Nuclear receptors

Schematic representation of the mechanism of action of type 1 nuclear receptors: The nuclear receptor (NR) is initially located in the cytosol , where it binds the hormone, which triggers the separation of the heat shock protein (HSP), dimerization and translocation into the cell nucleus . There it binds to DNA with a fixed base sequence (HRE). This triggers (in this case) the transcription of the affected gene

Schematic representation of the mechanism of action of type 2 nuclear receptors: The nuclear receptor (TR) is already in the cell nucleus, bound to DNA, but without a ligand it has no effect on transcription. Hormones can diffuse into the cell nucleus as small molecules, where they bind to nuclear receptors, which change their function and become a repressor or activator of transcription

Nuclear receptors (also: nuclear receptors (NR) or ligand-activated transcription factors ) are special proteins that occur in the nucleus of multicellular animals . These are transcription factors that are only able to bind to DNA through the binding of a ligand (usually hormones ) and suppress or initiate the transcription of one or more genes . Nuclear receptors are the target of hormones whose signal they convert by influencing the production of certain proteins. The function as a transcription factor can be modified after the binding of the ligand by further binding partners. In humans, 48 ​​nuclear receptors are known, but the ligand has only been identified in a fraction of them.

The nuclear receptors can be classified either according to their mechanism of action or according to their ligand. Since the phylogenetic origin can be found both in the amino acid sequence and in the mechanism of action, the following classification has been established.

With regard to the mechanism of action, a distinction is made between whether the NR is in the cytosol or already in the cell nucleus, bound to DNA at the time the ligand is bound, or whether the DNA is bound as a monomer or a dimer.

1. The classic steroid receptors (type 1) such as the androgen receptor (but not the estrogen receptor ) are in the inactive state bound to heat shock proteins in the cytoplasm . After the binding of its ligand, the heat shock protein is separated, the receptor translocates into the cell nucleus and binds as a dimer to the DNA, which always has a palindromic recognition sequence .
2. The nuclear receptors of types 2, 3 and 4 are already located in the cell nucleus during ligand binding. They all have a zinc finger structural motif that binds to the DNA base sequence AGGTCA. This includes:
   • Estrogen receptor
   • Thyroid hormone receptor -like receptors such as peroxisome proliferator-activated receptors or vitamin D receptors
   • Retinoid X receptor -like receptors
   • NGF1-b-like
   • SF1-like
   • GCNF-like and others

Classification

The following is a classification of nuclear receptors according to homology:

Subfamily 1: thyroid hormone receptor-like

• Group A: Thyroid hormone receptor ( thyroid hormones )
  • 1: Thyroid hormone receptor-α ( TRα ; NR1A1, THRA )
  • 2: Thyroid hormone receptor-β ( TRβ ; NR1A2, THRB )
• Group B: retinoic acid receptor ( vitamin A and related compounds)
  • 1: Retinoic Acid Receptor-α ( RARα ; NR1B1, RARA )
  • 2: Retinoic Acid Receptor-β ( RARβ ; NR1B2, RARB )
  • 3: Retinoic Acid Receptor-γ ( RARγ ; NR1B3, RARG )
• Group C: Peroxisome proliferator-activated receptors ( fatty acids , prostaglandins )
  • 1: Peroxisome proliferator-activated receptors-α ( PPARα ; NR1C1, PPARA )
  • 2: Peroxisome proliferator-activated receptors-β / δ ( PPARβ / δ ; NR1C2, PPARD )
  • 3: Peroxisome proliferator-activated receptors-γ ( PPARγ ; NR1C3, PPARG )
• Group D: Rev-ErbA ( heme )
  • 1: Rev-ErbAα ( Rev-ErbAα ; NR1D1 )
  • 2: Rev-ErbAβ ( Rev-ErbAβ ; NR1D2 )
• Group F: RAR-related orphan receptors ( cholesterol , ATRA )
  • 1: RAR-related orphan receptors-α ( RORα ; NR1F1, RORA )
  • 2: RAR-related orphan receptors-β ( RORβ ; NR1F2, RORB )
  • 3: RAR-related orphan receptors-γ ( RORγ ; NR1F3, RORC )
• Group H: Liver X receptors -like (oxy sterol )
  • 3: Liver X receptors-α ( LXRα ; NR1H3 )
  • 2: Liver X receptors-β ( LXRβ ; NR1H2 )
  • 4: Farnesoid X receptors ( FXR ; NR1H4 )
• Group I: Vitamin D receptor-like
  • 1: Vitamin D receptors ( VDR ; NR1I1, VDR ) ( vitamin D )
  • 2: Pregnan-X receptors ( PXR ; NR1I2 ) ( xenobiotic )
  • 3: constitutive androstane receptors ( CAR ; NR1I3 ) ( androstane )

