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46-1192: 2908 14815 ENSG00000113580 ENSMUSG00000024431 P04150 Q3MSN4 P06537 NM_001020825 NM_001024094 NM_001204258 NM_001204259 NM_001204260 NM_001204261 NM_001204262 NM_001204263 NM_001204264 NM_001204265 NM_001364180 NM_001364181 NM_001364182 NM_001364183 NM_001364184 NM_001364185 NM_008173 NM_001361209 NM_001361210 NM_001361211 NM_001361212 NP_001018661 NP_001019265 NP_001191187 NP_001191188 NP_001191189 NP_001191190 NP_001191191 NP_001191192 NP_001191193 NP_001191194 NP_001351109 NP_001351110 NP_001351111 NP_001351112 NP_001351113 NP_001351114 NP_000167.1 NP_001018084.1 NP_001018085.1 NP_001018086.1 NP_001018087.1 NP_001018661.1 NP_001019265.1 NP_001191187.1 NP_001191188.1 NP_001191189.1 NP_001191190.1 NP_001191191.1 NP_001191192.1 NP_001191193.1 NP_001348138 NP_001348139 NP_001348140 NP_001348141 NP_032199 The glucocorticoid receptor ( GR or GCR ) also known as NR3C1 ( nuclear receptor subfamily 3, group C, member 1)

92-495: A conformation of the receptor that preferentially binds coactivator proteins. These proteins often have an intrinsic histone acetyltransferase (HAT) activity, which weakens the association of histones to DNA, and therefore promotes gene transcription. Binding of antagonist ligands to nuclear receptors in contrast induces a conformation of the receptor that preferentially binds corepressor proteins. These proteins, in turn, recruit histone deacetylases (HDACs), which strengthens

138-640: A functional effect is seen in cells because of the large number of intermediate steps between nuclear receptor activation and changes in protein expression levels. However it has been observed that many effects of the application of nuclear hormones, such as changes in ion channel activity, occur within minutes which is inconsistent with the classical mechanism of nuclear receptor action. While the molecular target for these non-genomic effects of nuclear receptors has not been conclusively demonstrated, it has been hypothesized that there are variants of nuclear receptors which are membrane associated instead of being localized in

184-440: A group 2D for which the only member was Drosophila HR78/NR1D1 ( Q24142 ) and orthologues, but it was merged into group 2C later due to high similarity, forming a "group 2C/D". Knockout studies on mice and fruit flies support such a merged group. A topic of debate has been on the identity of the ancestral nuclear receptor as either a ligand-binding or an orphan receptor . This debate began more than twenty-five years ago when

230-497: 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. Most nuclear receptors have molecular masses between 50,000 and 100,000 daltons . Nuclear receptors are modular in structure and contain

276-481: A potential mechanism for integrating regulation of development and metabolism by thyroid hormone and receptor tyrosine kinases. In addition, thyroid hormone signaling through PI3K can alter gene expression. The following is a list of the 48 known human nuclear receptors (and their orthologs in other species) categorized according to sequence homology . The list also includes selected family members that lack human orthologs (NRNC symbol highlighted in yellow). Of

322-641: A process known as transrepression . One example of a nuclear receptor that are able to transrepress is the glucocorticoid receptor (GR). Furthermore, certain GR ligands known as Selective Glucocorticoid Receptor Agonists ( SEGRAs ) are able to activate GR in such a way that GR more strongly transrepresses than transactivates. This selectivity increases the separation between the desired antiinflammatory effects and undesired metabolic side effects of these selective glucocorticoids . The classical direct effects of nuclear receptors on gene regulation normally take hours before

368-595: A single tyrosine to phenylalanine substitution in TRβ without disrupting direct gene regulation. When mice were created with this single, conservative amino acid substitution in TRβ, synaptic maturation and plasticity in the hippocampus was impaired almost as effectively as completely blocking thyroid hormone synthesis. This mechanism appears to be conserved in all mammals but not in TRα or any other nuclear receptors. Thus, phosphotyrosine-dependent association of TRβ with PI3K provides

414-491: 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 are 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 receptors, in contrast to type I, are retained in

