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In the field of
molecular biology Molecular biology is the branch of biology that seeks to understand the molecular basis of biological activity in and between cells, including biomolecular synthesis, modification, mechanisms, and interactions. The study of chemical and phys ...
, nuclear receptors are a class of
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
s responsible for sensing
steroids A steroid is a biologically active organic compound with four rings arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes that alter membrane fluidity; and ...
,
thyroid The thyroid, or thyroid gland, is an endocrine gland in vertebrates. In humans it is in the neck and consists of two connected lobes. The lower two thirds of the lobes are connected by a thin band of tissue called the thyroid isthmus. The ...
hormone A hormone (from the Greek participle , "setting in motion") is a class of signaling molecules in multicellular organisms that are sent to distant organs by complex biological processes to regulate physiology and behavior. Hormones are required ...
s,
vitamins A vitamin is an organic molecule (or a set of molecules closely related chemically, i.e. vitamers) that is an essential micronutrient that an organism needs in small quantities for the proper functioning of its metabolism. Essential nutrie ...
, and certain other molecules. These receptors work with other proteins to regulate the expression of specific
gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
s thereby controlling the development,
homeostasis In biology, homeostasis ( British also homoeostasis) (/hɒmɪə(ʊ)ˈsteɪsɪs/) is the state of steady internal, physical, and chemical conditions maintained by living systems. This is the condition of optimal functioning for the organism and ...
, and
metabolism Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run ...
of the organism. Nuclear receptors bind directly to DNA regulating the expression of adjacent genes; hence these receptors are classified as
transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The f ...
s. The regulation of gene expression by nuclear receptors often occurs in the presence of a
ligand In coordination chemistry, a ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's elect ...
—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 is their direct control of
genomic Genomics is an interdisciplinary field of biology focusing on the structure, function, evolution, mapping, and editing of genomes. A genome is an organism's complete set of DNA, including all of its genes as well as its hierarchical, three-dim ...
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.


Species distribution

Nuclear receptors are specific to metazoans (animals) and are not found in
protist A protist () is any eukaryotic organism (that is, an organism whose cells contain a cell nucleus) that is not an animal, plant, or fungus. While it is likely that protists share a common ancestor (the last eukaryotic common ancestor), the e ...
s,
algae Algae (; singular alga ) is an informal term for a large and diverse group of photosynthetic eukaryotic organisms. It is a polyphyletic grouping that includes species from multiple distinct clades. Included organisms range from unicellular micr ...
,
fungi A fungus ( : fungi or funguses) is any member of the group of eukaryotic organisms that includes microorganisms such as yeasts and molds, as well as the more familiar mushrooms. These organisms are classified as a kingdom, separately fr ...
, or plants. Amongst the early-branching animal lineages with sequenced genomes, two have been reported from the
sponge Sponges, the members of the phylum Porifera (; meaning 'pore bearer'), are a basal animal clade as a sister of the diploblasts. They are multicellular organisms that have bodies full of pores and channels allowing water to circulate throu ...
'' Amphimedon queenslandica'', two from the
comb jelly Ctenophora (; ctenophore ; ) comprise a phylum of marine invertebrates, commonly known as comb jellies, that inhabit sea waters worldwide. They are notable for the groups of cilia they use for swimming (commonly referred to as "combs"), an ...
''
Mnemiopsis leidyi ''Mnemiopsis leidyi'', the warty comb jelly or sea walnut, is a species of tentaculate ctenophore (comb jelly). It is native to western Atlantic coastal waters, but has become established as an invasive species in European and western Asian re ...
'' four from the
placozoa The Placozoa are a basal form of marine free-living (non-parasitic) multicellular organism. They are the simplest in structure of all animals. Three genera have been found: the classical ''Trichoplax adhaerens'', '' Hoilungia hongkongensis'', a ...
n ''
Trichoplax adhaerens ''Trichoplax adhaerens'' is one of the three named species in the phylum Placozoa. The others are '' Hoilungia hongkongensis'' and '' Polyplacotoma mediterranea''. The Placozoa is a basal group of multicellular animals (metazoa). ''Trichoplax'' ...
'' and 17 from the
cnidarian Cnidaria () is a phylum under kingdom Animalia containing over 11,000 species of aquatic animals found both in freshwater and marine environments, predominantly the latter. Their distinguishing feature is cnidocytes, specialized cells that th ...
'' Nematostella vectensis''. There are 270 nuclear receptors in the roundworm ''
Caenorhabditis elegans ''Caenorhabditis elegans'' () is a free-living transparent nematode about 1 mm in length that lives in temperate soil environments. It is the type species of its genus. The name is a blend of the Greek ''caeno-'' (recent), ''rhabditis'' (r ...
'' alone, 21 in the fruit fly and other insects, 73 in
zebrafish The zebrafish (''Danio rerio'') is a freshwater fish belonging to the minnow family (Cyprinidae) of the order Cypriniformes. Native to South Asia, it is a popular aquarium fish, frequently sold under the trade name zebra danio (and thus often ca ...
. Humans, mice, and rats have respectively 48, 49, and 47 nuclear receptors each.


