TABLE 1

GR

Receptor nomenclature NR3C1
Receptor code 4.10.1:GC:3:C1
Other names GCCR, GCR, GRL
Molecular information Hs: 777aa, P04150, chr. 5q31-q321
Rn: 795aa, P06536, chr. 18p122
Mm: 783aa, P06537, chr. 18 B33
DNA binding
   Structure Homodimer
   HRE core sequence GGTACANNNTGTTCT (GRE, half-site, palindrome)
Partners HSP90 (physical, functional): cellular localization4–6; HMGB (physical, functional): DNA binding7,8; AP-1 (physical, functional): transactivation9–11; NF-κB (physical, functional): transactivation12,13; 14-3-3σ (physical, functional): cellular localization, transactivation14
Agonists Dexamethasone (1–8 nM),* triamcinolone acetonide (6 nM),* prednisolone (15 nM), triamcinolone (20 nM), cortisol (10–50 nM),* corticosterone (60 nM),* desoxycorticosterone (70 nM) [IC50]15–19
Antagonists RU-486 (0.4 nM)* [Kd]15,20
Coactivator CREBBP, NCOA2, MTI-II, NCOA6, PPARBP22–27
Corepressor BAG128
Biologically important isoforms GRα {Hs, Mm, Rn}: main isoform1; GRβ {Hs}: widely expressed alternative splicing variant lacking ligand binding, associated with several diseases1,29; GR-A, B, C, D {Hs, Mm, Rn}: alternative translation initiation isoforms with distinct transcriptional activities and tissue distribution patterns30
Tissue distribution Ubiquitous {Hs, Mm, Rn} [Northern blot, Q-PCR, in situ hybridization, Western blot]1,30–33
Functional assay Suppression of endogenous cortisol level by exogenous dexamethasone {Hs}34; apoptosis of thymocytes in the thymus {Rn}35; elevated blood glucose level by intravenous injection of glucocorticoids {Hs}36,37
Main target genes Activated: PEPCK-C {Hs},38 MKP-1 {Mm},39 lipocortin-1 {Hs},40,41; repressed: PEPCK-C {Hs},38 IL-8 {Hs},42 TNF-α {Hs}43
Mutant phenotype GR–/– mice die within hours because of respiratory failure; they have atelectatic lungs, impaired liver function, impaired HPA axis, increased plasma levels of ACTH and corticosterone and enlarged adrenal glands that produce no adrenaline {Mm} [knockout]44,45; mice expressing type II GR antisense RNA exhibit impaired T-cell function, disrupted HPA axis, increased plasma levels of ACTH and corticosterone, reduced GR binding, and alterations in thymocyte migration {Mm} [antisense oligonucleotide]46
Human disease Glucocorticoid resistance: due to various SNPs47,48; glucocorticoid hypersensitivity: due to an N363 polymorphism49; asthma: due to a receptor mutation50,51; acute childhood lymphoblastic leukemia: due to a receptor mutation52

  • aa, amino acids; chr., chromosome; HRE, hormone response element; RXR, retinoid X receptor; HMGB, chromosomal high-mobility group B; NK-κ B, nuclear factor-κ B; PPARBP, peroxisome proliferator-activated receptor binding protein; Q-PCR, quantitative polymerase chain reaction; HPA, hypothalamo-pituitary-adrenal; ACTH, adrenocorticotropin; SNP, single-nucleotide polymorphism; GRE, glucocorticoid response element; CREBBP, cAMP response element binding protein binding protein

  • ↵* Radioligand

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  • ↵18. Giannopoulos G and Keichline D (1981) Species-related differences in steroid-binding specificity of glucocorticoid receptors in lung. Endocrinology 108: 1414-1419

  • ↵19. Yoneda Y, Han D, Ogita K, and Watanabe A (1995) Distinction between binding of [3H]triamcinolone acetonide to a ligand binding domain on the glucocorticoid receptor complex in cytosol fractions of brain and liver from the rat with intact adrenals. Brain Res 685: 105-116

  • ↵20. Heikinheimo O, Kontula K, Croxatto H, Spitz I, Luukkainen T, and Lahteenmaki P (1987) Plasma concentrations and receptor binding of RU 486 and its metabolites in humans. J Steroid Biochem 26: 279-284

  • ↵21. Kamei Y, Xu L, Heinzel T, Torchia J, Kurokawa R, Gloss B, Lin SC, Heyman RA, Rose DW, Glass CK, et al. (1996) A CBP integrator complex mediates transcriptional activation and AP-1 inhibition by nuclear receptors. Cell 85: 403-414

  • ↵22. Hong H, Kohli K, Trivedi A, Johnson DL, and Stallcup MR (1996) GRIP1, a novel mouse protein that serves as a transcriptional coactivator in yeast for the hormone binding domains of steroid receptors. Proc Natl Acad Sci USA 93: 4948-4952

  • ↵23. Voegel JJ, Heine MJ, Zechel C, Chambon P, and Gronemeyer H (1996) TIF2, a 160 kDa transcriptional mediator for the ligand-dependent activation function AF-2 of nuclear receptors. EMBO (Eur Mol Biol Organ) J 15: 3667-3675

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  • ↵28. Kullmann M, Schneikert J, Moll J, Heck S, Zeiner M, Gehring U, and Cato AC (1998) RAP46 is a negative regulator of glucocorticoid receptor action and hormone-induced apoptosis. J Biol Chem 273: 14620-14625

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