Glucocorticoid receptor explained

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 glucocorticoids bind to GR, 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-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 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 FKBP4 (FK506-binding protein 4).^[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 response elements activating gene transcription. This mechanism of action is referred to as transactivation. The biological 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. 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. ^{[11] [12]}

Clinical significance

The GR is abnormal in familial glucocorticoid resistance.^[13]

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).^[14] 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.^{[15] [16]}

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.^[17]

Agonists and antagonists

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.

Interactions

Glucocorticoid receptor has been shown to interact with:

• BAG1,^{[18] [19]}
• CEBPB,^[20]
• CREBBP,^[21]
• DAP3,^[22]
• DAXX,^[23]
• HSP90AA1,^{[22] [24] [25] [26] [27] [28] [29]}
• HNRPU,^[30]
• MED1,
• MED14,^[31]
• Mineralocorticoid receptor,^[32]
• NRIP1,^{[33] [34]}
• NCOR1,^{[35] [36]}
• NCOA1,^[37]
• NCOA2,^{[38] [39]}
• NCOA3,^{[38] [40]}
• POU2F1,^{[41] [42]}
• RANBP9,^[43]
• RELA,^{[44] [45]}
• SMAD3,^{[46] [47]}
• SMARCD1,^[40]
• SMARCA4^{[40] [48]}
• STAT3,^{[49] [50]}
• STAT5B,^[51]
• Thioredoxin,^[52]
• TRIM28,^[53] and
• YWHAH.^[54]

See also

• Membrane glucocorticoid receptor
• Selective glucocorticoid receptor agonist (SEGRA)

Further reading

• Adcock IM, Ito K . Molecular mechanisms of corticosteroid actions . Monaldi Archives for Chest Disease = Archivio Monaldi per le Malattie del Torace . 55 . 3 . 256–266 . June 2000 . 10948677 .
• Chikanza IC . 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 . June 2002 . 12114257 . 10.1111/j.1749-6632.2002.tb04200.x . 85100496 . 2002NYASA.966...39C .
• Neeck G, Kluter A, Dotzlaw H, Eggert M . Involvement of the glucocorticoid receptor in the pathogenesis of rheumatoid arthritis . Annals of the New York Academy of Sciences . 966 . 1 . 491–495 . June 2002 . 12114309 . 10.1111/j.1749-6632.2002.tb04252.x . 5106644 . 2002NYASA.966..491N .
• Yudt MR, Cidlowski JA . The glucocorticoid receptor: coding a diversity of proteins and responses through a single gene . Molecular Endocrinology . 16 . 8 . 1719–1726 . August 2002 . 12145329 . 10.1210/me.2002-0106 . free .
• Torrego A, Pujols L, Picado C . [Response to glucocorticoid treatment in asthma. The role of alpha and beta isoforms of the glucocorticoid receptor] . Archivos de Bronconeumologia . 38 . 9 . 436–440 . September 2002 . 12237016 . 10.1016/S0300-2896(02)75258-7 .
• Bray PJ, Cotton RG . Variations of the human glucocorticoid receptor gene (NR3C1): pathological and in vitro mutations and polymorphisms . Human Mutation . 21 . 6 . 557–568 . June 2003 . 12754700 . 10.1002/humu.10213 . 26191891 .
• Kino T, Pavlakis GN . Partner molecules of accessory protein Vpr of the human immunodeficiency virus type 1 . DNA and Cell Biology . 23 . 4 . 193–205 . April 2004 . 15142377 . 10.1089/104454904773819789 .
• Lu NZ, Cidlowski JA . The origin and functions of multiple human glucocorticoid receptor isoforms . Annals of the New York Academy of Sciences . 1024 . 1 . 102–123 . June 2004 . 15265776 . 10.1196/annals.1321.008 . 36368837 . 2004NYASA1024..102L .
• Kino T, Chrousos GP . 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 . June 2004 . 15265780 . 10.1196/annals.1321.013 . 23655886 . 2004NYASA1024..153K .
• Andersen JL, Planelles V . The role of Vpr in HIV-1 pathogenesis . Current HIV Research . 3 . 1 . 43–51 . January 2005 . 15638722 . 10.2174/1570162052772988 .
• Le Rouzic E, Benichou S . The Vpr protein from HIV-1: distinct roles along the viral life cycle . Retrovirology . 2 . 1 . 11 . February 2005 . 15725353 . 554975 . 10.1186/1742-4690-2-11 . free .
• Muthumani K, Choo AY, Premkumar A, Hwang DS, Thieu KP, Desai BM, Weiner DB . Human immunodeficiency virus type 1 (HIV-1) Vpr-regulated cell death: insights into mechanism . Cell Death and Differentiation . 12 . Suppl 1 . 962–970 . August 2005 . 15832179 . 10.1038/sj.cdd.4401583 . free .
• Zhou J, Cidlowski JA . The human glucocorticoid receptor: one gene, multiple proteins and diverse responses . Steroids . 70 . 5–7 . 407–417 . 2005 . 15862824 . 10.1016/j.steroids.2005.02.006 . 24272404 .
• Chrousos GP, Kino T . Intracellular glucocorticoid signaling: a formerly simple system turns stochastic . Science's STKE . 2005 . 304 . pe48 . October 2005 . 16204701 . 10.1126/stke.3042005pe48 . 23148406 .
• Plotkin LL, Labutin AL, Lebedev LV, Khanukov LA, Zelikson OS . [Balloon probe for the removal of emboli and thrombi] . Meditsinskaya Tekhnika . 3 . 42–43 . 1975 . 1152650 .
• Subramaniam M, Colvard D, Keeting PE, Rasmussen K, Riggs BL, Spelsberg TC . Glucocorticoid regulation of alkaline phosphatase, osteocalcin, and proto-oncogenes in normal human osteoblast-like cells . Journal of Cellular Biochemistry . 50 . 4 . 411–424 . December 1992 . 1469072 . 10.1002/jcb.240500410 . 21381419 .
• Scherrer LC, Pratt WB . Association of the transformed glucocorticoid receptor with a cytoskeletal protein complex . The Journal of Steroid Biochemistry and Molecular Biology . 41 . 3–8 . 719–721 . March 1992 . 1562545 . 10.1016/0960-0760(92)90411-B . free . 43672040 . 2027.42/30199 .
• Cadepond F, Gasc JM, Delahaye F, Jibard N, Schweizer-Groyer G, Segard-Maurel I, Evans R, Baulieu EE . 6 . Hormonal regulation of the nuclear localization signals of the human glucocorticosteroid receptor . Experimental Cell Research . 201 . 1 . 99–108 . July 1992 . 1612132 . 10.1016/0014-4827(92)90352-9 .
• Hurley DM, Accili D, Stratakis CA, Karl M, Vamvakopoulos N, Rorer E, Constantine K, Taylor SI, Chrousos GP . 6 . 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 . February 1991 . 1704018 . 296359 . 10.1172/JCI115046 .
• Encío IJ, Detera-Wadleigh SD . The genomic structure of the human glucocorticoid receptor . The Journal of Biological Chemistry . 266 . 11 . 7182–7188 . April 1991 . 1707881 . 10.1016/S0021-9258(20)89627-6 . free .

External links

• Human Protein Reference Database

Notes and References

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