Ligands

Ligands that bind to and activate nuclear receptors include lipophilic substances such as
endogenous Endogenous substances and processes are those that originate from within a living system such as an organism, tissue, or cell. In contrast, exogenous substances and processes are those that originate from outside of an organism. For example, ...
hormone A hormone (from the Greek participle , "setting in motion") is a class of signaling molecules in multicellular organisms that are sent to distant organs by complex biological processes to regulate physiology and behavior. Hormones are required ...
s, vitamins A and D, and
xenobiotic A xenobiotic is a chemical substance found within an organism that is not naturally produced or expected to be present within the organism. It can also cover substances that are present in much higher concentrations than are usual. Natural compo ...
hormone A hormone (from the Greek participle , "setting in motion") is a class of signaling molecules in multicellular organisms that are sent to distant organs by complex biological processes to regulate physiology and behavior. Hormones are required ...
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 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 In the field of molecular biology, the peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptor proteins that function as transcription factors regulating the expression of genes. PPARs play essential roles in the reg ...
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 Cytochromes P450 (CYPs) are a superfamily of enzymes containing heme as a cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are important for the clearance of various co ...
enzymes that metabolize these xenobiotics.


Structure

Most nuclear receptors have
molecular mass The molecular mass (''m'') is the mass of a given molecule: it is measured in daltons (Da or u). Different molecules of the same compound may have different molecular masses because they contain different isotopes of an element. The related quant ...
es between 50,000 and 100,000 daltons. Nuclear receptors are modular in structure and contain the following domains: * (A-B)
N-terminal The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...
regulatory domain: Contains the activation function 1 (AF-1) whose action is independent of the presence of ligand. The transcriptional activation of AF-1 is normally very weak, but it does synergize with AF-2 in the E-domain (see below) to produce a more robust upregulation of gene expression. The A-B domain is highly variable in sequence between various nuclear receptors. * (C)
DNA-binding domain A DNA-binding domain (DBD) is an independently folded protein domain that contains at least one structural motif that recognizes double- or single-stranded DNA. A DBD can recognize a specific DNA sequence (a recognition sequence) or have a gener ...
(DBD): Highly conserved domain containing two
zinc finger A zinc finger is a small protein structural motif that is characterized by the coordination of one or more zinc ions (Zn2+) in order to stabilize the fold. It was originally coined to describe the finger-like appearance of a hypothesized struct ...
s that binds to specific sequences of DNA called
hormone response element Response elements are short sequences of DNA within a gene promoter or enhancer region that are able to bind specific transcription factors and regulate transcription of genes. Under conditions of stress, a transcription activator protein bin ...
s (HRE). Recently, a novel zinc finger motif (CHC2) is identified in parasitic flatworm NRs. * (D) Hinge region: Thought to be a flexible domain that connects the DBD with the LBD. Influences intracellular trafficking and subcellular distribution with a target peptide sequence. * (E) Ligand binding domain (LBD): Moderately conserved in sequence and highly conserved in structure between the various nuclear receptors. The
structure A structure is an arrangement and organization of interrelated elements in a material object or system, or the object or system so organized. Material structures include man-made objects such as buildings and machines and natural objects such a ...
of the LBD is referred to as an alpha helical sandwich fold in which three anti parallel alpha helices (the "sandwich filling") are flanked by two alpha helices on one side and three on the other (the "bread"). The ligand binding cavity is within the interior of the LBD and just below three anti parallel alpha helical sandwich "filling". Along with the DBD, the LBD contributes to the dimerization interface of the receptor and in addition, binds coactivator and
corepressor In the field of molecular biology, a corepressor is a molecule that represses the expression of genes. In prokaryotes, corepressors are small molecules whereas in eukaryotes, corepressors are proteins. A corepressor does not directly bind to DNA, ...
proteins. The LBD also contains the activation function 2 (AF-2) whose action is dependent on the presence of bound ligand, controlled by the conformation of helix 12 (H12). * (F) C-terminal domain: Highly variable in sequence between various nuclear receptors. The N-terminal (A/B), DNA-binding (C), and ligand binding (E) domains are independently well folded and structurally stable while the hinge region (D) and optional C-terminal (F) domains may be conformationally flexible and disordered. 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).


