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 OMIM138040 MGI95824 HomoloGene30960 IUPHAR: GeneCards: NR3C1 Gene
Pregled RNK izražavanja
PBB GE NR3C1 216321 s at tn.png
PBB GE NR3C1 201865 x at tn.png
PBB GE NR3C1 201866 s at tn.png
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[uredi - уреди]

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

Vezivanje liganda i respons[uredi - уреди]

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 - уреди]

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 - уреди]

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 - уреди]

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 - уреди]

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

Interacije[uredi - уреди]

Glukokortikoidni receptor može da formira interakcije sa:

Reference[uredi - уреди]

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