O receptor de glicocorticoides (GCR ou GR), tamén chamado NR3C1 (receptor nuclear subfamilia 3, grupo C, membro 1), é o receptor citosólico ao cal se unen o cortisol e outros glicocorticoides.
Datos rápidos NR3C1, Estruturas dispoñibles ...
NR3C1 |
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PDB | Buscar ortólogos: PDBe, RCSB
Lista de códigos PDB
- 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
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Nomenclatura |
Outros nomes
- NR3C1, GCCR, GCR, GCRST, GR, GRL, receptor nuclear subfamilia 3 grupo C membro 1, receptor de glicocorticoides
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Símbolos | NR3C1 (HGNC: 7978)
NR3C1, GCCR, GCR, GCRST, GR, GRL |
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Locus | Cr. 5 q31.3
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Padrón de expresión de ARNm |
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Pechar
O GCR exprésase en case todas as células do corpo e regula xenes que controlan o desenvolvemento, metabolismo e resposta inmune. Como o xene do receptor exprésase de varias formas, ten moitos efectos diferentes (pleiotrópicos) en diferentes partes do corpo.
Cando os glicocorticoides se unen a este receptor, o seu mecanimso primario de acción é a regulación da transcrición xénica.[1][2] O receptor non unido a ligando encóntrase no citosol da célula. Despois de que o receptor se une a un glicocorticoide, o complexo receptor-glicocorticoide pode tomar dous camiños posibles: o complexo do receptor activado regula á alza a expresión de proteínas antiinflamatorias no núcleo ou ben reprime a expresión de proteínas proinflamatorias no citosol (ao impedir a translocación doutros factores de transcrición do citosol ao núcleo).
En humanos, a proteína do receptor de glicocorticoides está codificada polo xene NR3C1 que está localizado no cromosoma 5 (5q31).[3][4]
Este receptor citosólico actúa por medio de mecanismos xenómicos, e non debe confundirse cos receptores de glicocorticoides de membrana, que se encontran na superficie celular e actúan por medio de cadoiros de sinalización.
Como outros receptores de esteroides,[5] o receptor de glicocortocoides ten estrutura modular.[6] e contén os seguintes dominios (designados do A ao F):
- A/B - dominio regulatorio N-terminal
- C - dominio de unión ao ADN (DBD)
- D - rexión bisagra
- E - dominio de unión ao ligando (LBD)
- F - dominio C-terminal.
En ausencia de hormona, o receptor de glicocorticoides (GCR) encóntrase no citosol formando un complexo con diversas proteínas, como a proteína de choque térmico 90 (hsp90), a proteína de choque térmico 70 (hsp70) e a proteína FKBP4 (proteína que se une a FK506 4).[7] A hormona glicocorticoide endóxena cortisol difunde a través da membrana plasmática ata o citoplasma e únese ao receptor de glicocorticoides, causando a liberación das proteínas de choque térmico que formaban o complexo. Como resultado o receptor queda activado e exhibe dous mecanismos principais de acción: transactivación e transrepresión,[8][9] que se describen máis abaixo.
Transactivación
Un mecanismo directo de acción implica a homodimerización do receptor, a translocación vía transporte activo ao núcleo celular e a unión a elementos de resposta ao ADN específicos activadores da
transcrición de xenes. Este mecanismo de acción denomínase transactivación. A resposta biolóxica depende do tipo celular.[10]
Transrepresión
En ausencia de GCR activado, outros factores de transcrición como NF-κB ou AP-1 poden transactivar xenes diana.[11] Porén, o GCR activado pode formar complexos con estes outros factores de transcrición e impedirlles unirse aos seus xenes diana e así reprimir a expresión de xenes que normalmente son regulados á alza por NF-κB ou AP-1. Este mecanismo indirecto de acción denomínase transrepresión.[12] A transrepresión do GCR por medio de NF-κB e AP-1 está restrinxida a só certos tipos celulares e non se considera o mecanismo universal para a represión de IκBα (I kapaB alfa é unha proteína inhibidora que impide o transporte nuclear e activación do factor de transcrición NF-kapaB). [12][13]
O GCR é anormal na resistencia a glicocorticoides familiar.[14]
En estruturas do sistema nervioso central, aumenta o interese polo receptor de glicocorticoides como novo representante da integración neuroendócrina, funcionando como un compoñente importante da influencia endócrina (especificamente a resposta ao estrés) sobre o cerebro. O receptor está agora implicado en adaptacións a curto e longo prazo observadas en resposta a estresantes e pode ser fundamental para comprender trastornos psicolóxicos, como algúns ou todos os subtipos de depresión e trastorno por estrés postraumático.[15] As observacións de longa duración como a desregulación do estado de ánimo típica da enfermidade de Cushing demostran o papel dos corticosteroides na regulación do estado psicolóxico; avances recentes demostraron interaccións coa norepinefrina e serotonina a nivel neural.[16][17]
Na preeclampsia (un trastorno hipertensivo que pode ocorrer en mulleres xestantes), o nivel de secuencias de microARN que posiblemente teñen como diana esta proteína é elevado no sangue da nai. A placenta eleva o nivel de exosomas que conteñen este microARN, o cal ten como resultado a inhibición da tradución da molécula. A importancia clínica desta información aínda non está clara.[18]
A dexametasona e outros corticosteroides son agonistas, mentres que a mifepristona e cetoconazol son antagonistas do GCR. Os esteroides anabólicos tamén impiden que o cortisol se una ao GCR.