Mechanism of action

Nuclear receptors are multifunctional proteins that transduce signals of their cognate
ligands In coordination chemistry, a ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's electr ...
. Nuclear receptors (NRs) may be classified into two broad classes according to their mechanism of action and subcellular distribution in the absence of ligand. Small lipophilic substances such as natural hormones diffuse through the cell membrane and bind to nuclear receptors located in the cytosol (type I NR) or nucleus (type II NR) of the cell. Binding causes a conformational change in the receptor which, depending on the class of receptor, triggers a cascade of downstream events that direct the NRs to DNA transcription regulation sites which result in up or down-regulation of gene expression. They generally function as homo/heterodimers. In addition, two additional classes, type III which are a variant of type I, and type IV that bind DNA as monomers have also been identified. 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 dissociation of
heat shock protein Heat shock proteins (HSP) are a family of proteins produced by cells in response to exposure to stressful conditions. They were first described in relation to heat shock, but are now known to also be expressed during other stresses including expo ...
s, homo-
dimerization A dimer () ('' di-'', "two" + ''-mer'', "parts") is an oligomer consisting of two monomers joined by bonds that can be either strong or weak, covalent or intermolecular. Dimers also have significant implications in polymer chemistry, inorganic che ...
, translocation (''i.e.'',
active transport In cellular biology, ''active transport'' is the movement of molecules or ions across a cell membrane from a region of lower concentration to a region of higher concentration—against the concentration gradient. Active transport requires cellul ...
) from the
cytoplasm In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. ...
into the
cell nucleus The cell nucleus (pl. nuclei; from Latin or , meaning ''kernel'' or ''seed'') is a membrane-bound organelle found in eukaryotic cells. Eukaryotic cells usually have a single nucleus, but a few cell types, such as mammalian red blood cells, h ...
, and binding to specific sequences of DNA known as
hormone response element Response elements are short sequences of DNA within a gene promoter or enhancer region that are able to bind specific transcription factors and regulate transcription of genes. Under conditions of stress, a transcription activator protein bin ...
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 The androgen receptor (AR), also known as NR3C4 (nuclear receptor subfamily 3, group C, member 4), is a type of nuclear receptor that is activated by binding any of the androgenic hormones, including testosterone and dihydrotestosterone in ...
, estrogen receptors, glucocorticoid receptor, and
progesterone receptor The progesterone receptor (PR), also known as NR3C3 or nuclear receptor subfamily 3, group C, member 3, is a protein found inside cells. It is activated by the steroid hormone progesterone. In humans, PR is encoded by a single ''PGR'' gene resid ...
. It has been noted that some of the NR subfamily 2 nuclear receptors may bind to direct repeat instead of inverted repeat HREs. In addition, some nuclear receptors that bind either as monomers or dimers, with only a single DNA binding domain of the receptor attaching to a single half site HRE. These nuclear receptors are considered orphan receptors, as their endogenous ligands are still unknown. The nuclear receptor/DNA complex then recruits other proteins that transcribe DNA downstream from the HRE into
messenger RNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of synthesizing a protein. mRNA is created during the ...
and eventually
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
, 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 RXR) to DNA. In the absence of ligand, type II nuclear receptors are often complexed with
corepressor In the field of molecular biology, a corepressor is a molecule that represses the expression of genes. In prokaryotes, corepressors are small molecules whereas in eukaryotes, corepressors are proteins. A corepressor does not directly bind to DNA, ...
proteins. Ligand binding to the nuclear receptor causes dissociation of corepressor and recruitment of coactivator proteins. Additional proteins including
RNA polymerase In molecular biology, RNA polymerase (abbreviated RNAP or RNApol), or more specifically DNA-directed/dependent RNA polymerase (DdRP), is an enzyme that synthesizes RNA from a DNA template. Using the enzyme helicase, RNAP locally opens th ...
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 The retinoic acid receptor (RAR) is a type of nuclear receptor which can also act as a ligand-activated transcription factor that is activated by both all-trans retinoic acid and 9-cis retinoic acid the retinoid active derivatives of Vitamin A ...
, retinoid X receptor and
thyroid hormone receptor The thyroid hormone receptor (TR) is a type of nuclear receptor that is activated by binding thyroid hormone. TRs act as transcription factors, ultimately affecting the regulation of gene transcription and translation. These receptors also have ...
.


