Nuclear receptor
Encyclopedia
In the field of molecular biology
, nuclear receptors are a class of protein
s found within cells that are responsible for sensing steroid and thyroid hormone
s and certain other molecules. In response, these receptors work with other proteins to regulate the expression
of specific gene
s, thereby controlling the development
, homeostasis, and metabolism of the organism.
Nuclear receptors have the ability to directly bind to DNA
and regulate the expression of adjacent genes, hence these receptors are classified as transcription factor
s. The regulation of gene expression by nuclear receptors generally only happens when a ligand
— a molecule that affects the receptor's behavior — is present. More specifically, ligand binding to a nuclear receptor results in a conformational change in the receptor, which, in turn, activates the receptor, resulting in up-regulation or down-regulation of gene expression.
A unique property of nuclear receptors that differentiates them from other classes of receptors
is their ability to directly interact with and control the expression of genomic DNA. As a consequence, nuclear receptors play key roles in both embryonic development
and adult homeostasis. As discussed below, nuclear receptors may be classified according to either mechanism or homology.
s (animals) and are not found in protist
s, algae
, fungi, or plants. Amongst the early-branching animal lineages with sequenced genomes, two have been reported from the sponge Amphimedon queenslandica
, two from the ctenophore
Mnemiopsis leidyi
four from the placozoan Trichoplax adhaerens and 17 from the cnidarian Nematostella vectensis. There are 270 nuclear receptors in the nematode
C. elegans
alone. 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
hormone
s, vitamins A and D, and xenobiotic
endocrine disruptor
s. 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 receptor
s, 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.
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 past the cell membrane and bind to nuclear receptors located in the cytosol (type I NR) or nucleus (type II NR) of the cell. This causes a change in the conformation of the receptor, which, depending on the mechanistic class (type I or II), triggers a number of down stream events that eventually results 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 defined.
Accordingly, nuclear receptors may be subdivided into the following four mechanistic classes:
of heat shock protein
s, 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 element
s (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 receptor
s, 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 a single DNA binding domain of the receptor attaching to a single half site HRE. As of now, these nuclear receptors are considered orphan receptor
s, 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.
) 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.
Type II nuclear receptors include principally subfamily 1, for example the retinoic acid receptor
, retinoid X receptor
and thyroid hormone receptor
.
HREs.
s) 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 the target gene either more or less accessible to transcription) or a bridging function to stabilize the binding of other coregulatory proteins.
proteins. These proteins often have an intrinsic histone acetyltransferase
(HAT) activity, which weakens the association of histone
s to DNA, and therefore promotes gene transcription.
proteins. These proteins, in turn, recruit histone deacetylase
s (HDACs), which strengthens 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.
and testosterone
) when bound to their cognate nuclear receptors 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 the figure to the right).
which binds to the glucocorticoid
and progesterone
receptors and therefore blocks the activity of the endogenous hormones cortisol
and progesterone
respectively. Antagonist ligands work by inducing a conformation of the receptor which prevents coactivator and promotes corepressor binding (see lower half of the figure to the right).
s.
s) and Selective Progesterone Receptor Modulators (SPRM
s). The mechanism of action of SRMs may vary depending on 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, the ligand behaves as an antagonist.
. 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 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 (SEGRA
s) 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 glucocorticoid
s.
mechanisms not involving gene regulation.
Molecular biology
Molecular biology is the branch of biology that deals with the molecular basis of biological activity. This field overlaps with other areas of biology and chemistry, particularly genetics and biochemistry...
, nuclear receptors are a class of protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
s found within cells that are responsible for sensing steroid and thyroid hormone
Hormone
A hormone is a chemical released by a cell or a gland in one part of the body that sends out messages that affect cells in other parts of the organism. Only a small amount of hormone is required to alter cell metabolism. In essence, it is a chemical messenger that transports a signal from one...
s and certain other molecules. In response, these receptors work with other proteins to regulate the expression
Gene expression
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as ribosomal RNA , transfer RNA or small nuclear RNA genes, the product is a functional RNA...
of specific gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
s, thereby controlling the development
Developmental biology
Developmental biology is the study of the process by which organisms grow and develop. Modern developmental biology studies the genetic control of cell growth, differentiation and "morphogenesis", which is the process that gives rise to tissues, organs and anatomy.- Related fields of study...
, homeostasis, and metabolism of the organism.
Nuclear receptors have the ability to directly bind to DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
and regulate the expression of adjacent genes, hence these receptors are classified as transcription factor
Transcription factor
In molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...
s. The regulation of gene expression by nuclear receptors generally only happens when a ligand
Ligand (biochemistry)
In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. In a narrower sense, it is a signal triggering molecule, binding to a site on a target protein.The binding occurs by intermolecular forces, such as ionic bonds, hydrogen...
— a molecule that affects the receptor's behavior — is present. More specifically, ligand binding to a nuclear receptor results in a conformational change in the receptor, which, in turn, activates the receptor, resulting in up-regulation or down-regulation of gene expression.
A unique property of nuclear receptors that differentiates them from other classes of receptors
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
is their ability to directly interact with and control the expression of genomic DNA. As a consequence, nuclear receptors play key roles in both embryonic development
Developmental biology
Developmental biology is the study of the process by which organisms grow and develop. Modern developmental biology studies the genetic control of cell growth, differentiation and "morphogenesis", which is the process that gives rise to tissues, organs and anatomy.- Related fields of study...
and adult homeostasis. As discussed below, nuclear receptors may be classified according to either mechanism or homology.
Species distribution
Nuclear receptors are specific to metazoanAnimal
Animals are a major group of multicellular, eukaryotic organisms of the kingdom Animalia or Metazoa. Their body plan eventually becomes fixed as they develop, although some undergo a process of metamorphosis later on in their life. Most animals are motile, meaning they can move spontaneously and...
s (animals) and are not found in protist
Protist
Protists are a diverse group of eukaryotic microorganisms. Historically, protists were treated as the kingdom Protista, which includes mostly unicellular organisms that do not fit into the other kingdoms, but this group is contested in modern taxonomy...
s, algae
Algae
Algae are a large and diverse group of simple, typically autotrophic organisms, ranging from unicellular to multicellular forms, such as the giant kelps that grow to 65 meters in length. They are photosynthetic like plants, and "simple" because their tissues are not organized into the many...
, fungi, or plants. Amongst the early-branching animal lineages with sequenced genomes, two have been reported from the sponge Amphimedon queenslandica
Amphimedon queenslandica
Amphimedon queenslandica is a sponge native to the Great Barrier Reef. Its genome has been sequenced. It has been the subject of various studies on the evolution of metazoan development.A...
