Figure 1.

Glucocorticoid Molecular Physiology. Once released from the adrenal cortex, glucocorticoids (GC) travel through blood with the carrier protein, corticosteroid-binding globulin (CBG). Only 5% of extracellular GCs remain bioactive after binding to CBG. GC diffuse through the cell membrane to either (1) be converted into inactive cortisone via 11β-hydroxysteroid dehydrogenase 2, (2) have non-genomic effects in the cytosol or mitochondria, or (3) bind to the glucocorticoid receptor (GCR) as a chaperone complex to later exert genomic effects in the nucleus. When no cytoplasmic bioactive GCs are present, a multiprotein complex begins GR maturation to prepare for GC binding. Once matured, GCR's two nuclear localizations signals are exposed, which are then bound by nucleoporin and importins that translocate cytoplasmic GC into the nuclear membrane. Inside the nucleus, the GCR complex can be released, and the GR can be transported back to the cytoplasm, or the GR-GC complex can exert its function. Genomic effects include three categories: (1) direct binding to GC response elements (GREs) or negative GREs (nGREs) which recruit transcriptional co-activators and co-repressors respectively, (2) protein-protein interaction with transcription factors (TF) that modify transcription, and (3) composite interactions that involve DNA binding to GRE to alter transcription (see text for further details).