Structure and regulation of the glucocorticoid hormone receptor.

The glucocorticoid receptor is an intracellular protein which possesses three distinct domains, one that binds agonist and antagonist steroids, one that binds DNA, and one that binds anti-receptor antibodies and is required for glucocorticoid modulation of gene expression. In intact cells, receptor number, affinity and activity can change in response to factors that bind to the receptor, or that act indirectly through ill-defined mechanisms which may include resumption or arrest of cell cycling and variations in intracellular calcium ion concentrations. Some of these factors appear to exert their effect by controlling critical receptor properties such as ATP-dependent phosphorylation, integrity of thiol groups, and exposure of key amino acid residues. Glucocorticoid agonists promote the 'transformation' of the receptor into the DNA-binding state, which is competent for modulating gene expression. Glucocorticoid antagonists are steroids that interact with the receptor but either fail to produce a stable complex or produce a stable but inefficient complex. Although substituent groups that confer agonist or antagonist activity to the steroid have been identified, the molecular determinants of this difference at the receptor level remain unknown. Most in vitro and in vivo data on receptor regulation can be accommodated by postulating the existence of an intracellular cycle that involves five states of the receptor. The active free receptor is phosphorylated, reduced, and presumably oligomeric (state A). Following binding of an agonist (state B), it can become transformed by dissociation into its subunits and dephosphorylation (state C). The transformed receptor then interacts with chromatin (state D). Dissociation of the steroid and oxidation of receptor thiol group(s) lead to the inactive receptor form (state E). Reduction and rephosphorylation of the receptor enable it to bind steroids again so that the cycle is closed.