, two from the ctenophore
Ctenophore
The Ctenophora are a phylum of animals that live in marine waters worldwide. Their most distinctive feature is the "combs", groups of cilia that they use for swimming, and they are the largest animals that swim by means of cilia – adults of various species range from a few millimeters to in size...
Mnemiopsis leidyi
Mnemiopsis leidyi
The warty comb jelly or sea walnut is a species of tentaculate ctenophore , originally native to the western Atlantic coastal waters. Three species have been named in the genus Mnemiopsis, but they are now believed to be different ecological forms of a single species M...
four from the placozoan Trichoplax adhaerens and 17 from the cnidarian Nematostella vectensis. There are 270 nuclear receptors in the nematode
Nematode
The nematodes or roundworms are the most diverse phylum of pseudocoelomates, and one of the most diverse of all animals. Nematode species are very difficult to distinguish; over 28,000 have been described, of which over 16,000 are parasitic. It has been estimated that the total number of nematode...
C. elegans
Caenorhabditis elegans
Caenorhabditis elegans is a free-living, transparent nematode , about 1 mm in length, which lives in temperate soil environments. Research into the molecular and developmental biology of C. elegans was begun in 1974 by Sydney Brenner and it has since been used extensively as a model...
alone. Humans, mice, and rats have respectively 48, 49, and 47 nuclear receptors each.
Ligands
Endogenous
Endogenous substances are those that originate from within an organism, tissue, or cell. Endogenous retroviruses are caused by ancient infections of germ cells in humans, mammals and other vertebrates...
hormone
Hormone
A hormone is a chemical released by a cell or a gland in one part of the body that sends out messages that affect cells in other parts of the organism. Only a small amount of hormone is required to alter cell metabolism. In essence, it is a chemical messenger that transports a signal from one...
s, vitamins A and D, and xenobiotic
Xenobiotic
A xenobiotic is a chemical which is found in an organism but which is not normally produced or expected to be present in it. It can also cover substances which are present in much higher concentrations than are usual...
endocrine disruptor
Endocrine disruptor
Endocrine disruptors are chemicals that interfere with endocrine in animals, including humans. These disruptions can cause cancerous tumors, birth defects, and other developmental disorders...
s. 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 receptor
Orphan receptor
An orphan receptor is an apparent receptor that has a similar structure to other identified receptors but whose endogenous ligand has not yet been identified. If a ligand for an orphan receptor is later discovered, the receptor is referred to as an "adopted orphan".-Examples:Examples of orphan...
s, have no known (or at least generally agreed upon) endogenous ligands. Some of these receptors such as FXR
Farnesoid X receptor
The bile acid receptor , also known as farnesoid X receptor or NR1H4 is a nuclear receptor that is encoded by the NR1H4 gene in humans.- Function :...
, LXR
Liver X receptor
The liver X receptor is a member of the nuclear receptor family of transcription factors and is closely related to nuclear receptors such as the PPARs, FXR and RXR. Liver X receptors are important regulators of cholesterol, fatty acid, and glucose homeostasis...
, 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
Constitutive androstane receptor
The constitutive androstane receptor also known as nuclear receptor subfamily 1, group I, member 3 is a protein that in humans is encoded by the NR1I3 gene...
and PXR
Pregnane X receptor
In the field of molecular biology, the pregnane X receptor , also known as the steroid and xenobiotic sensing nuclear receptor or nuclear receptor subfamily 1, group I, member 2 is a protein that in humans is encoded by the NR1I2 gene.PXR is a nuclear receptor whose primary function is to sense...
appear to function as xenobiotic sensors up-regulating the expression of cytochrome P450 enzymes that metabolize these xenobiotics.
Structure
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 domainDNA-binding domainA DNA-binding domain is an independently folded protein domain that contains at least one motif that recognizes double- or single-stranded DNA. A DBD can recognize a specific DNA sequence or have a general affinity to DNA...
(DBD): Highly conserved domain containing two zinc fingerZinc fingerZinc fingers are small protein structural motifs that can coordinate one or more zinc ions to help stabilize their folds. They can be classified into several different structural families and typically function as interaction modules that bind DNA, RNA, proteins, or small molecules...
s that binds to specific sequences of DNA called hormone response elementHormone response elementA hormone response element is a response element for hormones, a short sequence of DNA within the promoter of a gene that is able to bind a specific hormone receptor complex and therefore regulate transcription...
s (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 structureTertiary structureIn biochemistry and molecular biology, the tertiary structure of a protein or any other macromolecule is its three-dimensional structure, as defined by the atomic coordinates.-Relationship to primary structure:...
of the LBD is referred to as an alpha helicalAlpha helixA common motif in the secondary structure of proteins, the alpha helix is a right-handed coiled or spiral conformation, in which every backbone N-H group donates a hydrogen bond to the backbone C=O group of the amino acid four residues earlier...
sandwich foldProtein foldingProtein folding is the process by which a protein structure assumes its functional shape or conformation. It is the physical process by which a polypeptide folds into its characteristic and functional three-dimensional structure from random coil....
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 coactivatorCoactivation (Transcription)Coactivation is a process by which the transcription of RNA is increased. Proteins called coactivators are recruited to DNA-binding transcription factors through their activation domains and increase transcription by relaxing the chromatin structure to allow greater access to a gene or by bringing...
and corepressorCorepressor (genetics)In molecular genetics, a corepressor is a substance that inhibits the expression of genes. A corepressor downregulates the expression of genes not through direct interaction with a gene promoter , but rather indirectly through interaction with repressor proteins that in turn bind to the...
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.
 |
Mechanism of action
Small lipophilic substances such as natural hormones diffuse past the cell membrane and bind to nuclear receptors located in the cytosol (type I NR) or nucleus (type II NR) of the cell. This causes a change in the conformation of the receptor, which, depending on the mechanistic class (type I or II), triggers a number of down stream events that eventually results 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 defined.
Accordingly, nuclear receptors may be subdivided into the following four mechanistic classes:
Type I
Ligand binding to type I nuclear receptors in the cytosol results in the dissociationDissociation (chemistry)
Dissociation in chemistry and biochemistry is a general process in which ionic compounds separate or split into smaller particles, ions, or radicals, usually in a reversible manner...
of heat shock protein
Heat shock protein
Heat shock proteins are a class of functionally related proteins involved in the folding and unfolding of other proteins. Their expression is increased when cells are exposed to elevated temperatures or other stress. This increase in expression is transcriptionally regulated...
s, homo-dimerization, translocation (i.e., active transport
Active transport
Active transport is the movement of a substance against its concentration gradient . In all cells, this is usually concerned with accumulating high concentrations of molecules that the cell needs, such as ions, glucose, and amino acids. If the process uses chemical energy, such as from adenosine...