Subfamily 2: Retinoid X receptor-like

• Group A: Hepatocyte Nuclear Factor-4 (HNF4) ( fatty acids )
  • 1: Hepatocyte nuclear factor-4-α ( HNF4α ; NR2A1, HNF4A )
  • 2: Hepatocyte nuclear factor-4-γ ( HNF4γ ; NR2A2, HNF4G )
• Group B: Retinoid X receptors (RXRα) ( retinoids )
  • 1: Retinoid X receptors-α ( RXRα ; NR2B1, RXRA )
  • 2: Retinoid X receptors-β ( RXRβ ; NR2B2, RXRB )
  • 3: Retinoid X receptors-γ ( RXRγ ; NR2B3, RXRG )
• Group C: Testicular receptors
  • 1: Testicular receptors 2 ( TR2 ; NR2C1 )
  • 2: Testicular receptors 4 ( TR4 ; NR2C2 )
• Group E: TLX / PNR
  • 1: Human homologue of the Drosophila tailless gene ( TLX ; NR2E1 )
  • 3: Photoreceptors cell-specific core receptors ( PNR ; NR2E3 )
• Group F: COUP / EAR
  • 1: Chicken ovalbumin upstream promoter-transcription factor I ( COUP-TFI ; NR2F1 )
  • 2: Chicken ovalbumin upstream promoter-transcription factor II ( COUP-TFII ; NR2F2 )
  • 6: V-erbA-related gene | V-erbA-related ( EAR-2 ; NR2F6 )

Subfamily 3: Estrogen receptor-like

• Group A: estrogen receptor ( sex hormones : estrogens )
  • 1: Estrogen receptors-α ( ERα ; NR3A1, ESR1 )
  • 2: Estrogen receptors-β ( ERβ ; NR3A2, ESR2 )
• Group B: Estrogen linked receptors
  • 1: Estrogen-linked receptors-α ( ERRα ; NR3B1, ESRRA )
  • 2: Estrogen-linked receptors-β ( ERRβ ; NR3B2, ESRRB )
  • 3: Estrogen-linked receptors-γ ( ERRγ ; NR3B3, ESRRG )
• Group C: 3-ketosteroid receptors
  • 1: Glucocorticoid receptors ( GR ; NR3C1 ) ( cortisol )
  • 2: Mineralocorticoid receptors ( MR ; NR3C2 ) ( Aldosterone )
  • 3: Progesterone receptors ( PR ; NR3C3, PGR ) ( sex hormones : progesterones )
  • 4: Androgen receptor ( AR ; NR3C4, AR ) ( sex hormones : testosterones )

Subfamily 4: IB-like nerve growth factor

• Group A: NGFIB / NURR1 / NOR1
  • 1: Nerve growth factor IB ( NGFIB ; NR4A1 )
  • 2: nuclear receptors related 1 ( NURR1 ; NR4A2 )
  • 3: Neuron-derived orphan receptors 1 ( NOR1 ; NR4A3 )

Subfamily 5: Steroidogenic factor-like

• Group A: SF1 / LRH1
  • 1: Steroidogenic factor 1 ( SF1 ; NR5A1 ) ( phospholipids )
  • 2: liver receptor homolog-1 ( LRH-1 ; NR5A2 )

Subfamily 6: Germ Cell core factor-like

• Group A: GCNF
  • 1: Germ cell nuclear factor ( GCNF ; NR6A1 )

Subfamily 0: Miscellaneous

• Group B: DAX / SHP
  • 1: Dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1 ( DAX1 , NR0B1 )
  • 2: Small heterodimer partner ( SHP ; NR0B2 )

literature

• Bernhard Kleine: Hormones and the hormonal system . Springer, Berlin 2010, ISBN 978-3-642-00901-3 .

Individual evidence

1. ↑ Zhang Z, Burch PE, Cooney AJ, Lanz RB, Pereira FA, Wu J, Gibbs RA, Weinstock G, Wheeler DA: Genomic analysis of the nuclear receptor family: new insights into structure, regulation, and evolution from the rat genome . In: Genome Research . 14, No. 4, April 2004, pp. 580-90. doi : 10.1101 / gr.2160004 . PMID 15059999 . PMC 383302 (free full text).
2. ^ GO terminus ligand-dependent nuclear receptor activity .
3. ↑ ^{a b} Detlev Ganten, Klaus Ruckpaul: Molecular medical principles of endocrinopathies . Springer, Berlin 2001, ISBN 3-540-67788-7 , pp. 7th ff .
4. ^ Nuclear Receptors Nomenclature Committee: A unified nomenclature system for the nuclear receptor superfamily . In: Cell . 97, No. 2, 1999, pp. 161-3. doi : 10.1016 / S0092-8674 (00) 80726-6 . PMID 10219237 .
5. ↑ Laudet V: Evolution of the nuclear receptor superfamily: early diversification from an ancestral orphan receptor . In: J. Mol. Endocrinol. . 19, No. 3, 1997, pp. 207-26. doi : 10.1677 / jme.0.0190207 . PMID 9460643 .

Web links

• Vincent Laudet: The IUPHAR Compendium of the Pharmacology and Classification of the Nuclear Receptor Superfamily 2006E . The International Union of Basic and Clinical Pharmacology. 2006. Retrieved January 8, 2010.
• Nuclear Receptor Resource . Jack Vanden Heuvel. Retrieved January 8, 2010.