Glukokortikoidni receptor

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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
Simboli	NR3C1; GCCR; GCR; GR; GRL
Vanjski ID	OMIM: 138040 MGI: 95824 HomoloGene: 30960 IUPHAR: GeneCards: NR3C1 Gene
Ontologija gena Molekularna funkcija • za sekvencu specifično dejstvo DNK vezujućeg transkripcionog faktora • aktivnost glukokortikoidnog receptora • vezivanje steroida Celularna komponenta • nukleus • nukleoplazma • nukleolus Biološki proces • regulacija glukoneogeneze • transkripcija, DNK zavisna • transkripcija iz promotera RNK polimeraze II
Pregled RNK izražavanja
podaci
Ortolozi
Vrsta	Čovek	Miš
Entrez	2908	14815
Ensembl	ENSG00000113580	ENSMUSG00000024431
UniProt	P04150	E9PUR6
RefSeq (mRNA)	NM_000176	NM_008173
RefSeq (protein)	NP_000167	NP_032199
Lokacija (UCSC)	Chr 5: 142.66 - 142.82 Mb	Chr 18: 39.41 - 39.49 Mb
PubMed pretraga	[1]	[2]

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

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

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

• A/B - N-terminal regulatory domain
• C - DNK vezujući domen (DBD)
• D - region šarke
• E - ligand vezujući domen (LBD)
• F - C-terminalni domen

Vezivanje liganda i respons

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

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

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

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

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

Interacije

Glukokortikoidni receptor može da formira interakcije sa:

• BAG1,^[14][15]
• CEBPB,^[16]
• CREBBP,^[17]
• DAP3,^[18]
• DAXX,^[19]
• HSP90AA1,^{[18][20][21][22][23][24][25]}
• HNRPU,^[26]
• MED1,^[27][28]
• MED14,^[28]
• Mineralokortikoidni receptor,^[29]
• NRIP1,^[27][30][31]
• NCOR1,^[32][33]
• NCOA1,^[27][34]
• NCOA2,^[27][35]
• NCOA3,^[27][36]
• POU2F1,^[37][37][38]
• RANBP9,^[39]
• RELA,^[39][40][41]
• SMAD3,^[42][43]
• SMARCD1,^[36]
• SMARCA4^[36][44]
• STAT3,^[45][46]
• STAT5B,^[47]
• Tioredoksin,^[48]
• TRIM28,^[49] and
• YWHAH.^[50]

Reference

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Povezano

• Selektivni agonist glukokortikoidnog receptora (SEGRA)

Spoljašnje veze

• Human Protein Reference Database Arhivirano 2006-03-01 na Wayback Machine-u
• MeSH Glucocorticoid+receptors
• FactorBook GR