) from the cytoplasm
Cytoplasm
The cytoplasm is a small gel-like substance residing between the cell membrane holding all the cell's internal sub-structures , except for the nucleus. All the contents of the cells of prokaryote organisms are contained within the cytoplasm...
into the cell nucleus
Cell nucleus
In cell biology, the nucleus is a membrane-enclosed organelle found in eukaryotic cells. It contains most of the cell's genetic material, organized as multiple long linear DNA molecules in complex with a large variety of proteins, such as histones, to form chromosomes. The genes within these...
, and binding to specific sequences of DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
known as hormone response element
Hormone response element
A hormone response element is a response element for hormones, a short sequence of DNA within the promoter of a gene that is able to bind a specific hormone receptor complex and therefore regulate transcription...
s (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
Androgen receptor
The androgen receptor , also known as NR3C4 , is a type of nuclear receptor that is activated by binding of either of the androgenic hormones testosterone or dihydrotestosterone in the cytoplasm and then translocating into the nucleus...
, estrogen receptor
Estrogen receptor
Estrogen receptor refers to a group of receptors that are activated by the hormone 17β-estradiol . Two types of estrogen receptor exist: ER, which is a member of the nuclear hormone family of intracellular receptors, and the estrogen G protein-coupled receptor GPR30 , which is a G protein-coupled...
s, glucocorticoid receptor
Glucocorticoid receptor
The glucocorticoid receptor also known as NR3C1 is the receptor to which cortisol and other glucocorticoids bind....
, and progesterone receptor
Progesterone receptor
The progesterone receptor also known as NR3C3 , is an intracellular steroid receptor that specifically binds progesterone...
.
It has been noted that some of the NR subfamily 2 nuclear receptors may bind to direct repeat instead of inverted repeat
Inverted repeat
An inverted repeat is a sequence of nucleotides that is the reversed complement of another sequence further downstream.For example, 5'---GACTGC....GCAGTC---3'. When no nucleotides intervene between the sequence and its downstream complement, it is called a palindrome. Inverted repeats define the...
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. As of now, these nuclear receptors are considered orphan receptor
Orphan receptor
An orphan receptor is an apparent receptor that has a similar structure to other identified receptors but whose endogenous ligand has not yet been identified. If a ligand for an orphan receptor is later discovered, the receptor is referred to as an "adopted orphan".-Examples:Examples of orphan...
s, as their endogenous ligands still unknown.
The nuclear receptor/DNA complex
Complex (chemistry)
In chemistry, a coordination complex or metal complex, is an atom or ion , bonded to a surrounding array of molecules or anions, that are in turn known as ligands or complexing agents...
then recruits other proteins that transcribe
Transcription (genetics)
Transcription is the process of creating a complementary RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA by the action of the correct enzymes...
DNA downstream from the HRE into messenger RNA
Messenger RNA
Messenger RNA is a molecule of RNA encoding a chemical "blueprint" for a protein product. mRNA is transcribed from a DNA template, and carries coding information to the sites of protein synthesis: the ribosomes. Here, the nucleic acid polymer is translated into a polymer of amino acids: a protein...
and eventually protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
, which causes a change in cell function.
Type II
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 RXRRetinoid X receptor
The retinoid X receptor is a type of nuclear receptor that is activated by 9-cis retinoic acid. There are three retinoic X receptors : RXR-alpha, RXR-beta, and RXR-gamma, encoded by the , , genes, respectively....
) to DNA. In the absence of ligand, type II nuclear receptors are often complexed with corepressor
Corepressor (genetics)
In molecular genetics, a corepressor is a substance that inhibits the expression of genes. A corepressor downregulates the expression of genes not through direct interaction with a gene promoter , but rather indirectly through interaction with repressor proteins that in turn bind to the...
proteins. Ligand binding to the nuclear receptor causes dissociation of corepressor and recruitment of coactivator
Coactivation (Transcription)
Coactivation is a process by which the transcription of RNA is increased. Proteins called coactivators are recruited to DNA-binding transcription factors through their activation domains and increase transcription by relaxing the chromatin structure to allow greater access to a gene or by bringing...
proteins. Additional proteins including RNA polymerase
RNA polymerase
RNA polymerase is an enzyme that produces RNA. In cells, RNAP is needed for constructing RNA chains from DNA genes as templates, a process called transcription. RNA polymerase enzymes are essential to life and are found in all organisms and many viruses...
are then recruited to the NR/DNA complex that transcribe DNA into messenger RNA.
Type II nuclear receptors include principally subfamily 1, for example the retinoic acid receptor
Retinoic acid receptor
The retinoic acid receptor is a type of nuclear receptor that is activated by both all-trans retinoic acid and 9-cis retinoic acid. There are three retinoic acid receptors , RAR-alpha, RAR-beta, and RAR-gamma, encoded by the , , genes, respectively...
, retinoid X receptor
Retinoid X receptor
The retinoid X receptor is a type of nuclear receptor that is activated by 9-cis retinoic acid. There are three retinoic X receptors : RXR-alpha, RXR-beta, and RXR-gamma, encoded by the , , genes, respectively....
and thyroid hormone receptor
Thyroid hormone receptor
The thyroid hormone receptor is a type of nuclear receptor that is activated by binding thyroid hormone.-Function:Amongst the most important functions of thyroid hormone receptors are regulation of metabolism and heart rate...
.
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 repeatInverted repeat
An inverted repeat is a sequence of nucleotides that is the reversed complement of another sequence further downstream.For example, 5'---GACTGC....GCAGTC---3'. When no nucleotides intervene between the sequence and its downstream complement, it is called a palindrome. Inverted repeats define the...
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.Coregulatory proteins
Nuclear receptors bound to hormone response elements recruit a significant number of other proteins (referred to as transcription coregulatorTranscription coregulator
In molecular biology and genetics, transcription coregulators are proteins that interact with transcription factors to either activate or repress the transcription of specific genes. Transcription coregulators that activate gene transcription are referred to as coactivators while those that...
s) that facilitate or inhibit the transcription of the associated target gene into mRNA. The function of these coregulators are varied and include chromatin
Chromatin
Chromatin is the combination of DNA and proteins that make up the contents of the nucleus of a cell. The primary functions of chromatin are; to package DNA into a smaller volume to fit in the cell, to strengthen the DNA to allow mitosis and meiosis and prevent DNA damage, and to control gene...
remodeling (making the target gene either more or less accessible to transcription) or a bridging function to stabilize the binding of other coregulatory proteins.