460-500: 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. Human nuclear receptors are capable of dimerizing with many other nuclear receptors (homotypic dimerization), as has been shown from large-scale Y2H experiments and text mining efforts of the literature that were focused on specific interactions. Nevertheless, there exists specificity, with members of

506-494: 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 . 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

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552-578: A variant of type I, and type IV that bind DNA as monomers have also been identified. Accordingly, nuclear receptors may be subdivided into the following four mechanistic classes: 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

598-494: Is gaining interest as a novel representative of neuroendocrine integration, functioning as a major component of endocrine influence - specifically the stress response - upon the brain. The receptor is now implicated in both short and long-term adaptations seen in response to stressors and may be critical to the understanding of psychological disorders, including some or all subtypes of depression and post-traumatic stress disorder ( PTSD ). Indeed, long-standing observations such as

644-428: Is normally to upregulate gene expression. This stimulation of gene expression by the ligand is referred to as an agonist response. The agonistic effects of endogenous hormones can also be mimicked by certain synthetic ligands, for example, the glucocorticoid receptor anti-inflammatory drug dexamethasone . Agonist ligands work by inducing a conformation of the receptor which favors coactivator binding (see upper half of

690-421: Is the receptor to which cortisol and other glucocorticoids bind. The GR is expressed in almost every cell in the body and regulates genes controlling the development , metabolism , and immune response . Because the receptor gene is expressed in several forms, it has many different ( pleiotropic ) effects in different parts of the body. When glucocorticoids bind to GR, its primary mechanism of action

736-453: Is the regulation of gene transcription. The unbound receptor resides in the cytosol of the cell. After the receptor is bound to glucocorticoid, the receptor-glucocorticoid complex can take either of two paths. The activated GR complex up-regulates the expression of anti-inflammatory proteins in the nucleus or represses the expression of pro-inflammatory proteins in the cytosol (by preventing the translocation of other transcription factors from

782-441: Is their direct control of genomic DNA. Nuclear receptors play key roles in both embryonic development and adult homeostasis. As discussed below, nuclear receptors are classified according to mechanism or homology . Nuclear receptors are specific to metazoans (animals) and are not found in protists , algae , fungi , or plants. Amongst the early-branching animal lineages with sequenced genomes, two have been reported from

828-606: The sponge Amphimedon queenslandica , two from the comb jelly Mnemiopsis leidyi four from the placozoan Trichoplax adhaerens and 17 from the cnidarian Nematostella vectensis . There are 270 nuclear receptors in the roundworm Caenorhabditis elegans alone, 21 in the fruit fly and other insects, 73 in zebrafish . Humans, mice, and rats have respectively 48, 49, and 47 nuclear receptors each. Ligands that bind to and activate nuclear receptors include lipophilic substances such as endogenous hormones , vitamins A and D , and xenobiotic hormones . Because

874-592: The NR/DNA complex that transcribe DNA into messenger RNA. Type II nuclear receptors include principally subfamily 1, for example the retinoic acid receptor , retinoid X receptor and thyroid hormone receptor . 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 nuclear receptors bind either as monomers or dimers, but only

920-616: 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. They generally function as homo/heterodimers. In addition, two additional classes, type III which are

966-756: The activity of the endogenous hormones cortisol and progesterone respectively. Antagonist ligands work by inducing a conformation of the receptor which prevents coactivator binding, and promotes corepressor binding (see lower half of the figure to the right). Finally, some nuclear receptors promote a low level of gene transcription in the absence of agonists (also referred to as basal or constitutive activity). Synthetic ligands which reduce this basal level of activity in nuclear receptors are known as inverse agonists . A number of drugs that work through nuclear receptors display an agonist response in some tissues and an antagonistic response in other tissues. This behavior may have substantial benefits since it may allow retaining

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1012-466: The association of histones to DNA, and therefore represses gene transcription. Depending on the receptor involved, the chemical structure of the ligand and the tissue that is being affected, nuclear receptor ligands may display dramatically diverse effects ranging in a spectrum from agonism to antagonism to inverse agonism. The activity of endogenous ligands (such as the hormones estradiol and testosterone ) when bound to their cognate nuclear receptors