O receptor de glicocorticoides presenta interaccións con:
- BAG1,[19][20]
- CEBPB,[21]
- CREBBP,[22]
- DAP3,[23]
- DAXX,[24]
- HSP90AA1,[23][25][26][27][28][29][30]
- HNRPU,[31]
- MED1,[32][33]
- MED14,[33]
- Receptor de mineralocorticoides,[34]
- NRIP1,[32][35][36]
- NCOR1,[37][38]
- NCOA1,[32][39]
- NCOA2,[32][40]
- NCOA3,[32][41]
- POU2F1,[42][43]
- RANBP9,[44]
- RELA,[44][45][46]
- SMAD3,[47][48]
- SMARCD1,[41]
- SMARCA4[41][49]
- STAT3,[50][51]
- STAT5B,[52]
- Tiorredoxina,[53]
- TRIM28,[54] e
- YWHAH.[55]
Lu NZ, Wardell SE, Burnstein KL, Defranco D, Fuller PJ, Giguere V, et al. (decembro de 2006). "International Union of Pharmacology. LXV. The pharmacology and classification of the nuclear receptor superfamily: glucocorticoid, mineralocorticoid, progesterone, and androgen receptors". Pharmacological Reviews 58 (4): 782–797. PMID 17132855. doi:10.1124/pr.58.4.9. [texto completo libre]
Rhen T, Cidlowski JA (outubro de 2005). "Antiinflammatory action of glucocorticoids--new mechanisms for old drugs". The New England Journal of Medicine 353 (16): 1711–1723. PMID 16236742. doi:10.1056/NEJMra050541.
Kumar R, Thompson EB (abril de 2005). "Gene regulation by the glucocorticoid receptor: structure:function relationship". The Journal of Steroid Biochemistry and Molecular Biology 94 (5): 383–394. PMID 15876404. doi:10.1016/j.jsbmb.2004.12.046.
Gaurang C. Patel; J. Cameron Millar; Abbot F. Clark. Glucocorticoid Receptor Transactivation Is Required for Glucocorticoid-Induced Ocular Hypertension and Glaucoma. Investigative Ophthalmology & Visual Science., maio de 2019, Vol.60, 1967-1978. doi:https://doi.org/10.1167/iovs.18-26383
Mendonca BB, Leite MV, de Castro M, Kino T, Elias LL, Bachega TA, et al. (abril de 2002). "Female pseudohermaphroditism caused by a novel homozygous missense mutation of the GR gene". The Journal of Clinical Endocrinology and Metabolism 87 (4): 1805–1809. PMID 11932321. doi:10.1210/jcem.87.4.8379.
Schechter DS, Moser DA, Paoloni-Giacobino A, Stenz A, Gex-Fabry M, Aue T, Adouan W, Cordero MI, Suardi F, Manini A, Sancho Rossignol A, Merminod G, Ansermet F, Dayer AG, Rusconi Serpa S (epub May 29, 2015). Methylation of NR3C1 is related to maternal PTSD, parenting stress and maternal medial prefrontal cortical activity in response to child separation among mothers with histories of violence exposure. Frontiers in Psychology. http://www.frontiersin.org/Journal/Abstract.aspx?s=944&name=psychology_for_clinical_settings&ART_DOI=10.3389/fpsyg.2015.00690&field=&journalName=Frontiers_in_Psychology&id=139466
Salomon C, Guanzon D, Scholz-Romero K, Longo S, Correa P, Illanes SE, Rice GE (setembro de 2017). "Placental Exosomes as Early Biomarker of Preeclampsia: Potential Role of Exosomal MicroRNAs Across Gestation". The Journal of Clinical Endocrinology and Metabolism 102 (9): 3182–3194. PMID 28531338. doi:10.1210/jc.2017-00672.