Coactivators
Binding of agonist ligands (see section below) to nuclear receptors induces a conformation of the receptor that preferentially binds coactivatorCoactivator (genetics)
A coactivator is a protein that increases gene expression by binding to an activator which contains a DNA binding domain. The coactivator is unable to bind DNA by itself....
proteins. These proteins often have an intrinsic histone acetyltransferase
Histone acetyltransferase
Histone acetyltransferases are enzymes that acetylate conserved lysine amino acids on histone proteins by transferring an acetyl group from acetyl CoA to form ε-N-acetyl lysine....
(HAT) activity, which weakens the association of histone
Histone
In biology, histones are highly alkaline proteins found in eukaryotic cell nuclei that package and order the DNA into structural units called nucleosomes. They are the chief protein components of chromatin, acting as spools around which DNA winds, and play a role in gene regulation...
s to DNA, and therefore promotes gene transcription.
Corepressors
Binding of antagonist ligands to nuclear receptors in contrast induces a conformation of the receptor that preferentially binds corepressorCorepressor (genetics)
In molecular genetics, a corepressor is a substance that inhibits the expression of genes. A corepressor downregulates the expression of genes not through direct interaction with a gene promoter , but rather indirectly through interaction with repressor proteins that in turn bind to the...
proteins. These proteins, in turn, recruit histone deacetylase
Histone deacetylase
Histone deacetylases are a class of enzymes that remove acetyl groups from an ε-N-acetyl lysine amino acid on a histone. This is important because DNA is wrapped around histones, and DNA expression is regulated by acetylation and de-acetylation. Its action is opposite to that of histone...
s (HDACs), which strengthens the association of histones to DNA, and therefore represses gene transcription.
Agonism vs antagonism
Agonists
The activity of endogenous ligands (such as the hormones estradiolEstradiol
Estradiol is a sex hormone. Estradiol is abbreviated E2 as it has 2 hydroxyl groups in its molecular structure. Estrone has 1 and estriol has 3 . Estradiol is about 10 times as potent as estrone and about 80 times as potent as estriol in its estrogenic effect...
and testosterone
Testosterone
Testosterone is a steroid hormone from the androgen group and is found in mammals, reptiles, birds, and other vertebrates. In mammals, testosterone is primarily secreted in the testes of males and the ovaries of females, although small amounts are also secreted by the adrenal glands...
) when bound to their cognate nuclear receptors is normally to upregulate gene expression. This stimulation of gene expression by the ligand is referred to as an agonist
Agonist
An agonist is a chemical that binds to a receptor of a cell and triggers a response by that cell. Agonists often mimic the action of a naturally occurring substance...
response. The agonistic effects of endogenous hormones can also be mimicked by certain synthetic ligands, for example, the glucocorticoid receptor
Glucocorticoid receptor
The glucocorticoid receptor also known as NR3C1 is the receptor to which cortisol and other glucocorticoids bind....
anti-inflammatory drug dexamethasone
Dexamethasone
Dexamethasone is a potent synthetic member of the glucocorticoid class of steroid drugs. It acts as an anti-inflammatory and immunosuppressant...
. Agonist ligands work by inducing a conformation of the receptor which favors coactivator binding (see upper half of the figure to the right).
Antagonists
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 mifepristoneMifepristone
Mifepristone is a synthetic steroid compound used as a pharmaceutical. It is a progesterone receptor antagonist used as an abortifacient in the first months of pregnancy, and in smaller doses as an emergency contraceptive. During early trials, it was known as RU-38486 or simply RU-486, its...
which binds to the glucocorticoid
Glucocorticoid receptor
The glucocorticoid receptor also known as NR3C1 is the receptor to which cortisol and other glucocorticoids bind....
and progesterone
Progesterone receptor
The progesterone receptor also known as NR3C3 , is an intracellular steroid receptor that specifically binds progesterone...
receptors and therefore blocks the activity of the endogenous hormones cortisol
Cortisol
Cortisol is a steroid hormone, more specifically a glucocorticoid, produced by the adrenal gland. It is released in response to stress and a low level of blood glucocorticoids. Its primary functions are to increase blood sugar through gluconeogenesis; suppress the immune system; and aid in fat,...
and progesterone
Progesterone
Progesterone also known as P4 is a C-21 steroid hormone involved in the female menstrual cycle, pregnancy and embryogenesis of humans and other species...
respectively. Antagonist ligands work by inducing a conformation of the receptor which prevents coactivator and promotes corepressor binding (see lower half of the figure to the right).
Inverse agonists
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 agonistInverse agonist
In the field of pharmacology, an inverse agonist is an agent that binds to the same receptor as an agonist but induces a pharmacological response opposite to that agonist....
s.
Selective receptor modulators
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 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 (SERMSelective estrogen receptor modulator
Selective Estrogen Receptor Modulators are a class of compounds that act on the estrogen receptor. A characteristic that distinguishes these substances from pure receptor agonists and antagonists is that their action is different in various tissues, thereby granting the possibility to selectively...
s) and Selective Progesterone Receptor Modulators (SPRM
Selective progesterone receptor modulator
A selective progesterone receptor modulator is an agent that acts on the progesterone receptor. A characteristic that distinguishes such substances from receptor full agonists and full antagonists is that their action differs in different tissues...
s). The mechanism of action of SRMs may vary depending on 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
Coactivator (genetics)
A coactivator is a protein that increases gene expression by binding to an activator which contains a DNA binding domain. The coactivator is unable to bind DNA by itself....
proteins is higher than corepressors
Corepressor (genetics)
In molecular genetics, a corepressor is a substance that inhibits the expression of genes. A corepressor downregulates the expression of genes not through direct interaction with a gene promoter , but rather indirectly through interaction with repressor proteins that in turn bind to the...
, the equilibrium is shifted in the agonist direction. Conversely in tissues where corepressors
Corepressor (genetics)
In molecular genetics, a corepressor is a substance that inhibits the expression of genes. A corepressor downregulates the expression of genes not through direct interaction with a gene promoter , but rather indirectly through interaction with repressor proteins that in turn bind to the...
dominate, the ligand behaves as an antagonist.
Alternative mechanisms
Transrepression
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 transactivationTransactivation
In molecular biology and genetics, transactivation is an increased rate of gene expression triggered either by biological processes or by artificial means.- Natural 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 a process known as transrepression
Transrepression
In the field of molecular biology, transrepression is a process whereby one protein represses the activity of a second protein through a protein-protein interaction...
. One example of a nuclear receptor that are able to transrepress is the glucocorticoid receptor
Glucocorticoid receptor
The glucocorticoid receptor also known as NR3C1 is the receptor to which cortisol and other glucocorticoids bind....
