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Gene Review

Nr3c1  -  nuclear receptor subfamily 3, group C,...

Rattus norvegicus

Synonyms: GR, Gcr, Glucocorticoid receptor, Grl, Nuclear receptor subfamily 3 group C member 1
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Disease relevance of Nr3c1


Psychiatry related information on Nr3c1

  • They point to a new role of hippocampal GR, strongly implicating this receptor in determining individual differences in anxiety and novelty-seeking behavior [6].
  • We conclude that maternal food restriction during the perinatal period affects (1) the adult basal activity of the HPA axis with mainly opposite effects on hippocampal MR and GR gene expression and an increase in adenopituitary POMC gene expression, and (2) the responsiveness to water deprivation in adults [7].
  • The possibility of decreasing the behavioral and dopaminergic effects of opioids by an acute administration of GR antagonists may open new therapeutic strategies for treatment of drug addiction [8].
  • These results suggest that subsensitivity of the HPA axis to stress during nicotine withdrawal may be implicated in the precipitation of depression during smoking cessation, although GR and CRH in the HPA axis do not appear to play a significant role [9].
  • Since the hippocampus and PVN mediate negative feedback regulation of the HPA axis, an increased expression of GR mRNA in these regions may normalize HPA axis activity in mood disorders [10].

High impact information on Nr3c1

  • These results suggest a hit-and-run mechanism of transcriptional activation by glucocorticoid receptor: the activated receptor binds its target sequence, modifies local chromatin structure, then leaves its site accessible to another factor [11].
  • We isolated and sequenced 6.3 kb of cDNA encoding that rat glucocorticoid receptor, a protein that binds and activates a class of hormone-dependent transcriptional enhancers [12].
  • Using the rat liver glucocorticoid receptor for binding studies, two separate binding sites have been identified: a strong binding site that is destroyed by deletion of lysozyme sequences between positions -74 and -39 and a weaker binding site contained between positions -208 and -161 upstream of the lysozyme cap site [13].
  • DNA sequences bound specifically by glucocorticoid receptor in vitro render a heterologous promoter hormone responsive in vivo [14].
  • To elucidate the molecular mechanism by which steroid hormones exert their regulatory function, we investigated the interaction of a glucocorticoid-receptor complex with purified DNA fragments from cloned mouse mammary tumor (MMTV) proviral DNA [15].

Chemical compound and disease context of Nr3c1

  • Dexamethasone caused a down-regulation of the levels of GR mRNA and protein both in hepatoma tissue culture cells and rat liver in vivo [2].
  • Thus, the effect of chronic lithium on GR function may be involved in its antimanic and/or prophylactic activity in bipolar disorders [10].
  • These studies suggest that altered MR- and GR-mediated mechanisms may contribute to the resistance of the W/Fu rat strain to steroid-induced hypertension [16].
  • Since corticosterone activates both the mineralocorticoid (MR) and glucocorticoid (GR) receptors, the aim of this study was to determine the importance of MRs in the regulation of colorectal hypersensitivity through the use of aldosterone that preferentially binds to MRs [17].
  • The glucocorticoid receptor antagonist mifepristone and the beta-adrenoceptor antagonist propranolol were able to completely reverse the increased immobility time in the forced swimming test and the memory deficits in the NORT observed in MS rats [18].

Biological context of Nr3c1

  • The nature of any relationship between NGF, the transcription factors and GR remains to be determined, but the results demonstrate that chronic environmental manipulations alter hippocampal GR gene expression in adult rats [19].
  • Specific, high-affinity binding of glucocorticoid receptor (GR) DNA-binding domain to this promoter region was observed using an eletrophoretic mobility shift assay (EMSA) [20].
  • The mineralocorticoid and glucocorticoid receptors (MR and GR, respectively) are members of the intracellular receptor superfamily that bind as homodimers to the same hormone response elements (HREs) [21].
  • We developed a model system to study glucocorticoid receptor (GR)-mediated chromatin remodeling by the BRG1 complex [22].
  • In co-transfection experiments with GR response element reporter and overexpression constructs, UDCA did not enhance the transactivation of GR with TGF-beta1 [23].

Anatomical context of Nr3c1

  • Indeed, the anxiety level of LR rats becomes similar to HR rats after the administration into the hippocampus of a GR antagonist, RU38486 [6].
  • Given the differential action of MR and GR in the central nervous system, it is important to elucidate how the trafficking of these receptors between cytoplasm and nucleus is regulated by ligand [24].
  • In COS-1 cells, expressing no endogenous corticosteroid receptors, the YFP-MR chimera was accumulated in the nucleus faster than the CFP-GR chimera in the presence of 10(-9) M CORT, while there was no significant difference in the nuclear accumulation rates in the presence of 10(-6) M CORT [24].
  • GR mRNA expression was increased in hippocampal CA1 and the dentate gyrus of CRF1-antagonist treated nonhandled rats to levels commensurate with those in handled cohorts [25].
  • The behavioural and HPA effects may reflect GR gene programming in amygdala and hypothalamus, respectively [26].

