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Glucocorticoid receptor

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Title: Glucocorticoid receptor  
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Subject: Nuclear receptor, Glucocorticoid, Mifepristone, Behavioral epigenetics, Steroid hormone receptor
Collection: Genome Projects, Intracellular Receptors, Transcription Factors
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Glucocorticoid receptor

Nuclear receptor subfamily 3, group C, member 1 (glucocorticoid receptor)
Crystallographic structures of the glucocorticoid receptor DNA binding domain (DBD, left, ​ bound to DNA) and ligand binding domain [LBD, right, bound to dexamethasone (white sticks) and the TIF2 coactivator protein (red)]. Dashed yellow lines represent hydrogen bonding interactions between the receptor and ligand. The 2D structure of dexamethasone is also depicted in the lower right hand side of the picture for reference.
Available structures
PDB Ortholog search: PDBe, RCSB
Symbols  ; GCCR; GCR; GCRST; GR; GRL
External IDs IUPHAR: ChEMBL: GeneCards:
RNA expression pattern
Species Human Mouse
UniProt n/a
RefSeq (mRNA)
RefSeq (protein)
Location (UCSC)
PubMed search

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

The GR is expressed in almost every cell in the body and regulates genes controlling the development, metabolism, and immune response. Because the receptor gene is expressed in several forms, it has many different (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.[1][2] The unbound receptor resides in the 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 transcription factors from the cytosol into the nucleus).

In humans, the GR protein is encoded by NR3C1 gene which is located on chromosome 5 (5q31).[3][4]


  • Structure 1
  • Ligand binding and response 2
    • Transactivation 2.1
    • Transrepression 2.2
  • Clinical significance 3
  • Agonists and antagonists 4
  • Interactions 5
  • See also 6
  • References 7
  • Further reading 8
  • External links 9


Like the other steroid receptors,[5] the glucocorticoid receptor is modular in structure[6] and contains the following domains (labeled A - F):

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).[7] The endogenous glucocorticoid hormone cortisol diffuses through the cell membrane into the 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,[8][9] described below.


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.


In the absence of activated GR, other transcription factors such as NF-κB or AP-1 themselves are able to transactivate target genes.[10] 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.

Clinical significance

The GR is abnormal in familial glucocorticoid resistance.[11]

In central nervous system structures, the glucocorticoid receptor is gaining interest as a novel representative of 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 post-traumatic stress disorder (PTSD).[12] Indeed, long-standing observations such as the mood dysregulations typical of Cushing's disease demonstrate the role of corticosteroids in regulating psychologic state; recent advances have demonstrated interactions with norepinephrine and serotonin at the neural level.[13][14]

Agonists and antagonists

Dexamethasone and other corticosteroids are agonists, and mifepristone and ketoconazole are antagonists of the GR.


Glucocorticoid receptor has been shown to interact with:

See also


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Further reading

  • Adcock IM, Ito K (2000). "Molecular mechanisms of corticosteroid actions.". Monaldi archives for chest disease = Archivio Monaldi per le malattie del torace / Fondazione clinica del lavoro, IRCCS [and] Istituto di clinica tisiologica e malattie apparato respiratorio, Università di Napoli, Secondo ateneo 55 (3): 256–66.  
  • Chikanza IC (2002). "Mechanisms of corticosteroid resistance in rheumatoid arthritis: a putative role for the corticosteroid receptor beta isoform.". Ann. N. Y. Acad. Sci. 966: 39–48.  
  • Neeck G, Kluter A, Dotzlaw H, Eggert M (2002). "Involvement of the glucocorticoid receptor in the pathogenesis of rheumatoid arthritis.". Ann. N. Y. Acad. Sci. 966 (1): 491–5.  
  • Yudt MR, Cidlowski JA (2003). "The glucocorticoid receptor: coding a diversity of proteins and responses through a single gene.". Mol. Endocrinol. 16 (8): 1719–26.  
  • Torrego A, Pujols L, Picado C (2003). "[Response to glucocorticoid treatment in asthma. The role of alpha and beta isoforms of the glucocorticoid receptor]". Arch. Bronconeumol. 38 (9): 436–40.  
  • Bray PJ, Cotton RG (2003). "Variations of the human glucocorticoid receptor gene (NR3C1): pathological and in vitro mutations and polymorphisms.". Hum. Mutat. 21 (6): 557–68.  
  • Kino T, Pavlakis GN (2004). "Partner molecules of accessory protein Vpr of the human immunodeficiency virus type 1.". DNA Cell Biol. 23 (4): 193–205.  
  • Lu NZ, Cidlowski JA (2004). "The origin and functions of multiple human glucocorticoid receptor isoforms.". Ann. N. Y. Acad. Sci. 1024 (1): 102–23.  
  • Kino T, Chrousos GP (2004). "Human immunodeficiency virus type-1 accessory protein Vpr: a causative agent of the AIDS-related insulin resistance/lipodystrophy syndrome?". Ann. N. Y. Acad. Sci. 1024 (1): 153–67.  
  • Andersen JL, Planelles V (2005). "The role of Vpr in HIV-1 pathogenesis.". Curr. HIV Res. 3 (1): 43–51.  
  • Le Rouzic E, Benichou S (2006). "The Vpr protein from HIV-1: distinct roles along the viral life cycle.". Retrovirology 2 (1): 11.  
  • Muthumani K, Choo AY, Premkumar A, et al. (2006). "Human immunodeficiency virus type 1 (HIV-1) Vpr-regulated cell death: insights into mechanism.". Cell Death Differ. 12 (Suppl 1): 962–70.  
  • Zhou J, Cidlowski JA (2005). "The human glucocorticoid receptor: one gene, multiple proteins and diverse responses.". Steroids 70 (5-7): 407–17.  
  • Chrousos GP, Kino T (2006). "Intracellular glucocorticoid signaling: a formerly simple system turns stochastic.". Sci. STKE 2005 (304): pe48.  
  • Plotkin LL, Labutin AL, Lebedev LV, et al. (1975). "[Balloon probe for the removal of emboli and thrombi]". Meditsinskaia tekhnika (3): 42–3.  
  • Subramaniam M, Colvard D, Keeting PE, et al. (1993). "Glucocorticoid regulation of alkaline phosphatase, osteocalcin, and proto-oncogenes in normal human osteoblast-like cells.". J. Cell. Biochem. 50 (4): 411–24.  
  • Scherrer LC, Pratt WB (1992). "Association of the transformed glucocorticoid receptor with a cytoskeletal protein complex.". J. Steroid Biochem. Mol. Biol. 41 (3-8): 719–21.  
  • Cadepond F, Gasc JM, Delahaye F, et al. (1992). "Hormonal regulation of the nuclear localization signals of the human glucocorticosteroid receptor.". Exp. Cell Res. 201 (1): 99–108.  
  • Hurley DM, Accili D, Stratakis CA, et al. (1991). "Point mutation causing a single amino acid substitution in the hormone binding domain of the glucocorticoid receptor in familial glucocorticoid resistance.". J. Clin. Invest. 87 (2): 680–6.  
  • Encío IJ, Detera-Wadleigh SD (1991). "The genomic structure of the human glucocorticoid receptor.". J. Biol. Chem. 266 (11): 7182–8.  

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