(GR). Furthermore certain GR ligands known as Selective Glucocorticoid Receptor Agonists (SEGRA
Selective glucocorticoid receptor agonist
A selective glucocorticoid receptor agonist , sometimes called a dissociated glucocorticoid receptor agonist , is a type of experimental drug that is designed to share many of the desirable anti-inflammatory and immunosuppressive properties of classical glucocorticoid drugs but with fewer side...
s) 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 glucocorticoid
Glucocorticoid
Glucocorticoids are a class of steroid hormones that bind to the glucocorticoid receptor , which is present in almost every vertebrate animal cell...
s.
Non-genomic
The classical direct effects of nuclear receptors on gene regulation normally takes hours before 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 some effects from the application of hormones such as estrogen 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 the cytosol or nucleus. Furthermore these membrane associated receptors function through alternative signal transductionSignal transduction
Signal transduction occurs when an extracellular signaling molecule activates a cell surface receptor. In turn, this receptor alters intracellular molecules creating a response...
mechanisms not involving gene regulation.
Family members
The following is a list of the 48 known human nuclear receptors categorized according to sequence homology.| Subfamily | Group | Member | ||||||
|---|---|---|---|---|---|---|---|---|
| NRNC Symbol | Abbreviation | Name | Gene | Ligand(s) | ||||
| 1 | Thyroid Hormone Receptor-like | A | Thyroid hormone receptor Thyroid hormone receptor The thyroid hormone receptor is a type of nuclear receptor that is activated by binding thyroid hormone.-Function:Amongst the most important functions of thyroid hormone receptors are regulation of metabolism and heart rate... |
NR1A1 | TRα Thyroid hormone receptor alpha Thyroid hormone receptor alpha also known as nuclear receptor subfamily 1, group A, member 1 , is a nuclear receptor protein that in humans is encoded by the THRA gene.- Function :... |
Thyroid hormone receptor-α | thyroid hormone Thyroid hormone The thyroid hormones, thyroxine and triiodothyronine , are tyrosine-based hormones produced by the thyroid gland primarily responsible for regulation of metabolism. An important component in the synthesis of thyroid hormones is iodine. The major form of thyroid hormone in the blood is thyroxine ,... |
|
| NR1A2 | TRβ Thyroid hormone receptor beta Thyroid hormone receptor beta also known as nuclear receptor subfamily 1, group A, member 2 , is a nuclear receptor protein that in humans is encoded by the THRB gene.- Function :... |
Thyroid hormone receptor-β | ||||||
| B | Retinoic acid receptor Retinoic acid receptor The retinoic acid receptor is a type of nuclear receptor that is activated by both all-trans retinoic acid and 9-cis retinoic acid. There are three retinoic acid receptors , RAR-alpha, RAR-beta, and RAR-gamma, encoded by the , , genes, respectively... |
NR1B1 | RARα Retinoic acid receptor alpha Retinoic acid receptor alpha , also known as NR1B1 is a nuclear receptor that in humans is encoded by the RARA gene.- Function :... |
Retinoic acid receptor-α | vitamin A Vitamin A Vitamin A is a vitamin that is needed by the retina of the eye in the form of a specific metabolite, the light-absorbing molecule retinal, that is necessary for both low-light and color vision... and related compounds |
|||
| NR1B2 | RARβ Retinoic acid receptor beta Retinoic acid receptor beta , also known as NR1B2 is a nuclear receptor that in humans is encoded by the RARB gene.- Function :... |
Retinoic acid receptor-β | ||||||
| NR1B3 | RARγ Retinoic acid receptor gamma Retinoic acid receptor gamma , also known as NR1B3 is a nuclear receptor encoded by the RARG gene.- Interactions :... |
Retinoic acid receptor-γ | ||||||
| C | Peroxisome proliferator-activated receptor Peroxisome proliferator-activated receptor In the field of molecular biology, the peroxisome proliferator-activated receptors are a group of nuclear receptor proteins that function as transcription factors regulating the expression of genes... |
NR1C1 | PPARα Peroxisome proliferator-activated receptor alpha Peroxisome proliferator-activated receptor alpha , also known as NR1C1 , is a nuclear receptor protein that in humans is encoded by the PPARA gene.- Function :... |
Peroxisome proliferator-activated receptor-α | fatty acids, prostaglandin Prostaglandin A prostaglandin is any member of a group of lipid compounds that are derived enzymatically from fatty acids and have important functions in the animal body. Every prostaglandin contains 20 carbon atoms, including a 5-carbon ring.... s |
|||
| NR1C2 | PPAR-β/δ Peroxisome proliferator-activated receptor delta Peroxisome proliferator-activated receptor beta or delta , also known as NR1C2 is a nuclear receptor that in humans is encoded by the PPARD gene.... |
Peroxisome proliferator-activated receptor-β/δ | ||||||
| NR1C3 | PPARγ Peroxisome proliferator-activated receptor gamma Peroxisome proliferator-activated receptor gamma , also known as the glitazone receptor, or NR1C3 is a type II nuclear receptor that in humans is encoded by the PPARG gene.Two isoforms of PPARG are detected in the human and in the mouse: PPAR-γ1 and... |
Peroxisome proliferator-activated receptor-γ | ||||||
| D | Rev-ErbA Rev-ErbA The Rev-ErbA proteins are members of the nuclear receptor family of intracellular transcription factors. There are two forms of the receptor, alpha and beta, each encoded by a separate gene .... |
NR1D1 | Rev-ErbAα Rev-ErbA alpha Rev-ErbA alpha also known as NR1D1 , is a protein that in humans is encoded by the NR1D1 gene.Rev-erbα is member of the Rev-ErbA family of nuclear receptors and is a transcriptional repressor... |
Rev-ErbAα | heme Heme A heme or haem is a prosthetic group that consists of an iron atom contained in the center of a large heterocyclic organic ring called a porphyrin. Not all porphyrins contain iron, but a substantial fraction of porphyrin-containing metalloproteins have heme as their prosthetic group; these are... |
|||
| NR1D2 | Rev-ErbAβ Rev-ErbA beta Rev-ErbA beta also known as NR1D2 is a protein that in humans is encoded by the NR1D2 gene.Rev-erbβ is a member of the Rev-ErbA family of transcription factors... |
Rev-ErbAα | ||||||
| F | RAR-related orphan receptor RAR-related orphan receptor The RAR-related orphan receptors are members of the nuclear receptor family of intracellular transcription factors. There are three forms of ROR, ROR-α, -β, and -γ and each is encoded by a separate gene... |
