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Steroid receptors of the nuclear receptor family are all transcription factors. Depending upon the type of receptor, they are either located in the cytosol and move to the cell nucleus upon activation, or remain in the nucleus waiting for the steroid hormone to enter and activate them. This uptake into the nucleus is facilitated by nuclear localization signal (NLS) found in the hinge region of the receptor. This region of the receptor is covered up by heat shock proteins (HSPs) which bind the receptor until the hormone is present. Upon binding by the hormone the receptor undergoes a conformational change releasing the HSP, and the receptor together with the bound hormone enter the nucleus to act upon transcription.


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Ligands that bind to and activate nuclear receptors include lipophilic substances such as endogenous hormones, vitamins A and D, and xenobiotic endocrine disruptors. Because the expression of a large number of genes is regulated by nuclear receptors, ligands that activate these receptors can have profound effects on the organism. Many of these regulated genes are associated with various diseases, which explains why the molecular targets of approximately 13% of U.S. Food and Drug Administration (FDA) approved drugs are nuclear receptors. A number of nuclear receptors, referred to as orphan receptors, have no known (or at least generally agreed upon) endogenous ligands. Some of these receptors such as FXR, LXR, and PPAR bind a number of metabolic intermediates such as fatty acids, bile acids and/or sterols with relatively low affinity. These receptors hence may function as metabolic sensors. Other nuclear receptors, such as CAR and PXR appear to function as xenobiotic sensors up-regulating the expression of cytochrome P450 enzymes that metabolize these xenobiotics.


Genomic Depending on their mechanism of action and subcellular distribution, nuclear receptors may be classified into at least two classes.[1][2] Nuclear receptors that bind steroid hormones are all classified as type I receptors. Only type I receptors have a heat shock protein (HSP) associated with the inactive receptor that will be released when the receptor interacts with the ligand. Type I receptors may be found in homodimer or heterodimer forms. Type II nuclear receptors have no HSP, and in contrast to the classical type I receptor are located in the cell nucleus.

Free (that is, unbound) steroids enter the cell cytoplasm and interact with their receptor. In this process heat shock protein is dissociated, and the activated receptor-ligand complex is translocated into the nucleus.

After binding to the ligand (steroid hormone), steroid receptors often form dimers. In the nucleus, the complex acts as a transcription factor, augmenting or suppressing transcription particular genes by its action on DNA.

Type II receptors are located in the nucleus. Thus, their ligands pass through the cell membrane and cytoplasm and enter the nucleus where they activate the receptor without release of HSP. The activated receptor interacts with the hormone response element and the transcription process is initiated as with type I receptors.

Non-genomic The cell membrane aldosterone receptor has shown to increase the activity of the basolateral Na/K ATPase, ENaC sodium channels and ROMK potassium channels of the principal cell in the distal tubule and cortical collecting duct of nephrons (as well as in the large bowel and possibly in sweat glands).

There is some evidence that certain steroid hormone receptors can extend through lipid bilayer membranes at the surface of cells and might be able to interact with hormones that remain outside of cells.[3] Steroid hormone receptors can also function outside of the nucleus and couple to cytoplasmic signal transduction proteins such as PI3k and Akt kinase.[4]


Nuclear receptors are modular in structure and contain the following domains:

(A-B) N-terminal regulatory domain: Contains the activation function 1 (AF-1) whose action is independent of the presence of ligand.The transcriptional activation of AF-1 is normally very weak, but it does synergize with AF-2 in the E-domain (see below) to produce a more robust upregulation of gene expression. The A-B domain is highly variable in sequence between various nuclear receptors.

(C) DNA-binding domain (DBD): Highly conserved domain containing two zinc fingers that binds to specific sequences of DNA called hormone response elements (HRE).

(D) Hinge region: Thought to be a flexible domain that connects the DBD with the LBD. Influences intracellular trafficking and subcellular distribution.

(E) Ligand binding domain (LBD): Moderately conserved in sequence and highly conserved in structure between the various nuclear receptors. The structure of the LBD is referred to as an alpha helical sandwich fold in which three anti parallel alpha helices (the "sandwich filling") are flanked by two alpha helices on one side and three on the other (the "bread"). The ligand binding cavity is within the interior of the LBD and just below three anti parallel alpha helical sandwich "filling". Along with the DBD, the LBD contributes to the dimerization interface of the receptor and in addition, binds coactivator and corepressor proteins. The LBD also contains the activation function 2 (AF-2) whose action is dependent on the presence of bound ligand.

(F) C-terminal domain: Highly variable in sequence between various nuclear receptors. The N-terminal (A/B), DNA-binding (C), and ligand binding(E) domains are independently well folded and structurally stable while the hinge region (D) and optional C-terminal (F) domains may be conformationally flexible and disordered.

Nuclear receptors

Subfamily 3: Estrogen Receptor-like

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Group A: Estrogen receptor (Sex hormones: Estrogen)

1: Estrogen receptor-α (ERα; NR3A1, ESR1)

2: Estrogen receptor-β (ERβ; NR3A2, ESR2)

Group B: Estrogen related receptor

1: Estrogen-related receptor-α (ERRα; NR3B1, ESRRA)

2: Estrogen-related receptor-β (ERRβ; NR3B2, ESRRB)

3: Estrogen-related receptor-γ (ERRγ; NR3B3, ESRRG)

Group C: 3-Ketosteroid receptor

1: Glucocorticoid receptor (GR; NR3C1) (Cortisol)

2: Mineralocorticoid receptor (MR; NR3C2) (Aldosterone)

3: Progesterone receptor (PR; NR3C3, PGR) (Sex hormones: Progesterone)

4: Androgen receptor (AR; NR3C4, AR) (Sex hormones: Testosterone)

Mechanism of action

Nuclear receptors are multifunctional proteins that transduce signals of their cognate ligands. Nuclear receptors (NRs) may be classified into two broad classes according to their mechanism of action and subcellular distribution in the absence of ligand.

