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Glukokortikoidni receptor

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Glukokortikoidni receptor (GR, GCR, NR3C1, nuklearni receptor potfamilije 3, grupa C, član 1) receptor je za koji se vezuju kortizol i drugi glukokortikoidi.

Nuklearni receptor potfamilije 3, grupa C, član 1 (glukokortikoidni receptor)

Kristalografska struktura DNK vezujućeg domena glukokortikoidnog receptora (DBD, levo, 1R4O vezan za DNK) i ligand vezujući domen [LBD, desno, 1M2Z vezan za deksametazon (beli štapići) i TIF2 koaktivatorski protein (crveno)]. Isprekidane žute linije predstavljaju interakcije vodoničnog vezivanja između receptora i liganda. 2D struktura deksametazona je takođe prikazana u dole desno.
Dostupne strukture
1M2Z, 1NHZ, 1P93, 3BQD, 3CLD, 3E7C, 3H52, 3K22, 3K23, 4HN5, 4HN6
Identifikatori
SimboliNR3C1; GCCR; GCR; GR; GRL
Vanjski IDOMIM: 138040 MGI: 95824 HomoloGene: 30960 IUPHAR: GeneCards: NR3C1 Gene
Pregled RNK izražavanja
podaci
Ortolozi
VrstaČovekMiš
Entrez290814815
EnsemblENSG00000113580ENSMUSG00000024431
UniProtP04150E9PUR6
RefSeq (mRNA)NM_000176NM_008173
RefSeq (protein)NP_000167NP_032199
Lokacija (UCSC)Chr 5:
142.66 - 142.82 Mb		Chr 18:
39.41 - 39.49 Mb
PubMed pretraga[1][2]

GR je izražen u skoro svim ćelijma a telu i reguliše gene koji kontrolišu razviće, metabolizam, i imunski respons. Gen ovog receptora se izražava u nekoliko formi, te stoga GR ima mnoštvo različitih (pleiotropskih) dejstava u različitim delovima tela.

Kad se za GR vežu glukokortikoidi, njegov primarni mehanizam dejstva je regulacija trakripcije gena.[1][2] Nevezani receptor se nalazi u ćelijskom citosolu. Nakon vezivanja glukokortikoida za receptor, receptor-glukortikoidni kompleks može da povisi izražavanje antiinflamatornih proteina u jedru ili da suzbije izražavanje proinflamatornih proteina u citozolu (putem sprečavanja translokacije drugih transkripcionih faktora iz citozola u jedro).

Kod ljudi, GR protein je kodiran NR3C1 genom koji je lociran na hromozomu 5 (5q31).[3][4]

Strukture uredi

Poput drugih steroidnih receptora,[5] glukokortikoidni receptor ima modularu strukturu[6] i sadrži sledeće domene (obležene sa A - F):

Vezivanje liganda i respons uredi

U odsustvu hormona, glukokortikoidni receptor (GR) se nalazi u citosolu u kompleksu sa raznim proteinima uključujući protein toplotnog šoka 90 (hsp90), protein toplotnog šoka 70 (hsp70) i protein FKBP52 (FK506 vezujući protein 52).[7] Endogeni glukokortikoidni hormon kortizol difuzijom prolazi kroz ćelijsku membranu u citoplazmu i vezuje se za glukokortikoidni receptor (GR), što dovodi do oslobađanja proteina toplotnog šoka. Rezultirajuća aktivirana forma GR ima dva moguća mehanizma dejstva, transaktivacija i transrepresija.[8][9]

Transaktivacija uredi

Direktni mehanizam dejstva obuhvata homodimerizaciju receptora, translokaciju putem aktivnog transporta u jedro, i vezivanje za specifiće DNK responsivne elemente, čime se aktivira transkripcija gena. Ovaj mehanizam dejstva se naziva transaktivacija. Biološki respons zavisi od tipa ćelije.

Transrepresija uredi

U odsustvu aktiviranog GR, drugi transkripcini faktori kao što je NF-κB ili AP-1 mogu da transaktiviraju ciljne gene.[10] Aktivirani GR može da formira kompleks as tim drugim transkripcionim faktorima i da spreči njihovo vezivanje za ciljne gene i time suzbije izražavanje gena koje normalno kontrolišu NF-κB ili AP-1. Ovaj indirektni mehanizam dejstva se naziva transrepresija.