Type III

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


Type IV

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


Dimerization

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 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).


Coregulatory proteins

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 Chromatin is a complex of DNA and protein found in eukaryote, eukaryotic cells. The primary function is to package long DNA molecules into more compact, denser structures. This prevents the strands from becoming tangled and also plays important ...
remodeling (making 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.


Coactivators

Binding of agonist ligands (see section below) to nuclear receptors induces a conformation of the receptor that preferentially binds coactivator proteins. These proteins often have an intrinsic
histone acetyltransferase Histone acetyltransferases (HATs) are enzymes that acetylate conserved lysine amino acids on histone proteins by transferring an acetyl group from acetyl-CoA to form ε-''N''-acetyllysine. DNA is wrapped around histones, and, by transferring an ...
(HAT) activity, which weakens the association of
histone In biology, histones are highly basic proteins abundant in lysine and arginine residues that are found in eukaryotic cell nuclei. They act as spools around which DNA winds to create structural units called nucleosomes. Nucleosomes in turn a ...
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
corepressor In the field of molecular biology, a corepressor is a molecule that represses the expression of genes. In prokaryotes, corepressors are small molecules whereas in eukaryotes, corepressors are proteins. A corepressor does not directly bind to DNA, ...
proteins. These proteins, in turn, recruit
histone deacetylase Histone deacetylases (, HDAC) are a class of enzymes that remove acetyl groups (O=C-CH3) from an ε-N-acetyl lysine amino acid on a histone, allowing the histones to wrap the DNA more tightly. This is important because DNA is wrapped around hi ...
s (HDACs), which strengthens the association of histones to DNA, and therefore represses gene transcription.


Agonism vs antagonism

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.


Agonists

The activity of endogenous ligands (such as the hormones
estradiol Estradiol (E2), also spelled oestradiol, is an estrogen steroid hormone and the major female sex hormone. It is involved in the regulation of the estrous and menstrual female reproductive cycles. Estradiol is responsible for the development o ...
and
testosterone Testosterone is the primary sex hormone and anabolic steroid in males. In humans, testosterone plays a key role in the development of male reproductive tissues such as testes and prostate, as well as promoting secondary sexual characteristi ...
) 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 An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ag ...
response. The agonistic effects of endogenous hormones can also be mimicked by certain synthetic ligands, for example, the glucocorticoid receptor anti-inflammatory drug
dexamethasone Dexamethasone is a glucocorticoid medication used to treat rheumatic problems, a number of skin diseases, severe allergies, asthma, chronic obstructive lung disease, croup, brain swelling, eye pain following eye surgery, superior vena ...
. 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
mifepristone Mifepristone, also known as RU-486, is a medication typically used in combination with misoprostol to bring about a medical abortion during pregnancy and manage early miscarriage. This combination is 97% effective during the first 63 days of ...
which binds to the glucocorticoid and
progesterone Progesterone (P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species. It belongs to a group of steroid hormones called the progestogens and is the majo ...
receptors and therefore blocks the activity of the endogenous hormones
cortisol Cortisol is a steroid hormone, in the glucocorticoid class of hormones. When used as a medication, it is known as hydrocortisone. It is produced in many animals, mainly by the '' zona fasciculata'' of the adrenal cortex in the adrenal g ...
and
progesterone Progesterone (P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species. It belongs to a group of steroid hormones called the progestogens and is the majo ...
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 agonist In pharmacology, an inverse agonist is a drug that binds to the same receptor as an agonist but induces a pharmacological response opposite to that of the agonist. A neutral antagonist has no activity in the absence of an agonist or inverse ago ...
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 ( SERMs) and Selective Progesterone Receptor Modulators ( SPRMs). 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.