1058-404: The chemical structure of the ligand and the receptor involved, however it is thought that many SRMs work by promoting a conformation of the receptor that is closely balanced between agonism and antagonism. In tissues where the concentration of coactivator proteins is higher than corepressors , the equilibrium is shifted in the agonist direction. Conversely in tissues where corepressors dominate,

1104-446: The cytosol into the nucleus). In humans, the GR protein is encoded by NR3C1 gene which is located on chromosome 5 (5q31). Like the other steroid receptors , the glucocorticoid receptor is modular in structure and contains the following domains (labeled A - F ): In the absence of hormone, the glucocorticoid receptor (GR) resides in the cytosol complexed with a variety of proteins including heat shock protein 90 ( hsp90 ),

1150-403: The cytosol or nucleus. Furthermore, these membrane associated receptors function through alternative signal transduction mechanisms not involving gene regulation. While it has been hypothesized that there are several membrane associated receptors for nuclear hormones, many of the rapid effects have been shown to require canonical nuclear receptors. However, testing the relative importance of

1196-439: The desired beneficial therapeutic effects of a drug while minimizing undesirable side effects. Drugs with this mixed agonist/antagonist profile of action are referred to as selective receptor modulators (SRMs). Examples include Selective Androgen Receptor Modulators ( SARMs ), Selective Estrogen Receptor Modulators ( SERMs ) and Selective Progesterone Receptor Modulators ( SPRMs ). The mechanism of action of SRMs may vary depending on

1242-483: The emergence of a new hypothesis regarding the ancestral state of the nuclear receptor. This hypothesis suggests that the ancestral receptor may act as a lipid sensor with an ability to bind, albeit rather weakly, several different hydrophobic molecules such as, retinoids, steroids, hemes, and fatty acids. With its ability to interact with a variety of compounds, this receptor, through duplications, would either lose its ability for ligand-dependent activity, or specialize into

1288-575: 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 target 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

1334-504: The expression of adjacent genes; hence these receptors are classified as transcription factors . The regulation of gene expression by nuclear receptors often occurs in the presence of a ligand —a molecule that affects the receptor's behavior. Ligand binding to a nuclear receptor results in a conformational change activating the receptor. The result is up- or down-regulation of gene expression. A unique property of nuclear receptors that differentiates them from other classes of receptors

1380-426: The expression of genes that are normally upregulated by NF-κB or AP-1. This indirect mechanism of action is referred to as transrepression . GR transrepression via NF-κB and AP-1 is restricted only to certain cell types, and is not considered the universal mechanism for IκBα repression. The GR is abnormal in familial glucocorticoid resistance . In central nervous system structures, the glucocorticoid receptor

1426-425: The field of molecular biology , nuclear receptors are a class of proteins responsible for sensing steroids , thyroid hormones , vitamins , and certain other molecules. These intracellular receptors work with other proteins to regulate the expression of specific genes , thereby controlling the development , homeostasis , and metabolism of the organism. Nuclear receptors bind directly to DNA regulating

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1472-469: The figure to the right). Other synthetic nuclear receptor ligands have no apparent effect on gene transcription in the absence of endogenous ligand. However they block the effect of agonist through competitive binding to the same binding site in the nuclear receptor. These ligands are referred to as antagonists. An example of antagonistic nuclear receptor drug is mifepristone which binds to the glucocorticoid and progesterone receptors and therefore blocks

1518-517: The first ligands were identified as mammalian steroid and thyroid hormones. Shortly thereafter, the identification of the ecdysone receptor in Drosophila introduced the idea that nuclear receptors were hormonal receptors that bind ligands with a nanomolar affinity. At the time, the three known nuclear receptor ligands were steroids, retinoids, and thyroid hormone, and of those three, both steroids and retinoids were products of terpenoid metabolism. Thus, it

1564-749: The following domains : The DNA-binding (C), and ligand binding (E) domains are independently well folded and structurally stable while the N-terminal (A/B), hinge region (D) and optional C-terminal (F) domains may be conformationally flexible and disordered. Domains relative orientations are very different by comparing three known multi-domain crystal structures, two of them binding on DR1 (DBDs separated by 1 bp), one binding on DR4 (by 4 bp). 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

