Figure 2.

Genomic and non-genomic mechanisms through which GCs regulate gene transcription. Free circulating GCs easily diffuse through membranes such as the blood–brain barrier (BBB) and thus target both peripheral and CNS cells. The bioavailability of endogenous and exogenous GCs in the CNS is however limited at the organ level by efflux pumps expressed at the BBB and at the cellular level by enzymatic metabolism (11β-HSD enzymes). The unliganded GC receptor (GR) is sequestered in the cytoplasm by multiple chaperones. Ligation of the GR by a GC molecule (1:1 ratio) alters its conformation and results in the dissociation of the chaperones. The activated GR then translocates to the nucleus and dynamically modulate gene transcription through various mechanisms. Liganded GRs bind to four main types of GR-response elements (GREs). Activated GRs physically interact with DNA on simple (+GRE), negative (nGRE), and composite GREs (cGRE). The activated GR can also be recruited to other DNA-binding sequences (DBS) via protein–protein interactions (tGRE). Transactivation or transrepression activity of the GR is partly dictated by the type of GRE and its binding partners. Alternatively, GRs also regulate transcription through steric hindrance on DNA sites overlapping with GREs, by sequestering transcription factors from DNA and by competing for co-activators binding. Furthermore, liganded GRs may occupy other response elements by binding to overlapping GREs, sequester transcription factors from DNA and compete for co-activators.