NR1F1 | RORα RAR-related orphan receptor alpha RAR-related orphan receptor alpha , also known as NR1F1 is a nuclear receptor that in humans is encoded by the RORA gene.- Function :... |
RAR-related orphan receptor-α | cholesterol Cholesterol Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes... , ATRA Tretinoin Tretinoin is the acid form of vitamin A and is also known as all-trans retinoic acid or ATRA. It is a drug commonly used to treat acne vulgaris and keratosis pilaris. It is available as a cream or gel... |
|||
| NR1F2 | RORβ RAR-related orphan receptor beta RAR-related orphan receptor beta , also known as NR1F2 is a nuclear receptor that in humans is encoded by the RORB gene.- Function :... |
RAR-related orphan receptor-β | ||||||
| NR1F3 | RORγ RAR-related orphan receptor gamma RAR-related orphan receptor gamma is a protein that in humans is encoded by the RORC gene. RORγ is member of the nuclear receptor family of transcription factors.- Gene expression :... |
RAR-related orphan receptor-γ | ||||||
| H | Liver X receptor Liver X receptor The liver X receptor is a member of the nuclear receptor family of transcription factors and is closely related to nuclear receptors such as the PPARs, FXR and RXR. Liver X receptors are important regulators of cholesterol, fatty acid, and glucose homeostasis... -like |
NR1H3 | LXRα Liver X receptor alpha Liver X receptor alpha is a nuclear receptor protein that in humans is encoded by the NR1H3 gene .- Expression :... |
Liver X receptor-α | oxysterol Sterol Sterols, also known as steroid alcohols, are a subgroup of the steroids and an important class of organic molecules. They occur naturally in plants, animals, and fungi, with the most familiar type of animal sterol being cholesterol... s |
|||
| NR1H2 | LXRβ Liver X receptor beta Liver X receptor beta is a member of the nuclear receptor family of transcription factors. LXR-β is encoded by the gene .- Function :... |
Liver X receptor-β | ||||||
| NR1H4 | FXR Farnesoid X receptor The bile acid receptor , also known as farnesoid X receptor or NR1H4 is a nuclear receptor that is encoded by the NR1H4 gene in humans.- Function :... |
Farnesoid X receptor | ||||||
| I | Vitamin D receptor-like | NR1I1 | VDR | Vitamin D receptor | vitamin D Vitamin D Vitamin D is a group of fat-soluble secosteroids. In humans, vitamin D is unique both because it functions as a prohormone and because the body can synthesize it when sun exposure is adequate .... |
|||
| NR1I2 | PXR Pregnane X receptor In the field of molecular biology, the pregnane X receptor , also known as the steroid and xenobiotic sensing nuclear receptor or nuclear receptor subfamily 1, group I, member 2 is a protein that in humans is encoded by the NR1I2 gene.PXR is a nuclear receptor whose primary function is to sense... |
Pregnane X receptor | xenobiotic Xenobiotic A xenobiotic is a chemical which is found in an organism but which is not normally produced or expected to be present in it. It can also cover substances which are present in much higher concentrations than are usual... s |
|||||
| NR1I3 | CAR Constitutive androstane receptor The constitutive androstane receptor also known as nuclear receptor subfamily 1, group I, member 3 is a protein that in humans is encoded by the NR1I3 gene... |
Constitutive androstane receptor | androstane Androstane Androstane is a steroid nucleus. Androstane can exist as either of two isomers, known as 5α-androstane and 5β-androstane.... |
|||||
| X | NRs with two DNA binding domains | NR1X1 | 2DBD-NRα | |||||
| NR1X2 | 2DBD-NRβ | |||||||
| NR1X3 | 2DBD-NRγ | |||||||
| 2 | Retinoid X Receptor-like | A | Hepatocyte nuclear factor-4 Hnf4 HNF4 is a nuclear receptor protein mostly expressed in the liver, gut, kidney, and pancreatic beta cells that is critical for liver development... |
NR2A1 | HNF4α Hepatocyte nuclear factor 4 alpha Hepatocyte nuclear factor 4 alpha also known as NR2A1 is a nuclear receptor that in humans is encoded by the HNF4A gene.- Function :... |
Hepatocyte nuclear factor-4-α | fatty acid Fatty acid In chemistry, especially biochemistry, a fatty acid is a carboxylic acid with a long unbranched aliphatic tail , which is either saturated or unsaturated. Most naturally occurring fatty acids have a chain of an even number of carbon atoms, from 4 to 28. Fatty acids are usually derived from... s |
|
| NR2A2 | HNF4γ Hepatocyte nuclear factor 4 gamma Hepatocyte nuclear factor 4 gamma also known as NR2A2 is a nuclear receptor that in humans is encoded by the HNF4G gene.... |
Hepatocyte nuclear factor-4-γ | ||||||
| B | Retinoid X receptor Retinoid X receptor The retinoid X receptor is a type of nuclear receptor that is activated by 9-cis retinoic acid. There are three retinoic X receptors : RXR-alpha, RXR-beta, and RXR-gamma, encoded by the , , genes, respectively.... |
NR2B1 | RXRα Retinoid X receptor alpha Retinoid X receptor alpha , also known as NR2B1 is a nuclear receptor that in humans is encoded by the RXRA gene.- Function :... |
Retinoid X receptor-α | retinoid Retinoid The retinoids are a class of chemical compounds that are related chemically to vitamin A. Retinoids are used in medicine, primarily due to the way they regulate epithelial cell growth.... s |
|||
| NR2B2 | RXRβ Retinoid X receptor beta Retinoid X receptor beta , also known as NR2B2 is a nuclear receptor that in humans is encoded by the RXRB gene.... |
Retinoid X receptor-β | ||||||
| NR2B3 | RXRγ Retinoid X receptor gamma Retinoic acid receptor gamma , also known as NR2B3 is a nuclear receptor that in humans is encoded by the RXRG gene.... |
Retinoid X receptor-γ | ||||||
| C | Testicular receptor Testicular receptor The testicular receptor proteins are members of the nuclear receptor family of intracellular transcription factors. There are two forms of the receptor, TR2 and TR4, each encode by a separate gene .... |
NR2C1 | TR2 Testicular receptor 2 The testicular receptor 2 also known as NR2C1 is protein that in humans is encoded by the NR2C1 gene... |
Testicular receptor 2 | ||||
| NR2C2 | TR4 Testicular receptor 4 Testicular receptor 4 also known as NR2C2 is a protein that in humans is encoded by the NR2C2 gene.The testicular receptor 4 is a member of the nuclear receptor family of transcription factors.... |
Testicular receptor 4 | ||||||
| E | TLX/PNR | NR2E1 | TLX TLX Nuclear receptor TLX also known as NR2E1 is a protein that in humans is encoded by the NR2E1 gene... |
Homologue of the Drosophila tailless gene | ||||
| NR2E3 | PNR Photoreceptor cell-specific nuclear receptor The photoreceptor cell-specific nuclear receptor , also known as NR2E3 , is a protein that in humans is encoded by the NR2E3 gene. PNR is a member of the nuclear receptor super family of intracellular transcription factors.- Function :PNR is exclusively expressed in the retina... |