Kullmann M, Schneikert J, Moll J, Heck S, Zeiner M, Gehring U, Cato AC (xuño de 1998). "RAP46 is a negative regulator of glucocorticoid receptor action and hormone-induced apoptosis". The Journal of Biological Chemistry 273 (23): 14620–14625. PMID 9603979. doi:10.1074/jbc.273.23.14620.
Boruk M, Savory JG, Haché RJ (novembro de 1998). "AF-2-dependent potentiation of CCAAT enhancer binding protein beta-mediated transcriptional activation by glucocorticoid receptor". Molecular Endocrinology 12 (11): 1749–1763. PMID 9817600. doi:10.1210/mend.12.11.0191.
Almlöf T, Wallberg AE, Gustafsson JA, Wright AP (xuño de 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): 9586–9594. PMID 9649342. doi:10.1021/bi973029x.
Lin DY, Lai MZ, Ann DK, Shih HM (maio de 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". The Journal of Biological Chemistry 278 (18): 15958–15965. PMID 12595526. doi:10.1074/jbc.M300387200.
Jibard N, Meng X, Leclerc P, Rajkowski K, Fortin D, Schweizer-Groyer G, et al. (marzo de 1999). "Delimitation of two regions in the 90-kDa heat shock protein (Hsp90) able to interact with the glucocorticosteroid receptor (GR)". Experimental Cell Research 247 (2): 461–474. PMID 10066374. doi:10.1006/excr.1998.4375.
Kanelakis KC, Shewach DS, Pratt WB (setembro de 2002). "Nucleotide binding states of hsp70 and hsp90 during sequential steps in the process of glucocorticoid receptor.hsp90 heterocomplex assembly". The Journal of Biological Chemistry 277 (37): 33698–33703. PMID 12093808. doi:10.1074/jbc.M204164200.
Hecht K, Carlstedt-Duke J, Stierna P, Gustafsson J, Brönnegârd M, Wikström AC (outubro de 1997). "Evidence that the beta-isoform of the human glucocorticoid receptor does not act as a physiologically significant repressor". The Journal of Biological Chemistry 272 (42): 26659–26664. PMID 9334248. doi:10.1074/jbc.272.42.26659.
van den Berg JD, Smets LA, van Rooij H (febreiro de 1996). "Agonist-free transformation of the glucocorticoid receptor in human B-lymphoma cells". The Journal of Steroid Biochemistry and Molecular Biology 57 (3–4): 239–249. PMID 8645634. doi:10.1016/0960-0760(95)00271-5.
Stancato LF, Silverstein AM, Gitler C, Groner B, Pratt WB (abril de 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". The Journal of Biological Chemistry 271 (15): 8831–8836. PMID 8621522. doi:10.1074/jbc.271.15.8831.
Eggert M, Michel J, Schneider S, Bornfleth H, Baniahmad A, Fackelmayer FO, et al. (novembro de 1997). "The glucocorticoid receptor is associated with the RNA-binding nuclear matrix protein hnRNP U". The Journal of Biological Chemistry 272 (45): 28471–28478. PMID 9353307. doi:10.1074/jbc.272.45.28471.
Zilliacus J, Holter E, Wakui H, Tazawa H, Treuter E, Gustafsson JA (abril de 2001). "Regulation of glucocorticoid receptor activity by 14--3-3-dependent intracellular relocalization of the corepressor RIP140". Molecular Endocrinology 15 (4): 501–511. PMID 11266503. doi:10.1210/mend.15.4.0624.
Subramaniam N, Treuter E, Okret S (xuño de 1999). "Receptor interacting protein RIP140 inhibits both positive and negative gene regulation by glucocorticoids". The Journal of Biological Chemistry 274 (25): 18121–18127. PMID 10364267. doi:10.1074/jbc.274.25.18121.
Stevens A, Garside H, Berry A, Waters C, White A, Ray D (maio de 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". Molecular Endocrinology 17 (5): 845–859. PMID 12569182. doi:10.1210/me.2002-0320.