Klinički značaj uredi

GR je abnormalan u sučajevima familialne glukokortikoidne otpornosti.[11]

U strukturama centralnog nervnog sistema, glukokortikoidni receptor učestvuje u neuroendokrinoj integraciji. On funkcioniše kao glavna komponenta endokrinog uticaja na mozak, posebno u responsu na stres. Ovaj receptor je impliciran u kratkotrajnu i dugotrajnu adaptaciju u responsu na stresore, i važan je za razumevanje psiholoških poremećaja, uključujući pojedine tipove depresije.[12][13]

Agonisti i antagonisti uredi

Deksametazon je agonist, a RU486 i ciproteron su antagonisti GR. Isto tako, progesteron i DHEA deluju kao antagonisti na GR.

Interacije uredi

Glukokortikoidni receptor može da formira interakcije sa:

5

Reference uredi

  1. ↑ Lu NZ, Wardell SE, Burnstein KL, Defranco D, Fuller PJ, Giguere V, Hochberg RB, McKay L, Renoir JM, Weigel NL, Wilson EM, McDonnell DP, Cidlowski JA (2006). „International Union of Pharmacology. LXV. The pharmacology and classification of the nuclear receptor superfamily: glucocorticoid, mineralocorticoid, progesterone, and androgen receptors”. Pharmacol Revl 58 (4): 782–97. DOI:10.1124/pr.58.4.9. PMID 17132855.  [Free full text]
  2. ↑ Rhen T, Cidlowski JA (October 2005). „Antiinflammatory action of glucocorticoids--new mechanisms for old drugs”. N. Engl. J. Med. 353 (16): 1711–23. DOI:10.1056/NEJMra050541. PMID 16236742. 
  3. ↑ Hollenberg SM, Weinberger C, Ong ES, Cerelli G, Oro A, Lebo R, Thompson EB, Rosenfeld MG, Evans RM (1985). „Primary structure and expression of a functional human glucocorticoid receptor cDNA”. Nature 318 (6047): 635–41. DOI:10.1038/318635a0. PMID 2867473. 
  4. ↑ Francke U, Foellmer BE (May 1989). „The glucocorticoid receptor gene is in 5q31-q32 [corrected]”. Genomics 4 (4): 610–2. DOI:10.1016/0888-7543(89)90287-5. PMID 2744768. 
  5. ↑ Kumar R, Thompson EB (1999). „The structure of the nuclear hormone receptors”. Steroids 64 (5): 310–9. DOI:10.1016/S0039-128X(99)00014-8. PMID 10406480. 
  6. ↑ Kumar R, Thompson EB (2005). „Gene regulation by the glucocorticoid receptor: structure:function relationship”. J. Steroid Biochem. Mol. Biol. 94 (5): 383–94. DOI:10.1016/j.jsbmb.2004.12.046. PMID 15876404. 
  7. ↑ Pratt WB, Morishima Y, Murphy M, Harrell M (2006). „Chaperoning of glucocorticoid receptors”. Handb Exp Pharmacol 172 (172): 111–38. DOI:10.1007/3-540-29717-0_5. PMID 16610357. 
  8. ↑ Buckingham JC (2006). „Glucocorticoids: exemplars of multi-tasking”. Br J Pharmacol 147 (Supplement 1): S258–68. DOI:10.1038/sj.bjp.0706456. PMC 1760726. PMID 16402112. 
  9. ↑ Hayashi R, Wada H, Ito K, Adcock IM (2004). „Effects of glucocorticoids on gene transcription”. Eur J Pharmacol 500 (1-3): 51–62. DOI:10.1016/j.ejphar.2004.07.011. PMID 15464020. 
  10. ↑ Ray A, Prefontaine KE (January 1994). „Physical association and functional antagonism between the p65 subunit of transcription factor NF-kappa B and the glucocorticoid receptor”. Proc. Natl. Acad. Sci. U.S.A. 91 (2): 752–6. DOI:10.1073/pnas.91.2.752. PMC 43027. PMID 8290595. 
  11. ↑ Mendonca B, Leite M, de Castro M, Kino T, Elias L, Bachega T, Arnhold I, Chrousos G, Latronico A (2002). „Female pseudohermaphroditism caused by a novel homozygous missense mutation of the GR gene”. J Clin Endocrinol Metab 87 (4): 1805–9. DOI:10.1210/jc.87.4.1805. PMID 11932321. 
  12. ↑ Maletic V, Robinson M, Oakes T, Iyengar S, Ball SG, Russell J (2007). „Neurobiology of depression: an integrated view of key findings”. Int J Clin Pract 61 (12): 2030–40. DOI:10.1111/j.1742-1241.2007.01602.x. PMC 2228409. PMID 17944926.  [Free full text]