Photoreceptor cell-specific nuclear receptor | ||||||
| F | COUP Chicken ovalbumin upstream promoter-transcription factor The chicken ovalbumin upstream promoter transcription factor proteins are members of the nuclear receptor family of intracellular transcription factors. There are two variants of the COUP-TFs, labeled as COUP-TFI and COUP-TFII encoded by the and genes respectively.COUP-TFs play critical roles... /EAR |
NR2F1 | COUP-TFI COUP-TFI COUP-TF1 also known as NR2F1 is a protein that in humans is encoded by the NR2F1 gene... |
Chicken ovalbumin upstream promoter-transcription factor I | ||||
| NR2F2 | COUP-TFII COUP-TFII COUP-TFII , also known as NR2F2 is a protein that in humans is encoded by the NR2F2 gene... |
Chicken ovalbumin upstream promoter-transcription factor II | ||||||
| NR2F6 | EAR-2 V-erbA-related gene V-erbA-related protein 2 also known as NR2F6 is a protein that in humans is encoded by the NR2F6 gene... |
V-erbA-related | ||||||
| 3 | Estrogen Receptor-like | A | Estrogen receptor Estrogen receptor Estrogen receptor refers to a group of receptors that are activated by the hormone 17β-estradiol . Two types of estrogen receptor exist: ER, which is a member of the nuclear hormone family of intracellular receptors, and the estrogen G protein-coupled receptor GPR30 , which is a G protein-coupled... |
NR3A1 | ERα Estrogen receptor alpha Estrogen receptor alpha , also known as NR3A1 , is a nuclear receptor that is activated by the sex hormone estrogen... |
Estrogen receptor-α | estrogen Estrogen Estrogens , oestrogens , or œstrogens, are a group of compounds named for their importance in the estrous cycle of humans and other animals. They are the primary female sex hormones. Natural estrogens are steroid hormones, while some synthetic ones are non-steroidal... s |
|
| NR3A2 | ERβ Estrogen receptor beta Estrogen receptor beta , also known as NR3A2 , is a nuclear receptor which is activated by the sex hormone estrogen. In humans, ER-β is encoded by the ESR2 gene.- Function :... |
Estrogen receptor-β | ||||||
| B | Estrogen related receptor Estrogen related receptor There are three known estrogen related receptors:* ERRα * ERRβ * ERRγ The ERRs are members of the orphan nuclear receptor family.ERR's bind to estrogen response elements on DNA and modulate transcription but do not bind to endogenous estrogens.... |
NR3B1 | ERRα Estrogen-related receptor alpha Estrogen-related receptor alpha , also known as NR3B1 , is a nuclear receptor that in humans is encoded by the ESRRA gene.-Tissue distribution:... |
Estrogen-related receptor-α | ||||
| NR3B2 | ERRβ Estrogen-related receptor beta Estrogen-related receptor beta , also known as NR3B2 , is a nuclear receptor that in humans is encoded by the ESRRB gene .- Function :... |
Estrogen-related receptor-β | ||||||
| NR3B3 | ERRγ Estrogen-related receptor gamma Estrogen-related receptor gamma , also known as NR3B3 , is a nuclear receptor that in humans is encoded by the ESRRG gene. It behaves as a constitutive activator of transcription.This protein is a member of nuclear hormone receptor family of steroid hormone receptors... |
Estrogen-related receptor-γ | ||||||
| C | 3-Ketosteroid receptors | NR3C1 | GR Glucocorticoid receptor The glucocorticoid receptor also known as NR3C1 is the receptor to which cortisol and other glucocorticoids bind.... |
Glucocorticoid receptor | cortisol Cortisol Cortisol is a steroid hormone, more specifically a glucocorticoid, produced by the adrenal gland. It is released in response to stress and a low level of blood glucocorticoids. Its primary functions are to increase blood sugar through gluconeogenesis; suppress the immune system; and aid in fat,... |
|||
| NR3C2 | MR Mineralocorticoid receptor The mineralocorticoid receptor , also known as the aldosterone receptor or nuclear receptor subfamily 3, group C, member 2, is a protein that in humans is encoded by the NR3C2 gene that is located on chromosome 4q31.1-31.2.MR is a receptor with high affinity for mineralocorticoids... |
Mineralocorticoid receptor | aldosterone Aldosterone Aldosterone is a hormone that increases the reabsorption of sodium ions and water and the release of potassium in the collecting ducts and distal convoluted tubule of the kidneys' functional unit, the nephron. This increases blood volume and, therefore, increases blood pressure. Drugs that... |
|||||
| NR3C3 | PR Progesterone receptor The progesterone receptor also known as NR3C3 , is an intracellular steroid receptor that specifically binds progesterone... |
Progesterone receptor | progesterone Progesterone Progesterone also known as P4 is a C-21 steroid hormone involved in the female menstrual cycle, pregnancy and embryogenesis of humans and other species... |
|||||
| NR3C4 | AR Androgen receptor The androgen receptor , also known as NR3C4 , is a type of nuclear receptor that is activated by binding of either of the androgenic hormones testosterone or dihydrotestosterone in the cytoplasm and then translocating into the nucleus... |
Androgen receptor | testosterone Testosterone Testosterone is a steroid hormone from the androgen group and is found in mammals, reptiles, birds, and other vertebrates. In mammals, testosterone is primarily secreted in the testes of males and the ovaries of females, although small amounts are also secreted by the adrenal glands... |
|||||
| 4 | Nerve Growth Factor IB-like | A | NGFIB/NURR1/NOR1 | NR4A1 | NGFIB Nerve Growth factor IB The nerve Growth factor IB also known as Nur77 or NR4A1 is a protein that in humans is encoded by the NR4A1 gene.... |
Nerve Growth factor IB | ||
| NR4A2 | NURR1 Nuclear receptor related 1 protein The Nuclear receptor related 1 protein also known as NR4A2 is a protein that in humans is encoded by the NR4A2 gene. NURR1 is a member of the nuclear receptor family of intracellular transcription factors.NURR1 plays a key role in the maintenance of the dopaminergic system of the brain... |
Nuclear receptor related 1 | ||||||
| NR4A3 | NOR1 Neuron-derived orphan receptor 1 The neuron-derived orphan receptor 1 also known as NR4A3 is a protein that in humans is encoded by the NR4A3 gene... |
Neuron-derived orphan receptor 1 | ||||||
| 5 | Steroidogenic Factor-like | A | SF1/LRH1 | NR5A1 | SF1 Steroidogenic factor 1 The steroidogenic factor 1 protein controls sexual development in the embryo and at puberty.SF1 is a member of the nuclear receptor family of intracellular transcription factors and is encoded by the NR5A1 gene .- Function :SF-1 is a critical regulator of reproduction, regulating the transcription... |