1610-435: The genomic and nongenomic mechanisms in vivo has been prevented by the absence of specific molecular mechanisms for the nongenomic effects that could be blocked by mutation of the receptor without disrupting its direct effects on gene expression. A molecular mechanism for non-genomic signaling through the nuclear thyroid hormone receptor TRβ involves the phosphatidylinositol 3-kinase ( PI3K ). This signaling can be blocked by

1656-528: The heat shock protein 70 ( hsp70 ) and the protein FKBP4 ( FK506 -binding protein 4). The endogenous glucocorticoid hormone cortisol diffuses through the cell membrane into the cytoplasm and binds to the glucocorticoid receptor (GR) resulting in release of the heat shock proteins. The resulting activated form GR has two principal mechanisms of action, transactivation and transrepression, described below. A direct mechanism of action involves homodimerization of

1702-433: The ligand behaves as an antagonist. The most common mechanism of nuclear receptor action involves direct binding of the nuclear receptor to a DNA hormone response element. This mechanism is referred to as transactivation . However some nuclear receptors not only have the ability to directly bind to DNA, but also to other transcription factors. This binding often results in deactivation of the second transcription factor in

1748-405: The mood dysregulations typical of Cushing's disease demonstrate the role of corticosteroids in regulating psychologic state; recent advances have demonstrated interactions with norepinephrine and serotonin at the neural level. In preeclampsia (a hypertensive disorder commonly occurring in pregnant women), the level of a miRNA sequence possibly targeting this protein is elevated in the blood of

1794-518: The mother. Rather, the placenta elevates the level of exosomes containing this miRNA, which can result in inhibition of translation of molecule. Clinical significance of this information is not yet clarified. Dexamethasone and other corticosteroids are agonists , while mifepristone and ketoconazole are antagonists of the GR. Anabolic steroids also prevent cortisol from binding to the glucocorticoid receptor. Glucocorticoid receptor has been shown to interact with: Nuclear receptor In

1840-406: 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

1886-541: The receptor, translocation via active transport into the nucleus , and binding to specific DNA response elements activating gene transcription . This mechanism of action is referred to as transactivation . The biological response depends on the cell type. In the absence of activated GR, other transcription factors such as NF-κB or AP-1 themselves are able to transactivate target genes. However activated GR can complex with these other transcription factors and prevent them from binding their target genes and hence repress

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1932-525: The same subfamily having very similar NR dimerization partners and the underlying dimerization network has certain topological features, such as the presence of highly connected hubs (RXR and SHP). Nuclear receptors bound to hormone response elements recruit a significant number of other proteins (referred to as transcription coregulators ) that facilitate or inhibit the transcription of the associated target gene into mRNA. The function of these coregulators are varied and include chromatin remodeling (making

1978-403: The target gene either more or less accessible to transcription) or a bridging function to stabilize the binding of other coregulatory proteins. Nuclear receptors may bind specifically to a number of coregulator proteins, and thereby influence cellular mechanisms of signal transduction both directly, as well as indirectly. Binding of agonist ligands (see section below) to nuclear receptors induces

2024-434: The two 0-families, 0A has a family 1-like DBD, and 0B has a unique LBD. The second DBD of family 7 is probably related to the family 1 DBD. Three probably family-1 NRs from Biomphalaria glabrata possess a DBD along with a family 0B-like LBD. The placement of C. elegans nhr-1 ( Q21878 ) is disputed: although most sources place it as NR1K1, manual annotation at WormBase considers it a member of NR2A. There used to be

2070-496: Was postulated that ancestral receptor would have been liganded by a terpenoid molecule. In 1992, a comparison of the DNA-binding domain of all known nuclear receptors led to the construction of a phylogenic tree of nuclear receptor that indicated that all nuclear receptors shared a common ancestor. As a result, there was an increased effort upon uncovering the state of the first nuclear receptor, and by 1997 an alternative hypothesis

2116-446: Was suggested: the ancestral nuclear receptor was an orphan receptor and it acquired ligand-binding ability over time This hypothesis was proposed based on the following arguments: Over the next 10 years, experiments were conducted to test this hypothesis and counterarguments soon emerged: A combination of this recent evidence, as well as an in-depth study of the physical structure of the nuclear receptor ligand binding domain has led to

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