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.
Quick Facts NR3C1, Available structures ...
NR3C1 |
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![](//upload.wikimedia.org/wikipedia/commons/thumb/f/f0/Glucocorticoid_receptor.png/250px-Glucocorticoid_receptor.png) |
Available structures |
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PDB | Ortholog search: PDBe RCSB |
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List of PDB id codes |
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1M2Z, 1NHZ, 1P93, 3BQD, 3CLD, 3E7C, 3H52, 3K22, 3K23, 4CSJ, 4HN5, 4HN6, 4LSJ, 4MDD, 4P6W, 4P6X, 5CBY, 5CBX, 4UDC, 4UDD, 5CBZ, 5CC1, 5EMQ, 5EMC, 5EMP |
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Identifiers |
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Aliases | NR3C1, GCCR, GCR, GCRST, GR, GRL, nuclear receptor subfamily 3 group C member 1, Glucocorticoid Receptor |
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External IDs | OMIM: 138040; MGI: 95824; HomoloGene: 30960; GeneCards: NR3C1; OMA:NR3C1 - orthologs |
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Wikidata |
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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 glucocorticoids bind to GR, its primary mechanism of action is the regulation of gene transcription.[5][6] The unbound receptor resides in the cytosol of the cell. After the receptor is bound to glucocorticoid, the receptor-glucocorticoid 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).[7][8]
Like the other steroid receptors,[9] the glucocorticoid receptor is modular in structure[10] and contains the following domains (labeled A - F):
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 FKBP4 (FK506-binding protein 4).[11] 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,[12][13] 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 response elements activating gene transcription. This mechanism of action is referred to as transactivation. The biological response depends on the cell type.[citation needed]
Transrepression
In the absence of activated GR, other transcription factors such as NF-κB or AP-1 themselves are able to transactivate target genes.[14] 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.[citation needed] GR transrepression via NF-κB and AP-1 is restricted only to certain cell types, and is not considered the universal mechanism for IκBα repression. [15][16]
The GR is abnormal in familial glucocorticoid resistance.[17]
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).[18] 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.[19][20]
In preeclampsia (a hypertensive disorder commonly occurring in pregnant women), the level of a miRNA sequence possibly targeting this protein is elevated in the blood of the mother. Rather, the placenta elevates the level of exosomes containing this miRNA, which can result in inhibition of translation of molecule. Clinical significance of this information is not yet clarified.[21]
Dexamethasone and other corticosteroids are agonists, while mifepristone and ketoconazole are antagonists of the GR. Anabolic steroids also prevent cortisol from binding to the glucocorticoid receptor.
Glucocorticoid receptor has been shown to interact with:
- BAG1,[22][23]
- CEBPB,[24]
- CREBBP,[25]
- DAP3,[26]
- DAXX,[27]
- HSP90AA1,[26][28][29][30][31][32][33]
- HNRPU,[34]
- MED1,[35][36]
- MED14,[36]
- Mineralocorticoid receptor,[37]
- NRIP1,[35][38][39]
- NCOR1,[40][41]
- NCOA1,[35][42]
- NCOA2,[35][43]
- NCOA3,[35][44]
- POU2F1,[45][46]
- RANBP9,[47]
- RELA,[47][48][49]
- SMAD3,[50][51]
- SMARCD1,[44]
- SMARCA4[44][52]
- STAT3,[53][54]
- STAT5B,[55]
- Thioredoxin,[56]
- TRIM28,[57] and
- YWHAH.[58]
Lu NZ, Wardell SE, Burnstein KL, Defranco D, Fuller PJ, Giguere V, et al. (December 2006). "International Union of Pharmacology. LXV. The pharmacology and classification of the nuclear receptor superfamily: glucocorticoid, mineralocorticoid, progesterone, and androgen receptors". Pharmacological Reviews. 58 (4): 782–797. doi:10.1124/pr.58.4.9. PMID 17132855. S2CID 28626145. [Free full text]
Boruk M, Savory JG, Haché RJ (November 1998). "AF-2-dependent potentiation of CCAAT enhancer binding protein beta-mediated transcriptional activation by glucocorticoid receptor". Molecular Endocrinology. 12 (11): 1749–1763. doi:10.1210/mend.12.11.0191. PMID 9817600.
Almlöf T, Wallberg AE, Gustafsson JA, Wright AP (June 1998). "Role of important hydrophobic amino acids in the interaction between the glucocorticoid receptor tau 1-core activation domain and target factors". Biochemistry. 37 (26): 9586–9594. doi:10.1021/bi973029x. PMID 9649342.
Jibard N, Meng X, Leclerc P, Rajkowski K, Fortin D, Schweizer-Groyer G, et al. (March 1999). "Delimitation of two regions in the 90-kDa heat shock protein (Hsp90) able to interact with the glucocorticosteroid receptor (GR)". Experimental Cell Research. 247 (2): 461–474. doi:10.1006/excr.1998.4375. PMID 10066374.
van den Berg JD, Smets LA, van Rooij H (February 1996). "Agonist-free transformation of the glucocorticoid receptor in human B-lymphoma cells". The Journal of Steroid Biochemistry and Molecular Biology. 57 (3–4): 239–249. doi:10.1016/0960-0760(95)00271-5. PMID 8645634. S2CID 20582144.
- Adcock IM, Ito K (June 2000). "Molecular mechanisms of corticosteroid actions". Monaldi Archives for Chest Disease = Archivio Monaldi per le Malattie del Torace. 55 (3): 256–266. PMID 10948677.