Steroidogenic factor 1 | phosphatidylinositol Phosphatidylinositol Phosphatidylinositol is a negatively charged phospholipid and a minor component in the cytosolic side of eukaryotic cell membranes.... s |
|
| NR5A2 | LRH-1 Liver receptor homolog-1 The liver receptor homolog-1 also known as NR5A2 is a protein that in humans is encoded by the NR5A2 gene... |
Liver receptor homolog-1 | phosphatidylinositol Phosphatidylinositol Phosphatidylinositol is a negatively charged phospholipid and a minor component in the cytosolic side of eukaryotic cell membranes.... s |
|||||
| 6 | Germ Cell Nuclear Factor-like | A | GCNF | NR6A1 | GCNF Germ cell nuclear factor The germ cell nuclear factor , also known as RTR or NR6A1 , is a protein that in humans is encoded by the NR6A1 gene... |
Germ cell nuclear factor | ||
| 0 | Miscellaneous | A | DAX/SHP | NR0B1 | DAX1 DAX1 DAX1 is a nuclear receptor protein that in humans is encoded by the NR0B1 gene... |
Dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1 | ||
| NR0B2 | SHP Small heterodimer partner The small heterodimer partner also known as NR0B2 is a protein that in humans is encoded by the NR0B2 gene. SHP is a member of the nuclear receptor family of intracellular transcription factors. SHP is unusual for a nuclear receptor in that it lacks a DNA binding domain... |
Small heterodimer partner | ||||||
History
Below is a brief selection of key events in the history of nuclear receptor research.- 1905 – Ernest Starling coined the word hormoneHormoneA hormone is a chemical released by a cell or a gland in one part of the body that sends out messages that affect cells in other parts of the organism. Only a small amount of hormone is required to alter cell metabolism. In essence, it is a chemical messenger that transports a signal from one...
- 1926 – Edward Calvin KendallEdward Calvin KendallEdward Calvin Kendall was an American chemist. In 1950, Kendall was awarded the 1950 Nobel Prize for Physiology or Medicine along with Swiss chemist Tadeus Reichstein and Mayo Clinic physician Philip S. Hench, for their work with the hormones of the adrenal gland...
and Tadeus ReichsteinTadeus ReichsteinTadeusz Reichstein was a Polish-born Swiss chemist and Nobel laureate.Reichstein was born into a Jewish family at Włocławek, Congress Poland, and spent his early childhood at Kiev, where his father was an engineer...
isolated and determined the structures of cortisoneCortisoneCortisone is a steroid hormone. It is one of the main hormones released by the adrenal gland in response to stress. In chemical structure, it is a corticosteroid closely related to corticosterone. It is used to treat a variety of ailments and can be administered intravenously, orally,...
and thyroxineThyroxineThyroxine, or 3,5,3',5'-tetraiodothyronine , a form of thyroid hormones, is the major hormone secreted by the follicular cells of the thyroid gland.-Synthesis and regulation:... - 1929 – Adolf ButenandtAdolf ButenandtAdolf Friedrich Johann Butenandt was a German biochemist and member of the Nazi party. He was awarded the Nobel Prize in Chemistry in 1939 for his "work on sex hormones." He initially rejected the award in accordance with government policy, but accepted it in 1949 after World War...
and Edward Adelbert DoisyEdward Adelbert DoisyEdward Adelbert Doisy was an American biochemist. He received the Nobel Prize in Physiology or Medicine in 1943 with Henrik Dam for their discovery of vitamin K and its chemical structure.Doisy was born in Hume, Illinois, on November 3, 1893. He completed his A.B. degree in 1914 and his M.S...
– independently isolated and determined the structure of estrogenEstrogenEstrogens , oestrogens , or œstrogens, are a group of compounds named for their importance in the estrous cycle of humans and other animals. They are the primary female sex hormones. Natural estrogens are steroid hormones, while some synthetic ones are non-steroidal... - 1958 – Elwood JensenElwood V. JensenElwood V. Jensen is the Distinguished University Professor, George and Elizabeth Wile Chair in Cancer Research at the University of Cincinnati College of Medicine's Vontz Center for Molecular Studies. In 2004 he received the Albert Lasker Award for Basic Medical Research for his research on...
– isolated the estrogen receptorEstrogen receptorEstrogen receptor refers to a group of receptors that are activated by the hormone 17β-estradiol . Two types of estrogen receptor exist: ER, which is a member of the nuclear hormone family of intracellular receptors, and the estrogen G protein-coupled receptor GPR30 , which is a G protein-coupled... - 1980s – cloning of the estrogen, glucocorticoid, and thyroid hormone receptors by Pierre Chambon, Ronald EvansRonald M. EvansRonald M. Evans is an American professor and biologist who works at the Salk Institute for Biological Studies in La Jolla, California. He received his BS and PhD degrees from UCLA, followed by a postdoctoral training in Rockefeller University...
, and Björn Vennström respectively - 2004 – Pierre Chambon, Ronald Evans, and Elwood Jensen were awarded the Albert Lasker Award for Basic Medical ResearchAlbert Lasker Award for Basic Medical ResearchThe Albert Lasker Award for Basic Medical Research is one of the prizes awarded by the Lasker Foundation for the understanding, diagnosis, prevention, treatment, and cure of disease...
, an award that frequently precedes a Nobel Prize in MedicineNobel Prize in Physiology or MedicineThe Nobel Prize in Physiology or Medicine administered by the Nobel Foundation, is awarded once a year for outstanding discoveries in the field of life science and medicine. It is one of five Nobel Prizes established in 1895 by Swedish chemist Alfred Nobel, the inventor of dynamite, in his will...
See also
- ReceptorReceptor (biochemistry)In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
- Intracellular receptorIntracellular receptorIntracellular receptors are receptors located inside the cell rather than on its cell membrane. Examples are the class of nuclear receptors located in the cell nucleus and the IP3 receptor located on the endoplasmic reticulum...
- Steroid hormone receptorSteroid hormone receptorSteroid hormone receptors are found on the plasma membrane, in the cytosol and also in the nucleus of target cells. They are generally intracellular receptors and initiate signal transduction for steroid hormones which lead to changes in gene expression over a time period of hours to days...
- Transcription factorTranscription factorIn molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...
- ObesogenObesogenObesogens are foreign chemical compounds that disrupt normal development and balance of lipid metabolism, which in some cases, can lead to obesity...