Small lipophilic substances such as natural hormones diffuse through the cell membrane and bind to nuclear receptors located in the cytosol (type I NR) or nucleus (type II NR) of the cell. Binding causes a conformational change in the receptor which, depending on the class of receptor, triggers a cascade of downstream events that direct the NRs to DNA transcription regulation sites which result in up or down-regulation of gene expression. In addition, two additional classes, type III which are a variant of type I, and type IV that bind DNA as monomers have also been identified.[5] Accordingly, nuclear receptors may be subdivided into the following four mechanistic classes:[5][6]

Type I

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Ligand binding to type I nuclear receptors in the cytosol results in the dissociation of heat shock proteins, homo-dimerization, translocation (i.e., active transport) from the cytoplasm into the cell nucleus, and binding to specific sequences of DNA known as hormone response elements (HREs). Type I nuclear receptors bind to HREs consisting of two half-sites separated by a variable length of DNA, and the second half-site has a sequence inverted from the first (inverted repeat). Type I nuclear receptors include members of subfamily 3, such as the androgen receptor, estrogen receptors, glucocorticoid receptor, and progesterone receptor.[7]

It has been noted that some of the NR subfamily 2 nuclear receptors may bind to direct repeat instead of inverted repeat HREs. In addition, some nuclear receptors that bind either as monomers or dimers, with only a single DNA binding domain of the receptor attaching to a single half site HRE. These nuclear receptors are considered orphan receptors, as their endogenous ligands still unknown.

The nuclear receptor/DNA complex then recruits other proteins that transcribe DNA downstream from the HRE into messenger RNA and eventually protein, which causes a change in cell function.

Type II

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Type II receptors, in contrast to type I, are retained in the nucleus regardless of the ligand binding status and in addition bind as hetero-dimers (usually with RXR) to DNA. In the absence of ligand, type II nuclear receptors are often complexed with corepressor proteins. Ligand binding to the nuclear receptor causes dissociation of corepressor and recruitment of coactivator proteins. Additional proteins including RNA polymerase are then recruited to the NR/DNA complex that transcribe DNA into messenger RNA.

nuclear receptors include principally subfamily 1, for example the retinoic acid receptor, retinoid X receptor and thyroid hormone receptor.[8] Type III

Type III nuclear receptors (principally NR subfamily 2) are similar to type I receptors in that both classes bind to DNA as homodimers. However, type III nuclear receptors, in contrast to type I, bind to direct repeat instead of inverted repeat HREs.

Type IV

Type IV nuclear receptors bind either as monomers or dimers, but only a single DNA binding domain of the receptor binds to a single half site HRE. Examples of type IV receptors are found in most of the NR subfamilies.

Labs working on this gene

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  1. Mangelsdorf DJ, Thummel C, Beato M, Herrlich P, Schutz G, Umesono K, Blumberg B, Kastner P, Mark M, Chambon P, Evans RM (1995). "The nuclear receptor superfamily: the second decade". Cell 83 (6): 835–9. doi:10.1016/0092-8674(95)90199-X. PMID 852.
  2. Novac N, Heinzel T (2004). "Nuclear receptors: overview and classification". Curr Drug Targets Inflamm Allergy 3 (4): 335–46. doi:10.2174/1568010042634541. PMID 15584884.
  3. Luconi M, Francavilla F, Porazzi I, Macerola B, Forti G, Baldi E (August 2004). "Human spermatozoa as a model for studying membrane receptors mediating rapid nongenomic effects of progesterone and estrogens". Steroids 69 (8–9): 553–9. doi:10.1016/j.steroids.2004.05.013. PMID 15288769.
  4. Aquila S, Sisci D, Gentile M, Middea E, Catalano S, Carpino A, Rago V, Andò S (March 2004). "Estrogen receptor (ER)alpha and ER beta are both expressed in human ejaculated spermatozoa: evidence of their direct interaction with phosphatidylinositol-3-OH kinase/Akt pathway". J. Clin. Endocrinol. Metab. 89 (3): 1443–51. doi:10.1210/jc.2003-031681. PMID 15001646.
  5. 5.0 5.1 Mangelsdorf DJ, Thummel C, Beato M, Herrlich P, Schutz G, Umesono K, Blumberg B, Kastner P, Mark M, Chambon P, Evans RM (1995). "The nuclear receptor superfamily: the second decade". Cell 83 (6): 835–9. doi:10.1016/0092-8674(95)90199-X. PMID 8521507.
  6. Jump up to: a b Novac N, Heinzel T (2004). "Nuclear receptors: overview and classification". Curr Drug Targets Inflamm Allergy 3 (4): 335–46. doi:10.2174/1568010042634541. PMID 15584884.
  7. Linja MJ, Porkka KP, Kang Z, Savinainen KJ, Jänne OA, Tammela TL, Vessella RL, Palvimo JJ, Visakorpi T (February 2004). "Expression of androgen receptor coregulators in prostate cancer". Clin. Cancer Res. 10 (3): 1032–40. doi:10.1158/1078-0432.CCR-0990-3. PMID 14871982.
  8. Klinge CM, Bodenner DL, Desai D, Niles RM, Traish AM (May 1997). "Binding of type II nuclear receptors and estrogen receptor to full and half-site estrogen response elements in vitro". Nucleic Acids Res. 25 (10): 1903–12. doi:10.1093/nar/25.10.1903. PMC 146682. PMID 9115356.

Structured Information