Figure 2. Molecular mechanisms of action of glucocorticoid receptors.

Glucocorticoids (GCs) are lipophilic compounds that freely penetrate the plasma membrane (PM). Upon entering the cytosol, GCs bind to the high affinity ligand binding site on the cytoplasmic GRα complex that also contains several heat shock proteins (HSPs) and immunophilins (not shown). The ligand bound GRα, undergoes a conformational change that dissociates the other proteins in the complex to form activated GRα monomers. The activated monomers are actively transported along microtubules to the nuclear membrane (NM), where they enter the nucleus through nuclear pores. Once inside the nucleus, GRα monomers dimerize and bind to palindromic GC response elements (GREs) on GC regulated genes to turn on transcription in a process known as transactivation. Activated nuclear GRα monomers can also bind to several other transcription factors (TF) including AP1 and NFkB, thereby preventing these TFs from binding and activating their own response elements (TREs) in a process known as transrepression. Many, but not all, of the anti-inflammatory activities of GCs are mediated by transrepression.