  13. ↑ Savitz J, Lucki I, Drevets WC (2009). „5HT1A receptor function in Major Depressive Disorder”. Prog Neurobiol 88 (1): 17–31. DOI:10.1016/j.pneurobio.2009.01.009. PMC 2736801. PMID 19428959.  [Free full text]
  14. ↑ Kullmann M, Schneikert J, Moll J, Heck S, Zeiner M, Gehring U, Cato AC (June 1998). „RAP46 is a negative regulator of glucocorticoid receptor action and hormone-induced apoptosis”. J. Biol. Chem. 273 (23): 14620–5. DOI:10.1074/jbc.273.23.14620. PMID 9603979. 
  15. ↑ Schneikert J, Hübner S, Langer G, Petri T, Jäättelä M, Reed J, Cato AC (December 2000). „Hsp70-RAP46 interaction in downregulation of DNA binding by glucocorticoid receptor”. EMBO J. 19 (23): 6508–16. DOI:10.1093/emboj/19.23.6508. PMC 305849. PMID 11101523. 
  16. ↑ Boruk M, Savory JG, Haché RJ (November 1998). „AF-2-dependent potentiation of CCAAT enhancer binding protein beta-mediated transcriptional activation by glucocorticoid receptor”. Mol. Endocrinol. 12 (11): 1749–63. DOI:10.1210/me.12.11.1749. PMID 9817600. 
  17. ↑ 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): 9586–94. DOI:10.1021/bi973029x. PMID 9649342. 
  18. ↑ 18,0 18,1 Hulkko SM, Wakui H, Zilliacus J (August 2000). „The pro-apoptotic protein death-associated protein 3 (DAP3) interacts with the glucocorticoid receptor and affects the receptor function”. Biochem. J.. 349 Pt 3: 885–93. PMC 1221218. PMID 10903152. 
  19. ↑ Lin DY, Lai MZ, Ann DK, Shih HM (May 2003). „Promyelocytic leukemia protein (PML) functions as a glucocorticoid receptor co-activator by sequestering Daxx to the PML oncogenic domains (PODs) to enhance its transactivation potential”. J. Biol. Chem. 278 (18): 15958–65. DOI:10.1074/jbc.M300387200. PMID 12595526. 
  20. ↑ Jibard N, Meng X, Leclerc P, Rajkowski K, Fortin D, Schweizer-Groyer G, Catelli MG, Baulieu EE, Cadepond F (March 1999). „Delimitation of two regions in the 90-kDa heat shock protein (Hsp90) able to interact with the glucocorticosteroid receptor (GR)”. Exp. Cell Res. 247 (2): 461–74. DOI:10.1006/excr.1998.4375. PMID 10066374. 
  21. ↑ Kanelakis KC, Shewach DS, Pratt WB (September 2002). „Nucleotide binding states of hsp70 and hsp90 during sequential steps in the process of glucocorticoid receptor.hsp90 heterocomplex assembly”. J. Biol. Chem. 277 (37): 33698–703. DOI:10.1074/jbc.M204164200. PMID 12093808. 
  22. ↑ Hecht K, Carlstedt-Duke J, Stierna P, Gustafsson J, Brönnegârd M, Wikström AC (October 1997). „Evidence that the beta-isoform of the human glucocorticoid receptor does not act as a physiologically significant repressor”. J. Biol. Chem. 272 (42): 26659–64. DOI:10.1074/jbc.272.42.26659. PMID 9334248. 
  23. ↑ de Castro M, Elliot S, Kino T, Bamberger C, Karl M, Webster E, Chrousos GP (September 1996). „The non-ligand binding beta-isoform of the human glucocorticoid receptor (hGR beta): tissue levels, mechanism of action, and potential physiologic role”. Mol. Med. 2 (5): 597–607. PMC 2230188. PMID 8898375. 
  24. ↑ van den Berg JD, Smets LA, van Rooij H (February 1996). „Agonist-free transformation of the glucocorticoid receptor in human B-lymphoma cells”. J. Steroid Biochem. Mol. Biol. 57 (3-4): 239–49. DOI:10.1016/0960-0760(95)00271-5. PMID 8645634. 
  25. ↑ Stancato LF, Silverstein AM, Gitler C, Groner B, Pratt WB (April 1996). „Use of the thiol-specific derivatizing agent N-iodoacetyl-3-[125I]iodotyrosine to demonstrate conformational differences between the unbound and hsp90-bound glucocorticoid receptor hormone binding domain”. J. Biol. Chem. 271 (15): 8831–6. DOI:10.1074/jbc.271.15.8831. PMID 8621522. 