- Chikanza IC (June 2002). "Mechanisms of corticosteroid resistance in rheumatoid arthritis: a putative role for the corticosteroid receptor beta isoform". Annals of the New York Academy of Sciences. 966 (1): 39–48. Bibcode:2002NYASA.966...39C. doi:10.1111/j.1749-6632.2002.tb04200.x. PMID 12114257. S2CID 85100496.
- Neeck G, Kluter A, Dotzlaw H, Eggert M (June 2002). "Involvement of the glucocorticoid receptor in the pathogenesis of rheumatoid arthritis". Annals of the New York Academy of Sciences. 966 (1): 491–495. Bibcode:2002NYASA.966..491N. doi:10.1111/j.1749-6632.2002.tb04252.x. PMID 12114309. S2CID 5106644.
- Yudt MR, Cidlowski JA (August 2002). "The glucocorticoid receptor: coding a diversity of proteins and responses through a single gene". Molecular Endocrinology. 16 (8): 1719–1726. doi:10.1210/me.2002-0106. PMID 12145329.
- Torrego A, Pujols L, Picado C (September 2002). "[Response to glucocorticoid treatment in asthma. The role of alpha and beta isoforms of the glucocorticoid receptor]". Archivos de Bronconeumologia. 38 (9): 436–440. doi:10.1016/S0300-2896(02)75258-7. PMID 12237016.
- Bray PJ, Cotton RG (June 2003). "Variations of the human glucocorticoid receptor gene (NR3C1): pathological and in vitro mutations and polymorphisms". Human Mutation. 21 (6): 557–568. doi:10.1002/humu.10213. PMID 12754700. S2CID 26191891.
- Kino T, Pavlakis GN (April 2004). "Partner molecules of accessory protein Vpr of the human immunodeficiency virus type 1". DNA and Cell Biology. 23 (4): 193–205. doi:10.1089/104454904773819789. PMID 15142377.
- Lu NZ, Cidlowski JA (June 2004). "The origin and functions of multiple human glucocorticoid receptor isoforms". Annals of the New York Academy of Sciences. 1024 (1): 102–123. Bibcode:2004NYASA1024..102L. doi:10.1196/annals.1321.008. PMID 15265776. S2CID 36368837.
- Kino T, Chrousos GP (June 2004). "Human immunodeficiency virus type-1 accessory protein Vpr: a causative agent of the AIDS-related insulin resistance/lipodystrophy syndrome?". Annals of the New York Academy of Sciences. 1024 (1): 153–167. Bibcode:2004NYASA1024..153K. doi:10.1196/annals.1321.013. PMID 15265780. S2CID 23655886.
- Andersen JL, Planelles V (January 2005). "The role of Vpr in HIV-1 pathogenesis". Current HIV Research. 3 (1): 43–51. doi:10.2174/1570162052772988. PMID 15638722.
- Le Rouzic E, Benichou S (February 2005). "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.
- Muthumani K, Choo AY, Premkumar A, Hwang DS, Thieu KP, Desai BM, Weiner DB (August 2005). "Human immunodeficiency virus type 1 (HIV-1) Vpr-regulated cell death: insights into mechanism". Cell Death and Differentiation. 12 (Suppl 1): 962–970. 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): 407–417. doi:10.1016/j.steroids.2005.02.006. PMID 15862824. S2CID 24272404.
- Chrousos GP, Kino T (October 2005). "Intracellular glucocorticoid signaling: a formerly simple system turns stochastic". Science's STKE. 2005 (304): pe48. doi:10.1126/stke.3042005pe48. PMID 16204701. S2CID 23148406.
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- Subramaniam M, Colvard D, Keeting PE, Rasmussen K, Riggs BL, Spelsberg TC (December 1992). "Glucocorticoid regulation of alkaline phosphatase, osteocalcin, and proto-oncogenes in normal human osteoblast-like cells". Journal of Cellular Biochemistry. 50 (4): 411–424. doi:10.1002/jcb.240500410. PMID 1469072. S2CID 21381419.
- Scherrer LC, Pratt WB (March 1992). "Association of the transformed glucocorticoid receptor with a cytoskeletal protein complex". The Journal of Steroid Biochemistry and Molecular Biology. 41 (3–8): 719–721. doi:10.1016/0960-0760(92)90411-B. hdl:2027.42/30199. PMID 1562545. S2CID 43672040.
- Cadepond F, Gasc JM, Delahaye F, Jibard N, Schweizer-Groyer G, Segard-Maurel I, et al. (July 1992). "Hormonal regulation of the nuclear localization signals of the human glucocorticosteroid receptor". Experimental Cell Research. 201 (1): 99–108. doi:10.1016/0014-4827(92)90352-9. PMID 1612132.
- Hurley DM, Accili D, Stratakis CA, Karl M, Vamvakopoulos N, Rorer E, et al. (February 1991). "Point mutation causing a single amino acid substitution in the hormone binding domain of the glucocorticoid receptor in familial glucocorticoid resistance". The Journal of Clinical Investigation. 87 (2): 680–686. doi:10.1172/JCI115046. PMC 296359. PMID 1704018.
- Encío IJ, Detera-Wadleigh SD (April 1991). "The genomic structure of the human glucocorticoid receptor". The Journal of Biological Chemistry. 266 (11): 7182–7188. doi:10.1016/S0021-9258(20)89627-6. PMID 1707881.