Associations of Nr3c1 with chemical compounds

  • Dexamethasone-GR activation did not inhibit nuclear translocation of C/EBPbeta or Nrf2 nor their DNA binding activities induced by oltipraz or t-BHQ [27].
  • Dexamethasone that activates GR inhibited constitutive and oltipraz- or tert-butylhydroquinone (t-BHQ)-inducible GSTA2 expression in H4IIE cells [27].
  • On the other hand, in primary cultured hippocampal neurons expressing endogenous receptors, the nuclear accumulation rates of the YFP-MR chimera and CFP-GR chimera were nearly the same in the presence of both concentrations of CORT [24].
  • These studies indicate that this dose of dexamethasone exerts its inhibitory effects on the HPA axis primarily by acting at GR in the pituitary [28].
  • These results support and extend other studies which suggest that the DST provides a direct test of the effects of increased GR activation in the pituitary on ACTH and cortisol secretion [28].

Physical interactions of Nr3c1


Co-localisations of Nr3c1


Regulatory relationships of Nr3c1

  • However, whether hypothalamic CRF levels influence changes in hippocampal GR expression (and memory function), via reduced CRF receptor activation and consequent lower plasma glucocorticoid levels, is unclear [25].
  • We observed that the GR agonist RU 28362 blocks the attenuating action of the MR agonist aldosterone on responses to 3, 10 and 30 microM 5HT; RU 28362 by itself did not affect 5HT responses [35].
  • Our results with short interference RNA (siRNA) technology confirmed that UDCA significantly reduces TGF-beta1-induced apoptosis of primary rat hepatocytes through a GR-dependent effect [23].
  • Supplementation with corticosterone (20 or GR-specific dexamethasone (1 during low endogenous corticosterone suppressed renal COX-2 mRNA and protein and led to a restricted distribution of COX-2 immunolabeling [36].
  • As a functional correlate of increased 11betaHSD-2 expression in colon, the GR-stimulated sodium-hydrogen exchanger NHE-3 was lowered by NaCl restriction [37].