  26. ↑ Eggert M, Michel J, Schneider S, Bornfleth H, Baniahmad A, Fackelmayer FO, Schmidt S, Renkawitz R (November 1997). „The glucocorticoid receptor is associated with the RNA-binding nuclear matrix protein hnRNP U”. J. Biol. Chem. 272 (45): 28471–8. DOI:10.1074/jbc.272.45.28471. PMID 9353307. 
  27. ↑ 27,0 27,1 27,2 27,3 27,4 Zilliacus J, Holter E, Wakui H, Tazawa H, Treuter E, Gustafsson JA (April 2001). „Regulation of glucocorticoid receptor activity by 14--3-3-dependent intracellular relocalization of the corepressor RIP140”. Mol. Endocrinol. 15 (4): 501–11. DOI:10.1210/me.15.4.501. PMID 11266503. 
  28. ↑ 28,0 28,1 Hittelman AB, Burakov D, Iñiguez-Lluhí JA, Freedman LP, Garabedian MJ (October 1999). „Differential regulation of glucocorticoid receptor transcriptional activation via AF-1-associated proteins”. EMBO J. 18 (19): 5380–8. DOI:10.1093/emboj/18.19.5380. PMC 1171607. PMID 10508170. 
  29. ↑ Savory JG, Préfontaine GG, Lamprecht C, Liao M, Walther RF, Lefebvre YA, Haché RJ (February 2001). „Glucocorticoid receptor homodimers and glucocorticoid-mineralocorticoid receptor heterodimers form in the cytoplasm through alternative dimerization interfaces”. Mol. Cell. Biol. 21 (3): 781–93. DOI:10.1128/MCB.21.3.781-793.2001. PMC 86670. PMID 11154266. 
  30. ↑ Tazawa H, Osman W, Shoji Y, Treuter E, Gustafsson JA, Zilliacus J (June 2003). „Regulation of subnuclear localization is associated with a mechanism for nuclear receptor corepression by RIP140”. Mol. Cell. Biol. 23 (12): 4187–98. DOI:10.1128/MCB.23.12.4187-4198.2003. PMC 156128. PMID 12773562. 
  31. ↑ Subramaniam N, Treuter E, Okret S (June 1999). „Receptor interacting protein RIP140 inhibits both positive and negative gene regulation by glucocorticoids”. J. Biol. Chem. 274 (25): 18121–7. DOI:10.1074/jbc.274.25.18121. PMID 10364267. 
  32. ↑ Stevens A, Garside H, Berry A, Waters C, White A, Ray D (May 2003). „Dissociation of steroid receptor coactivator 1 and nuclear receptor corepressor recruitment to the human glucocorticoid receptor by modification of the ligand-receptor interface: the role of tyrosine 735”. Mol. Endocrinol. 17 (5): 845–59. DOI:10.1210/me.2002-0320. PMID 12569182. 
  33. ↑ Schulz M, Eggert M, Baniahmad A, Dostert A, Heinzel T, Renkawitz R (July 2002). „RU486-induced glucocorticoid receptor agonism is controlled by the receptor N terminus and by corepressor binding”. J. Biol. Chem. 277 (29): 26238–43. DOI:10.1074/jbc.M203268200. PMID 12011091. 
  34. ↑ Kucera T, Waltner-Law M, Scott DK, Prasad R, Granner DK (July 2002). „A point mutation of the AF2 transactivation domain of the glucocorticoid receptor disrupts its interaction with steroid receptor coactivator 1”. J. Biol. Chem. 277 (29): 26098–102. DOI:10.1074/jbc.M204013200. PMID 12118039. 
  35. ↑ Bledsoe RK, Montana VG, Stanley TB, Delves CJ, Apolito CJ, McKee DD, Consler TG, Parks DJ, Stewart EL, Willson TM, Lambert MH, Moore JT, Pearce KH, Xu HE (July 2002). „Crystal structure of the glucocorticoid receptor ligand binding domain reveals a novel mode of receptor dimerization and coactivator recognition”. Cell 110 (1): 93–105. DOI:10.1016/S0092-8674(02)00817-6. PMID 12151000. 
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  37. ↑ 37,0 37,1 Préfontaine, G G; Walther R, Giffin W, Lemieux M E, Pope L, Haché R J (1999). „Selective binding of steroid hormone receptors to octamer transcription factors determines transcriptional synergism at the mouse mammary tumor virus promoter”. J. Biol. Chem. (UNITED STATES) 274 (38): 26713–9. DOI:10.1074/jbc.274.38.26713. ISSN 0021-9258. PMID 10480874. 
