nat. Rev. Endocrinol. doi:10.1038/nrendo.2017.97