Glucocorticoid receptor

The glucocorticoid receptor (GR or GCR) also known by its gene name NR3C1 (nuclear receptor subfamily 3, group C, member 1) is the steroid receptor for glucocorticoids such as cortisol.

NR3C1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 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
Identifiers
Aliases	NR3C1, GCCR, GCR, GCRST, GR, GRL, nuclear receptor subfamily 3 group C member 1, Glucocorticoid Receptor
External IDs	OMIM: 138040; MGI: 95824; HomoloGene: 30960; GeneCards: NR3C1; OMA:NR3C1 - orthologs
Gene location (Human) Chr. Chromosome 5 (human)[1] Band 5q31.3 Start 143,277,931 bp[1] End 143,435,512 bp[1]
Gene location (Mouse) Chr. Chromosome 18 (mouse)[2] Band 18 B3|18 21.09 cM Start 39,543,598 bp[2] End 39,652,474 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in endothelial cell tibia cartilage tissue Skeletal muscle tissue of rectus abdominis Brodmann area 23 superficial temporal artery visceral pleura synovial joint nipple parietal pleura Top expressed in median eminence left lung ankle left lung lobe skin of external ear medial dorsal nucleus lobe of cerebellum ciliary body triceps brachii muscle arcuate nucleus More reference expression data BioGPS More reference expression data
Gene ontology Molecular function steroid hormone binding DNA binding sequence-specific DNA binding DNA-binding transcription factor activity zinc ion binding DNA-binding transcription activator activity, RNA polymerase II-specific glucocorticoid receptor activity nuclear receptor activity metal ion binding RNA polymerase II cis-regulatory region sequence-specific DNA binding steroid hormone receptor activity steroid binding protein binding lipid binding RNA binding SUMO binding Hsp90 protein binding DNA-binding transcription factor activity, RNA polymerase II-specific protein kinase binding Cellular component cytoplasm nucleoplasm mitochondrial matrix mitochondrion nucleus cytoskeleton spindle microtubule organizing center cytosol nuclear speck protein-containing complex Biological process cellular response to steroid hormone stimulus regulation of transcription, DNA-templated glucocorticoid mediated signaling pathway transcription by RNA polymerase II transcription initiation from RNA polymerase II promoter glucocorticoid receptor signaling pathway signal transduction steroid hormone mediated signaling pathway cell cycle cell division apoptotic process chromosome segregation negative regulation of transcription by RNA polymerase II transcription, DNA-templated cellular response to dexamethasone stimulus cellular response to transforming growth factor beta stimulus positive regulation of transcription by RNA polymerase II cellular response to glucocorticoid stimulus chromatin organization positive regulation of pri-miRNA transcription by RNA polymerase II Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 2908 14815 Ensembl ENSG00000113580 ENSMUSG00000024431 UniProt P04150 Q3MSN4 P06537 RefSeq (mRNA) NM_000176 NM_001018074 NM_001018075 NM_001018076 NM_001018077 NM_001020825 NM_001024094 NM_001204258 NM_001204259 NM_001204260 NM_001204261 NM_001204262 NM_001204263 NM_001204264 NM_001204265 NM_001364180 NM_001364181 NM_001364182 NM_001364183 NM_001364184 NM_001364185 NM_008173 NM_001361209 NM_001361210 NM_001361211 NM_001361212 RefSeq (protein) NP_000167 NP_001018084 NP_001018085 NP_001018086 NP_001018087 NP_001018661 NP_001019265 NP_001191187 NP_001191188 NP_001191189 NP_001191190 NP_001191191 NP_001191192 NP_001191193 NP_001191194 NP_001351109 NP_001351110 NP_001351111 NP_001351112 NP_001351113 NP_001351114 NP_000167.1 NP_001018084.1 NP_001018085.1 NP_001018086.1 NP_001018087.1 NP_001018661.1 NP_001019265.1 NP_001191187.1 NP_001191188.1 NP_001191189.1 NP_001191190.1 NP_001191191.1 NP_001191192.1 NP_001191193.1 NP_001348138 NP_001348139 NP_001348140 NP_001348141 NP_032199 Location (UCSC) Chr 5: 143.28 – 143.44 Mb Chr 18: 39.54 – 39.65 Mb PubMed search [3] [4]
Wikidata
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The GR is expressed in almost every cell in the body and regulates genes controlling the development, metabolism, inflammation, and immune response. Because the receptor gene is expressed in several forms, it has many different (pleiotropic) effects in different parts of the body and in the context of different diseases.

GR is a steroid receptor and thus its canonical action is similar to other steroid receptors.^[5][6] The unbound receptor resides in the cytosol of the cell. When glucocorticoids bind to the receptor, GR translocates to the nucleus of the cell where it acts as a transcription factor. 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).^[6]

In humans, the GR protein is encoded by NR3C1 gene which is located on chromosome 5 (5q31).^[7][8]

Structure

Like the other steroid receptors,^[9] GR is modular in structure^[10] 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).^[11] The endogenous glucocorticoid hormone cortisol diffuses through the cell membrane into the cytoplasm and binds to the glucocorticoid receptor (GR) resulting in the 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]

Clinical significance

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]

Agonists and antagonists

Dexamethasone and other corticosteroids are agonists, while mifepristone and ketoconazole are antagonists of GR. Anabolic steroids also prevent cortisol from binding to the glucocorticoid receptor.

Interactions

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]

See also

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