Glucocorticoid receptor

The glucocorticoid receptor (GR) also known as NR3C1 (nuclear receptor subfamily 3, group C, member 1) is a ligand-activated transcription factor  that binds with high affinity to cortisol and other glucocorticoids.

The GR is expressed in almost every cell in the body and regulates either directly or indirectly genes controlling a wide variety of processes including the development, metabolism, and immune response of the organism.

The GR protein is encoded by gene on chromosome 5 (5q31).

Structure
Like the other steroid receptors, the glucocorticoid receptor is modular in structure and contains the following domains (labeled A - F):
 * A/B - N-terminal regulatory domain
 * C - DNA-binding domain (DBD)
 * D - hinge region
 * E - ligand-binding domain (LBD)
 * F - C-terminal domain

Ligand binding and response
In the absence of hormone, the glucocorticoid receptor (GR) resides in the cytosol complexed with a variety of proteins including heat shock protein 90 (hsp90), the heat shock protein 70 (hsp70) and the protein FKBP52 (FK506-binding protein 52). The endogenous glucocortiod hormone cortisol diffuses through the cell membrane into the cytoplasm and binds to the glucocorticoid receptor (GR) resulitng in release of the heat shock proteins. The resulting activated form GR has two principle mechanisms of action:

Transactivation
A direct mechanism of action involves homodimerization of the receptor, translocation via active transport into the nucleus, and binding to specific DNA responsive elements activating gene transcription. This mechanism of action is referred to as transactivation. The biologic response depends on the cell type.

Transrepression
In the absence of activated GR, other transcription factors such as NF-κB or AP-1 themselves are able to transactivate target genes. However activated GR can complex with these other transcription factors and prevent them from binding their target genes and hence repress the expression of genes that are normally upregulated by NF-κB or AP-1. This indirect mechanism of action is referred to as transrepression.

Agonists and antagonists
Dexamethasone is an agonist, and RU486 and cyproterone are antagonists of the GR. Also, progesterone and DHEA have antagonist effects on the GR.

The GR is abnormal in familial glucocorticoid resistance.