Glucocorticoid receptor

The glucocorticoid receptor (GR, or GCR) also known as NR3C1 (is_associated_with::nuclear receptor subfamily 3, group C, member 1) is the receptor to which is_associated_with::cortisol and other is_associated_with::glucocorticoids bind.

The GR is expressed in almost every cell in the body and regulates is_associated_with::genes controlling the development, is_associated_with::metabolism, and immune response. Because the receptor gene is expressed in several forms, it has many different (is_associated_with::pleiotropic) effects in different parts of the body.

When the GR binds to glucocorticoids, its primary mechanism of action is the regulation of gene transcription. The unbound receptor resides in the is_associated_with::cytosol of the cell. After the receptor is bound to glucocorticoid, the receptor-glucorticoid complex can take either of two paths. The activated GR complex up-regulates the expression of anti-inflammatory proteins in the nucleus or represses the expression of pro-inflammatory proteins in the cytosol (by preventing the translocation of other is_associated_with::transcription factors from the cytosol into the nucleus).

In humans, the GR protein is encoded by NR3C1 is_associated_with::gene which is located on chromosome 5 (5q31).

Structure
Like the other is_associated_with::steroid receptors, the glucocorticoid receptor is modular in structure and contains the following domains (labeled A - F):
 * A/B - N-terminal regulatory domain
 * C - is_associated_with::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 is_associated_with::heat shock protein 90 (is_associated_with::hsp90), the heat shock protein 70 (is_associated_with::hsp70) and the protein is_associated_with::FKBP52 (is_associated_with::FK506-binding protein 52). The endogenous glucocorticoid hormone is_associated_with::cortisol diffuses through the is_associated_with::cell membrane into the is_associated_with::cytoplasm and binds to the glucocorticoid receptor (GR) resulting in release of the heat shock proteins. The resulting activated form GR has two principle mechanisms of action, transactivation and transrepression, described below.

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

Transrepression
In the absence of activated GR, other transcription factors such as is_associated_with::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 is_associated_with::transrepression.

Clinical significance
The GR is abnormal in is_associated_with::familial glucocorticoid resistance.

In is_associated_with::central nervous system structures, the glucocorticoid receptor is gaining interest as a novel representative of is_associated_with::neuroendocrine integration, functioning as a major component of endocrine influence - specifically the stress response - upon the brain. The receptor is now implicated in both short and long-term adaptations seen in response to stressors and may be critical to the understanding of psychological disorders, including some or all subtypes of depression and is_associated_with::post-traumatic stress disorder (is_associated_with::PTSD). Indeed, long-standing observations such as the mood dysregulations typical of is_associated_with::Cushing's disease demonstrate the role of corticosteroids in regulating psychologic state; recent advances have demonstrated interactions with is_associated_with::norepinephrine and is_associated_with::serotonin at the neural level.

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

Interactions
Glucocorticoid receptor has been shown to interact with:


 * is_associated_with::BAG1,
 * is_associated_with::CEBPB,
 * CREBBP,
 * is_associated_with::DAP3,
 * DAXX,
 * HSP90AA1,
 * is_associated_with::HNRPU,
 * is_associated_with::MED1,
 * is_associated_with::MED14,
 * is_associated_with::Mineralocorticoid receptor,
 * is_associated_with::NRIP1,
 * NCOR1,
 * NCOA1,
 * NCOA2,
 * NCOA3,
 * is_associated_with::POU2F1,
 * is_associated_with::RANBP9,
 * is_associated_with::RELA,
 * SMAD3,
 * is_associated_with::SMARCD1,
 * is_associated_with::SMARCA4
 * is_associated_with::STAT3,
 * is_associated_with::STAT5B,
 * is_associated_with::Thioredoxin,
 * is_associated_with::TRIM28, and
 * is_associated_with::YWHAH.