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 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 In the field of molecular biology, transrepression is a process whereby one protein represses (i.e., inhibits) the activity of a second protein through a protein-protein interaction. Since this repression occurs between two different protein mole ...
. 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.


Non-genomic

The classical direct effects of nuclear receptors on gene regulation normally take 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 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 the cytosol or nucleus. Furthermore, these membrane associated receptors function through alternative
signal transduction Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events, most commonly protein phosphorylation catalyzed by protein kinases, which ultimately results in a cellula ...
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 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 a single
tyrosine -Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a non-essential amino acid with a polar side group. The word "tyrosine" is from the G ...
to
phenylalanine Phenylalanine (symbol Phe or F) is an essential α-amino acid with the formula . It can be viewed as a benzyl group substituted for the methyl group of alanine, or a phenyl group in place of a terminal hydrogen of alanine. This essential amin ...
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 The hippocampus (via Latin from Greek , 'seahorse') is a major component of the brain of humans and other vertebrates. Humans and other mammals have two hippocampi, one in each side of the brain. The hippocampus is part of the limbic syste ...
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 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.


Family members

The following is a list of the 48 known human nuclear receptors (and their orthologs in other species) categorized according to
sequence homology Sequence homology is the biological homology between DNA, RNA, or protein sequences, defined in terms of shared ancestry in the evolutionary history of life. Two segments of DNA can have shared ancestry because of three phenomena: either a ...
. The list also includes selected family members that lack human orthologs (NRNC symbol highlighted in yellow). Of the two 0-families, 0A has a family 1-like DBD, and 0B has a very unique LBD. The second DBD of family 7 is probably related to the family 1 DBD. Three probably family-1 NRs from ''
Biomphalaria glabrata ''Biomphalaria glabrata'' is a species of air-breathing freshwater snail, an aquatic pulmonate gastropod mollusk in the family Planorbidae, the ram's horn snails. ''Biomphalaria glabrata'' is an intermediate snail host for the trematode ''Sch ...
'' possess a DBD along with an family 0B-like LBD. The placement of ''
C. elegans ''Caenorhabditis elegans'' () is a free-living transparent nematode about 1 mm in length that lives in temperate soil environments. It is the type species of its genus. The name is a blend of the Greek ''caeno-'' (recent), ''rhabditis'' (r ...
'' nhr-1 () is disputed: although most sources place it as NR1K1, manual annotation at WormBase considers it a member of NR2A. There used to be a group 2D for which the only member was ''
Drosophila ''Drosophila'' () is a genus of flies, belonging to the family Drosophilidae, whose members are often called "small fruit flies" or (less frequently) pomace flies, vinegar flies, or wine flies, a reference to the characteristic of many speci ...
'' HR78/NR1D1 () 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.