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". The Journal of Biological Chemistry 277 (29): 26238–26243. PMID 12011091. doi:10.1074/jbc.M203268200.
Kucera T, Waltner-Law M, Scott DK, Prasad R, Granner DK (xullo de 2002). "A point mutation of the AF2 transactivation domain of the glucocorticoid receptor disrupts its interaction with steroid receptor coactivator 1". The Journal of Biological Chemistry 277 (29): 26098–26102. PMID 12118039. doi:10.1074/jbc.M204013200.
Bledsoe RK, Montana VG, Stanley TB, Delves CJ, Apolito CJ, McKee DD, et al. (xullo de 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. PMID 12151000. doi:10.1016/S0092-8674(02)00817-6.
Préfontaine GG, Walther R, Giffin W, Lemieux ME, Pope L, Haché RJ (setembro 1999). "Selective binding of steroid hormone receptors to octamer transcription factors determines transcriptional synergism at the mouse mammary tumor virus promoter". The Journal of Biological Chemistry 274 (38): 26713–26719. PMID 10480874. doi:10.1074/jbc.274.38.26713.
Rao MA, Cheng H, Quayle AN, Nishitani H, Nelson CC, Rennie PS (decembro de 2002). "RanBPM, a nuclear protein that interacts with and regulates transcriptional activity of androgen receptor and glucocorticoid receptor". The Journal of Biological Chemistry 277 (50): 48020–48027. PMID 12361945. doi:10.1074/jbc.M209741200.
Caldenhoven E, Liden J, Wissink S, Van de Stolpe A, Raaijmakers J, Koenderman L, et al. (abril de 1995). "Negative cross-talk between RelA and the glucocorticoid receptor: a possible mechanism for the antiinflammatory action of glucocorticoids". Molecular Endocrinology 9 (4): 401–412. PMID 7659084. doi:10.1210/mend.9.4.7659084.
Li G, Wang S, Gelehrter TD (outubro de 2003). "Identification of glucocorticoid receptor domains involved in transrepression of transforming growth factor-beta action". The Journal of Biological Chemistry 278 (43): 41779–41788. PMID 12902338. doi:10.1074/jbc.M305350200.
Zhang Z, Jones S, Hagood JS, Fuentes NL, Fuller GM (decembro de 1997). "STAT3 acts as a co-activator of glucocorticoid receptor signaling". The Journal of Biological Chemistry 272 (49): 30607–30610. PMID 9388192. doi:10.1074/jbc.272.49.30607.
Makino Y, Yoshikawa N, Okamoto K, Hirota K, Yodoi J, Makino I, Tanaka H (xaneiro de 1999). "Direct association with thioredoxin allows redox regulation of glucocorticoid receptor function". The Journal of Biological Chemistry 274 (5): 3182–3188. PMID 9915858. doi:10.1074/jbc.274.5.3182.
Wakui H, Wright AP, Gustafsson J, Zilliacus J (marzo de 1997). "Interaction of the ligand-activated glucocorticoid receptor with the 14-3-3 eta protein". The Journal of Biological Chemistry 272 (13): 8153–8156. PMID 9079630. doi:10.1074/jbc.272.13.8153.
Bibliografía
- Adcock IM, Ito K (xuño de 2000). "Molecular mechanisms of corticosteroid actions". Monaldi Archives for Chest Disease = Archivio Monaldi per le Malattie del Torace 55 (3): 256–266. PMID 10948677.
- Chikanza IC (xuño de 2002). "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. Bibcode:2002NYASA.966...39C. PMID 12114257. doi:10.1111/j.1749-6632.2002.tb04200.x.
- Neeck G, Kluter A, Dotzlaw H, Eggert M (xuño de 2002). "Involvement of the glucocorticoid receptor in the pathogenesis of rheumatoid arthritis". Annals of the New York Academy of Sciences 966 (1): 491–495. Bibcode:2002NYASA.966..491N. PMID 12114309. doi:10.1111/j.1749-6632.2002.tb04252.x.
- Yudt MR, Cidlowski JA (agosto de 2002). "The glucocorticoid receptor: coding a diversity of proteins and responses through a single gene". Molecular Endocrinology 16 (8): 1719–1726. PMID 12145329. doi:10.1210/me.2002-0106.