Other interactions of Nr3c1


Analytical, diagnostic and therapeutic context of Nr3c1


  1. Effects of diabetes and recurrent hypoglycemia on the regulation of the sympathoadrenal system and hypothalamo-pituitary-adrenal axis. Inouye, K.E., Chan, O., Yue, J.T., Matthews, S.G., Vranic, M. Am. J. Physiol. Endocrinol. Metab. (2005) [Pubmed]
  2. Regulation of glucocorticoid receptor expression: evidence for transcriptional and posttranslational mechanisms. Dong, Y., Poellinger, L., Gustafsson, J.A., Okret, S. Mol. Endocrinol. (1988) [Pubmed]
  3. The maternal diet during pregnancy programs altered expression of the glucocorticoid receptor and type 2 11beta-hydroxysteroid dehydrogenase: potential molecular mechanisms underlying the programming of hypertension in utero. Bertram, C., Trowern, A.R., Copin, N., Jackson, A.A., Whorwood, C.B. Endocrinology (2001) [Pubmed]
  4. Hyperthermic stress stimulates the association of both constitutive and inducible isoforms of 70 kDa heat shock protein with rat liver glucocorticoid receptor. Cvoro, A., Matić, G. Int. J. Biochem. Cell Biol. (2002) [Pubmed]
  5. 11-beta Hydroxysteroid dehydrogenase type 2 expression in white adipose tissue is strongly correlated with adiposity. Milagro, F.I., Campión, J., Martínez, J.A. J. Steroid Biochem. Mol. Biol. (2007) [Pubmed]
  6. Neurobiological correlates of individual differences in novelty-seeking behavior in the rat: differential expression of stress-related molecules. Kabbaj, M., Devine, D.P., Savage, V.R., Akil, H. J. Neurosci. (2000) [Pubmed]
  7. Altered control of the hypothalamo-pituitary-adrenal axis in adult male rats exposed perinatally to food deprivation and/or dehydration. Sebaai, N., Lesage, J., Vieau, D., Alaoui, A., Dupouy, J.P., Deloof, S. Neuroendocrinology (2002) [Pubmed]
  8. Dopamine-dependent responses to morphine depend on glucocorticoid receptors. Marinelli, M., Aouizerate, B., Barrot, M., Le Moal, M., Piazza, P.V. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  9. Nicotine withdrawal induces subsensitivity of hypothalamic-pituitary-adrenal axis to stress in rats: implications for precipitation of depression during smoking cessation. Semba, J., Wakuta, M., Maeda, J., Suhara, T. Psychoneuroendocrinology (2004) [Pubmed]
  10. Chronic lithium chloride injection increases glucocorticoid receptor but not mineralocorticoid receptor mRNA expression in rat brain. Semba, J., Watanabe, H., Suhara, T., Akanuma, N. Neurosci. Res. (2000) [Pubmed]
  11. In vivo footprinting of rat TAT gene: dynamic interplay between the glucocorticoid receptor and a liver-specific factor. Rigaud, G., Roux, J., Pictet, R., Grange, T. Cell (1991) [Pubmed]
  12. Genetic complementation of a glucocorticoid receptor deficiency by expression of cloned receptor cDNA. Miesfeld, R., Rusconi, S., Godowski, P.J., Maler, B.A., Okret, S., Wikström, A.C., Gustafsson, J.A., Yamamoto, K.R. Cell (1986) [Pubmed]
  13. Sequences in the promoter region of the chicken lysozyme gene required for steroid regulation and receptor binding. Renkawitz, R., Schütz, G., von der Ahe, D., Beato, M. Cell (1984) [Pubmed]
  14. DNA sequences bound specifically by glucocorticoid receptor in vitro render a heterologous promoter hormone responsive in vivo. Chandler, V.L., Maler, B.A., Yamamoto, K.R. Cell (1983) [Pubmed]
  15. Specific binding of the glucocorticoid-receptor complex to the mouse mammary tumor proviral promoter region. Pfahl, M. Cell (1982) [Pubmed]
  16. The resistance of the Wistar/Furth rat strain to steroid hypertension. Kayes, K., Ziegler, L., Yu, C.P., Brownie, A.C., Gallant, S. Endocr. Res. (1996) [Pubmed]
  17. Visceromotor and spinal neuronal responses to colorectal distension in rats with aldosterone onto the amygdala. Qin, C., Greenwood-Van Meerveld, B., Foreman, R.D. J. Neurophysiol. (2003) [Pubmed]
  18. Cognitive impairment associated to HPA axis hyperactivity after maternal separation in rats. Aisa, B., Tordera, R., Lasheras, B., Del Río, J., Ramírez, M.J. Psychoneuroendocrinology (2007) [Pubmed]
  19. Glucocorticoid receptor and NGFI-A gene expression are induced in the hippocampus after environmental enrichment in adult rats. Olsson, T., Mohammed, A.H., Donaldson, L.F., Henriksson, B.G., Seckl, J.R. Brain Res. Mol. Brain Res. (1994) [Pubmed]
  20. Localization of a negative glucocorticoid response element of the human corticotropin releasing hormone gene. Malkoski, S.P., Handanos, C.M., Dorin, R.I. Mol. Cell. Endocrinol. (1997) [Pubmed]
  21. Steroid receptor heterodimerization demonstrated in vitro and in vivo. Liu, W., Wang, J., Sauter, N.K., Pearce, D. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  22. Reconstitution of glucocorticoid receptor-dependent transcription in vivo. Trotter, K.W., Archer, T.K. Mol. Cell. Biol. (2004) [Pubmed]
  23. Nuclear translocation of UDCA by the glucocorticoid receptor is required to reduce TGF-beta1-induced apoptosis in rat hepatocytes. Solá, S., Amaral, J.D., Castro, R.E., Ramalho, R.M., Borralho, P.M., Kren, B.T., Tanaka, H., Steer, C.J., Rodrigues, C.M. Hepatology (2005) [Pubmed]
