Glucocorticoid receptor

Nuclear receptor subfamily 3, group C, member 1 (glucocorticoid receptor)
Crystallographic structures of the glucocorticoid receptor DNA binding domain (DBD, left, PDB 1R4O bound to DNA) and ligand binding domain [LBD, right, 1M2Z 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 1M2Z, 1NHZ, 1P93, 3BQD, 3CLD, 3E7C, 3H52, 3K22, 3K23
Identifiers
Symbols	NR3C1; GCCR; GCR; GR; GRL
External IDs	OMIM: 138040 MGI: 95824 HomoloGene: 30960 GeneCards: NR3C1 Gene
Gene Ontology Molecular function • sequence-specific DNA binding transcription factor activity • glucocorticoid receptor activity • steroid binding • protein binding • zinc ion binding • sequence-specific DNA binding • metal ion binding Cellular component • nucleus • nucleoplasm • nucleolus • cytoplasm • mitochondrial matrix Biological process • transcription, DNA-dependent • transcription from RNA polymerase II promoter • signal transduction • gene expression • chromatin modification • regulation of transcription from RNA polymerase II promoter by nuclear hormone receptor • glucocorticoid receptor signaling pathway • glucocorticoid mediated signaling pathway • response to protein stimulus Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	2908	14815
Ensembl	ENSG00000113580	ENSMUSG00000024431
UniProt	P04150	Q05DD1
RefSeq (mRNA)	NM_000176.2	NM_008173.3
RefSeq (protein)	NP_000167.1	NP_032199.3
Location (UCSC)	Chr 5: 142.66 – 142.82 Mb	Chr 18: 39.57 – 39.65 Mb
PubMed search	[1]	[2]

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 glucorticoids, its primary mechanism of action is the regulation of gene transcription.^[1][2] The unbound receptor resides in the cytosol of the cell (the part of the cell outside of the nucleus). 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

Like the other steroid receptors,^[5] the glucocorticoid receptor is modular in structure^[6] 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).^[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 principal mechanisms of action, transactivation and transrepression,^[8][9] described below.

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.^[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.^[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]

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.

Interactions

Glucocorticoid receptor has been shown to interact with:

• BAG1,^[14][15]
• CEBPB,^[16]
• CREBBP,^[17]
• DAP3,^[18]
• DAXX,^[19]
• HSP90AA1,^{[18][20][21][22][23][24][25]}
• HNRPU,^[26]
• MED1,^[27][28]
• MED14,^[28]
• Mineralocorticoid receptor,^[29]
• NRIP1,^[27][30][31]
• NCOR1,^[32][33]
• NCOA1,^[27][34]
• NCOA2,^[27][35]
• NCOA3,^[27][36]
• POU2F1,^[37][37][38]
• RANBP9,^[39]
• RELA,^[39][40][41]
• SMAD3,^[42][43]
• SMARCD1,^[36]
• SMARCA4^[36][44]
• STAT3,^[45][46]
• STAT5B,^[47]
• Thioredoxin,^[48]
• TRIM28,^[49] and
• YWHAH.^[50]

See also

• Familial/sporadic glucocorticoid resistance (Chrousos Syndrome)
• Selective glucocorticoid receptor agonist (SEGRA)

References

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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. PMID 10948677. 
• 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. doi:10.1111/j.1749-6632.2002.tb04200.x. PMID 12114257. 
• 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. doi:10.1111/j.1749-6632.2002.tb04252.x. PMID 12114309. 
• 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. doi:10.1210/me.2002-0106. PMID 12145329. 
• 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. PMID 12237016. 
• 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. doi:10.1002/humu.10213. PMID 12754700. 
• 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. doi:10.1089/104454904773819789. PMID 15142377. 
• Lu NZ, Cidlowski JA (2004). "The origin and functions of multiple human glucocorticoid receptor isoforms.". Ann. N. Y. Acad. Sci. 1024 (1): 102–23. doi:10.1196/annals.1321.008. PMID 15265776. 
• 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. doi:10.1196/annals.1321.013. PMID 15265780. 
• Andersen JL, Planelles V (2005). "The role of Vpr in HIV-1 pathogenesis.". Curr. HIV Res. 3 (1): 43–51. doi:10.2174/1570162052772988. PMID 15638722. 
• Le Rouzic E, Benichou S (2006). "The Vpr protein from HIV-1: distinct roles along the viral life cycle.". Retrovirology 2 (1): 11. doi:10.1186/1742-4690-2-11. PMC 554975. PMID 15725353. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=554975. 
• 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. doi:10.1038/sj.cdd.4401583. PMID 15832179. 
• Zhou J, Cidlowski JA (2005). "The human glucocorticoid receptor: one gene, multiple proteins and diverse responses.". Steroids 70 (5-7): 407–17. doi:10.1016/j.steroids.2005.02.006. PMID 15862824. 
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External links

• Human Protein Reference Database
• MeSH Glucocorticoid+receptors
• FactorBook GR