Evolution

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 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 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 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: # The nuclear receptor sequences that had been identified in the earliest metazoans (cnidarians and ''Schistosoma'') were all members of the COUP-TF, RXR, and FTZ-F1 groups of receptors. Both COUP-TF and FTZ-F1 are orphan receptors, and RXR is only found to bind a ligand in vertebrates. # While orphan receptors had known arthropod homologs, no orthologs of liganded vertebrate receptors had been identified outside vertebrates, suggesting that orphan receptors are older than liganded-receptors. # Orphan receptors are found amongst all six subfamilies of nuclear receptors, while ligand-dependent receptors are found amongst three. Thus, since the ligand-dependent receptors were believed to be predominantly member of recent subfamilies, it seemed logical that they gained the ability to bind ligands independently. # The phylogenetic position of a given nuclear receptor within the tree correlates to its DNA-binding domain and dimerization abilities, but there is no identified relationship between a ligand-dependent nuclear receptor and the chemical nature of its ligand. In addition to this, the evolutionary relationships between ligand-dependent receptors did not make much sense as closely related receptors of subfamilies bound ligands originating from entirely different biosynthetic pathways (e.g. TRs and RARs). On the other hand, subfamilies that are not evolutionarily related bind similar ligands (RAR and RXR both bind all-trans and 9-cis retinoic acid respectively). # In 1997, it was discovered that nuclear receptors did not exist in static off and on conformations, but that a ligand could alter the equilibrium between the two states. Furthermore, it was found that nuclear receptors could be regulated in a ligand-independent manner, through either phosphorylation or other post-translational modifications. Thus, this provided a mechanism for how an ancestral orphan receptor was regulated in a ligand-independent manner, and explained why the ligand binding domain was conserved. Over the next 10 years, experiments were conducted to test this hypothesis and counterarguments soon emerged: # Nuclear receptors were identified in the newly sequenced genome of the
demosponge Demosponges (Demospongiae) are the most diverse class in the phylum Porifera. They include 76.2% of all species of sponges with nearly 8,800 species worldwide (World Porifera Database). They are sponges with a soft body that covers a har ...
''Amphimedon queenslandica'', a member Porifera, the most ancient metazoan phylum. The ''A. queenslandica'' genome contains two nuclear receptors known as AqNR1 and AqNR2 and both were characterized to bind and be regulated by ligands. # Homologs for ligand-dependent vertebrate receptors were found outside vertebrates in mollusks and Platyhelminthes. Furthermore, the nuclear receptors found in cnidarians were found to have structural ligands in mammals, which could mirror the ancestral situation. # Two putative orphan receptors, HNF4 and USP were found, via structural and mass spectrometry analysis, to bind fatty acids and phospholipids respectively. # Nuclear receptors and ligands are found to be a lot less specific than was previously thought. Retinoids can bind mammalian receptors other than RAR and RXR such as, PPAR, RORb, or COUP-TFII. Furthermore, RXR is sensitive to a wide range of molecules including retinoids, fatty acids, and phospholipids. # Study of steroid receptor evolution revealed that the ancestral steroid receptor could bind a ligand, estradiol. Conversely, the estrogen receptor found in mollusks is constitutively active and did not bind estrogen-related hormones. Thus, this provided an example of how an ancestral ligand-dependent receptor could lose its ability to bind ligands. 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 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 a highly specific receptor for a particular molecule.


History

Below is a brief selection of key events in the history of nuclear receptor research. * 1905 –
Ernest Starling Ernest Henry Starling (17 April 1866 – 2 May 1927) was a British physiologist who contributed many fundamental ideas to this subject. These ideas were important parts of the British contribution to physiology, which at that time led the world ...
coined the word
hormone A hormone (from the Greek participle , "setting in motion") is a class of signaling molecules in multicellular organisms that are sent to distant organs by complex biological processes to regulate physiology and behavior. Hormones are required ...
* 1926 – Edward Calvin Kendall and
Tadeus Reichstein Tadeusz Reichstein (20 July 1897 – 1 August 1996) was a Polish-Swiss chemist and the Nobel Prize in Physiology or Medicine laureate (1950), which was awarded for his work on the isolation of cortisone. Early life Reichstein was born into a Po ...
isolated and determined the structures of
cortisone Cortisone is a pregnene (21-carbon) steroid hormone. It is a naturally-occurring corticosteroid metabolite that is also used as a pharmaceutical prodrug; it is not synthesized in the adrenal glands. Cortisol is converted by the action of the enz ...
and thyroxine * 1929 – Adolf Butenandt and Edward Adelbert Doisy – independently isolated and determined the structure of
estrogen Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal ac ...
* 1958 – Elwood Jensen – isolated the estrogen receptor * 1980s – cloning of the estrogen, glucocorticoid, and thyroid hormone receptors by
Pierre Chambon Pierre Chambon (born 7 February 1931 in Mulhouse, France) was the founder of the in Strasbourg, France. He was one of the leading molecular biologists who utilized gene cloning and sequencing technology to first decipher the structure of eukaryot ...
, Ronald Evans, and Björn Vennström respectively * 2004 – Pierre Chambon, Ronald Evans, and Elwood Jensen were awarded the
Albert Lasker Award for Basic Medical Research The Albert Lasker Award for Basic Medical Research is one of the prizes awarded by the Lasker Foundation for a fundamental discovery that opens up a new area of biomedical science. The award frequently precedes a Nobel Prize in Medicine; almost 5 ...
, an award that frequently precedes a Nobel Prize in Medicine


See also

* NucleaRDB *
Thyroid hormone receptor The thyroid hormone receptor (TR) is a type of nuclear receptor that is activated by binding thyroid hormone. TRs act as transcription factors, ultimately affecting the regulation of gene transcription and translation. These receptors also have ...
* Steroid hormone receptor * Receptors


References


External links

* * * * * * {{Authority control *