  24. Dynamic changes in subcellular localization of mineralocorticoid receptor in living cells: in comparison with glucocorticoid receptor using dual-color labeling with green fluorescent protein spectral variants. Nishi, M., Ogawa, H., Ito, T., Matsuda, K.I., Kawata, M. Mol. Endocrinol. (2001) [Pubmed]
  25. Enduring, handling-evoked enhancement of hippocampal memory function and glucocorticoid receptor expression involves activation of the corticotropin-releasing factor type 1 receptor. Fenoglio, K.A., Brunson, K.L., Avishai-Eliner, S., Stone, B.A., Kapadia, B.J., Baram, T.Z. Endocrinology (2005) [Pubmed]
  26. Inhibition of 11beta-hydroxysteroid dehydrogenase, the foeto-placental barrier to maternal glucocorticoids, permanently programs amygdala GR mRNA expression and anxiety-like behaviour in the offspring. Welberg, L.A., Seckl, J.R., Holmes, M.C. Eur. J. Neurosci. (2000) [Pubmed]
  27. Glucocorticoid receptor (GR)-associated SMRT binding to C/EBPbeta TAD and Nrf2 Neh4/5: role of SMRT recruited to GR in GSTA2 gene repression. Ki, S.H., Cho, I.J., Choi, D.W., Kim, S.G. Mol. Cell. Biol. (2005) [Pubmed]
  28. Dexamethasone suppression of corticosteroid secretion: evaluation of the site of action by receptor measures and functional studies. Cole, M.A., Kim, P.J., Kalman, B.A., Spencer, R.L. Psychoneuroendocrinology (2000) [Pubmed]
  29. Aldosterone modulates glucocorticoid receptor binding in hippocampal cell cultures via the mineralocorticoid receptor. O'Donnell, D., Meaney, M.J. Brain Res. (1994) [Pubmed]
  30. Comparison of the whey acidic protein genes of the rat and mouse. Campbell, S.M., Rosen, J.M., Hennighausen, L.G., Strech-Jurk, U., Sippel, A.E. Nucleic Acids Res. (1984) [Pubmed]
  31. Yin-yang 1 and glucocorticoid receptor participate in the Stat5-mediated growth hormone response of the serine protease inhibitor 2.1 gene. Bergad, P.L., Towle, H.C., Berry, S.A. J. Biol. Chem. (2000) [Pubmed]
  32. Spaceflight modulates insulin-like growth factor binding proteins and glucocorticoid receptor in osteoblasts. Kumei, Y., Shimokawa, H., Katano, H., Akiyama, H., Hirano, M., Mukai, C., Nagaoka, S., Whitson, P.A., Sams, C.F. J. Appl. Physiol. (1998) [Pubmed]
  33. Maternal programming of steroid receptor expression and phenotype through DNA methylation in the rat. Szyf, M., Weaver, I.C., Champagne, F.A., Diorio, J., Meaney, M.J. Frontiers in neuroendocrinology. (2005) [Pubmed]
  34. Demonstration of glucocorticoid receptor-like immunoreactivity in glucocorticoid-sensitive vasopressin and corticotropin-releasing factor neurons in the hypothalamic paraventricular nucleus. Uht, R.M., McKelvy, J.F., Harrison, R.W., Bohn, M.C. J. Neurosci. Res. (1988) [Pubmed]
  35. Coordinative mineralocorticoid and glucocorticoid receptor-mediated control of responses to serotonin in rat hippocampus. Joëls, M., De Kloet, E.R. Neuroendocrinology (1992) [Pubmed]
  36. Low endogenous glucocorticoid allows induction of kidney cortical cyclooxygenase-2 during postnatal rat development. Madsen, K., Stubbe, J., Yang, T., Skøtt, O., Bachmann, S., Jensen, B.L. Am. J. Physiol. Renal Physiol. (2004) [Pubmed]
  37. Stimulation of 11-beta-hydroxysteroid dehydrogenase type 2 in rat colon but not in kidney by low dietary NaCl intake. Nørregaard, R., Uhrenholt, T.R., Bistrup, C., Skøtt, O., Jensen, B.L. Am. J. Physiol. Renal Physiol. (2003) [Pubmed]
  38. Long-term antidepressant administration alters corticotropin-releasing hormone, tyrosine hydroxylase, and mineralocorticoid receptor gene expression in rat brain. Therapeutic implications. Brady, L.S., Whitfield, H.J., Fox, R.J., Gold, P.W., Herkenham, M. J. Clin. Invest. (1991) [Pubmed]
  39. 11 beta-Hydroxysteroid dehydrogenase activity and corticosteroid hormone action. Stewart, P.M., Whorwood, C.B. Steroids (1994) [Pubmed]
  40. The novel progestin drospirenone and its natural counterpart progesterone: biochemical profile and antiandrogenic potential. Fuhrmann, U., Krattenmacher, R., Slater, E.P., Fritzemeier, K.H. Contraception. (1996) [Pubmed]
  41. Region-specific onset of handling-induced changes in corticotropin-releasing factor and glucocorticoid receptor expression. Fenoglio, K.A., Brunson, K.L., Avishai-Eliner, S., Chen, Y., Baram, T.Z. Endocrinology (2004) [Pubmed]
  42. Lack of decrease in hypothalamic and hippocampal glucocorticoid receptor mRNA during starvation. Makino, S., Kaneda, T., Nishiyama, M., Asaba, K., Hashimoto, K. Neuroendocrinology (2001) [Pubmed]
  43. Corticotropin-releasing factor and glucocorticoid receptor (GR) gene expression in the paraventricular nucleus of immune-challenged transgenic mice expressing type II GR antisense ribonucleic acid. Laflamme, N., Barden, N., Rivest, S. J. Mol. Neurosci. (1997) [Pubmed]
  44. Regulation of hippocampal glucocorticoid receptor gene transcription and protein expression in vivo. Herman, J.P., Spencer, R. J. Neurosci. (1998) [Pubmed]
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