- Torrego A, Pujols L, Picado C (September 2002). "[Response to glucocorticoid treatment in asthma. The role of alpha and beta isoforms of the glucocorticoid receptor]". Archivos de Bronconeumologia 38 (9): 436–440. PMID 12237016. doi:10.1016/S0300-2896(02)75258-7.
- Bray PJ, Cotton RG (xuño de 2003). "Variations of the human glucocorticoid receptor gene (NR3C1): pathological and in vitro mutations and polymorphisms". Human Mutation 21 (6): 557–568. PMID 12754700. doi:10.1002/humu.10213.
- Kino T, Pavlakis GN (abril de 2004). "Partner molecules of accessory protein Vpr of the human immunodeficiency virus type 1". DNA and Cell Biology 23 (4): 193–205. PMID 15142377. doi:10.1089/104454904773819789.
- Lu NZ, Cidlowski JA (xuño de 2004). "The origin and functions of multiple human glucocorticoid receptor isoforms". Annals of the New York Academy of Sciences 1024 (1): 102–123. Bibcode:2004NYASA1024..102L. PMID 15265776. doi:10.1196/annals.1321.008.
- Kino T, Chrousos GP (xuño de 2004). "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. Bibcode:2004NYASA1024..153K. PMID 15265780. doi:10.1196/annals.1321.013.
- Andersen JL, Planelles V (xaneiro de 2005). "The role of Vpr in HIV-1 pathogenesis". Current HIV Research 3 (1): 43–51. PMID 15638722. doi:10.2174/1570162052772988.
- Le Rouzic E, Benichou S (febreiro de 2005). "The Vpr protein from HIV-1: distinct roles along the viral life cycle". Retrovirology 2 (1): 11. PMC 554975. PMID 15725353. doi:10.1186/1742-4690-2-11.
- Muthumani K, Choo AY, Premkumar A, Hwang DS, Thieu KP, Desai BM, Weiner DB (agosto de 2005). "Human immunodeficiency virus type 1 (HIV-1) Vpr-regulated cell death: insights into mechanism". Cell Death and Differentiation 12 (Suppl 1): 962–970. PMID 15832179. doi:10.1038/sj.cdd.4401583.
- Zhou J, Cidlowski JA (2005). "The human glucocorticoid receptor: one gene, multiple proteins and diverse responses". Steroids 70 (5–7): 407–417. PMID 15862824. doi:10.1016/j.steroids.2005.02.006.
- Chrousos GP, Kino T (outubro de 2005). "Intracellular glucocorticoid signaling: a formerly simple system turns stochastic". Science's STKE 2005 (304): pe48. PMID 16204701. doi:10.1126/stke.3042005pe48.
- Plotkin LL, Labutin AL, Lebedev LV, Khanukov LA, Zelikson OS (1975). "[Balloon probe for the removal of emboli and thrombi]". Meditsinskaya Tekhnika (3): 42–43. PMID 1152650.
- Subramaniam M, Colvard D, Keeting PE, Rasmussen K, Riggs BL, Spelsberg TC (decembro de 1992). "Glucocorticoid regulation of alkaline phosphatase, osteocalcin, and proto-oncogenes in normal human osteoblast-like cells". Journal of Cellular Biochemistry 50 (4): 411–424. PMID 1469072. doi:10.1002/jcb.240500410.
- Scherrer LC, Pratt WB (marzo de 1992). "Association of the transformed glucocorticoid receptor with a cytoskeletal protein complex". The Journal of Steroid Biochemistry and Molecular Biology 41 (3–8): 719–721. PMID 1562545. doi:10.1016/0960-0760(92)90411-B.
- Cadepond F, Gasc JM, Delahaye F, Jibard N, Schweizer-Groyer G, Segard-Maurel I, et al. (xullo de 1992). "Hormonal regulation of the nuclear localization signals of the human glucocorticosteroid receptor". Experimental Cell Research 201 (1): 99–108. PMID 1612132. doi:10.1016/0014-4827(92)90352-9.
- Hurley DM, Accili D, Stratakis CA, Karl M, Vamvakopoulos N, Rorer E, et al. (febreiro de 1991). "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. PMC 296359. PMID 1704018. doi:10.1172/JCI115046.
- Encío IJ, Detera-Wadleigh SD (abril de 1991). "The genomic structure of the human glucocorticoid receptor". The Journal of Biological Chemistry 266 (11): 7182–7188. PMID 1707881. doi:10.1016/S0021-9258(20)89627-6.