  38. ↑ Préfontaine GG, Lemieux ME, Giffin W, Schild-Poulter C, Pope L, LaCasse E, Walker P, Haché RJ (June 1998). „Recruitment of octamer transcription factors to DNA by glucocorticoid receptor”. Mol. Cell. Biol. 18 (6): 3416–30. PMC 108923. PMID 9584182. 
  39. ↑ 39,0 39,1 Rao, Mira A; Cheng Helen, Quayle Alandra N, Nishitani Hideo, Nelson Colleen C, Rennie Paul S (December 2002). „RanBPM, a nuclear protein that interacts with and regulates transcriptional activity of androgen receptor and glucocorticoid receptor”. J. Biol. Chem. (United States) 277 (50): 48020–7. DOI:10.1074/jbc.M209741200. ISSN 0021-9258. PMID 12361945. 
  40. ↑ Nissen RM, Yamamoto KR (September 2000). „The glucocorticoid receptor inhibits NFkappaB by interfering with serine-2 phosphorylation of the RNA polymerase II carboxy-terminal domain”. Genes Dev. 14 (18): 2314–29. DOI:10.1101/gad.827900. PMC 316928. PMID 10995388. 
  41. ↑ Caldenhoven E, Liden J, Wissink S, Van de Stolpe A, Raaijmakers J, Koenderman L, Okret S, Gustafsson JA, Van der Saag PT (April 1995). „Negative cross-talk between RelA and the glucocorticoid receptor: a possible mechanism for the antiinflammatory action of glucocorticoids”. Mol. Endocrinol. 9 (4): 401–12. DOI:10.1210/me.9.4.401. PMID 7659084. 
  42. ↑ Li G, Wang S, Gelehrter TD (October 2003). „Identification of glucocorticoid receptor domains involved in transrepression of transforming growth factor-beta action”. J. Biol. Chem. 278 (43): 41779–88. DOI:10.1074/jbc.M305350200. PMID 12902338. 
  43. ↑ Song CZ, Tian X, Gelehrter TD (October 1999). „Glucocorticoid receptor inhibits transforming growth factor-beta signaling by directly targeting the transcriptional activation function of Smad3”. Proc. Natl. Acad. Sci. U.S.A. 96 (21): 11776–81. DOI:10.1073/pnas.96.21.11776. PMC 18362. PMID 10518526. 
  44. ↑ Wallberg AE, Neely KE, Hassan AH, Gustafsson JA, Workman JL, Wright AP (March 2000). „Recruitment of the SWI-SNF chromatin remodeling complex as a mechanism of gene activation by the glucocorticoid receptor tau1 activation domain”. Mol. Cell. Biol. 20 (6): 2004–13. DOI:10.1128/MCB.20.6.2004-2013.2000. PMC 110817. PMID 10688647. 
  45. ↑ Lerner L, Henriksen MA, Zhang X, Darnell JE (October 2003). „STAT3-dependent enhanceosome assembly and disassembly: synergy with GR for full transcriptional increase of the alpha 2-macroglobulin gene”. Genes Dev. 17 (20): 2564–77. DOI:10.1101/gad.1135003. PMC 218150. PMID 14522952. 
  46. ↑ Zhang Z, Jones S, Hagood JS, Fuentes NL, Fuller GM (December 1997). „STAT3 acts as a co-activator of glucocorticoid receptor signaling”. J. Biol. Chem. 272 (49): 30607–10. DOI:10.1074/jbc.272.49.30607. PMID 9388192. 
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  48. ↑ Makino Y, Yoshikawa N, Okamoto K, Hirota K, Yodoi J, Makino I, Tanaka H (January 1999). „Direct association with thioredoxin allows redox regulation of glucocorticoid receptor function”. J. Biol. Chem. 274 (5): 3182–8. DOI:10.1074/jbc.274.5.3182. PMID 9915858. 
  49. ↑ Chang CJ, Chen YL, Lee SC (October 1998). „Coactivator TIF1beta interacts with transcription factor C/EBPbeta and glucocorticoid receptor to induce alpha1-acid glycoprotein gene expression”. Mol. Cell. Biol. 18 (10): 5880–7. PMC 109174. PMID 9742105. 
  50. ↑ Wakui H, Wright AP, Gustafsson J, Zilliacus J (March 1997). „Interaction of the ligand-activated glucocorticoid receptor with the 14-3-3 eta protein”. J. Biol. Chem. 272 (13): 8153–6. DOI:10.1074/jbc.272.13.8153. PMID 9079630. 

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