Steroid hormone receptor
Encyclopedia
Steroid hormone receptors are found on the plasma membrane, in the cytosol
and also in the nucleus
of target cells. They are generally intracellular receptor
s (typically cytoplasmic) and initiate signal transduction
for steroid hormone
s which lead to changes in gene expression over a time period of hours to days. The best studied steroid hormone receptors
are members of the nuclear receptor
subfamily 3 (NR3) that include receptors for estrogen
(group NR3A) and 3-ketosteroids (group NR3C).
s. Depending upon the intracellular steroid hormone that they bind, they are either located in the cytosol
and move to the cell nucleus
upon activation, or spend their life in the nucleus waiting for the steroid hormone to enter and activate them. This uptake into the nucleus has to do with Nuclear Localization Signal
s (NLS) found in a region of the receptor. In most cases this signal is covered up by heat shock proteins (hsp) which bind the receptor until the hormone is present. Upon binding by the hormone the receptor undergoes a conformational change, the hsp come off, and the receptor together with the bound hormone enter the nucleus to act upon transcription.
Depending on their mechanism of action and subcellular distribution, nuclear receptors may be classified into at least two classes. Nuclear receptors that bind steroid hormones are all classified as type I receptors. Only type I receptors have a heat shock protein
(hsp) associated with the inactive receptor that will be released when the receptor interacts with the ligand. Type I receptors may be found in homodimer or heterodimer forms. Type II nuclear receptors have no hsp, and in contrast to the classical type I receptor are located in the cell nucleus.
Free (that is, unbound) steroids enter the cell cytoplasm and interact with their receptor. In this process heat shock protein is dissociated, and the activated receptor-ligand complex is translocated into the nucleus.
After binding to the ligand
(steroid hormone), steroid receptors often form dimer
s. In the nucleus, the complex acts as a transcription factor
, augmenting or suppressing transcription
particular gene
s by its action on DNA.
Type II receptors are located in the nucleus. Thus, their ligands pass through the cell wall and cytoplasm and enter the nucleus where they activate the receptor without release of hsp. The activated receptor interacts with the hormone response element and the transcription process is initiated as with type I receptors.
The cell membrane aldosterone receptor
has shown to increase the activity of the basolateral Na/K ATPase, ENaC sodium channels and ROMK potassium channels of the principal cell in the distal tubule and cortical collecting duct of nephron
s (as well as in the large bowel and possibly in sweat glands).
There is some evidence that certain steroid hormone receptors can extend through lipid bilayer membranes at the surface of cells and might be able to interact with hormones that remain outside of cells.
Steroid hormone receptors can also function outside of the nucleus and couple to cytoplasmic signal transduction proteins such as PI3k
and Akt kinase
.
, GPR30
has been found to function a steroid receptor. GPR30 binds to and is activated by estrogen
.
s bind to and modulate the activity of several ion channels including the GABAA, NMDA
, and sigma receptor
s.
The steroid progesterone
has been found to modulate the activity of CatSper
(cation channels of sperm) voltage-gated
Ca2+ channels. Since eggs release progesterone, sperm may use progesterone as a homing signal to swim toward eggs (chemotaxis
).
second messenger. Hence the SHBG/SHBG-R complex appears to act as a transmembrane
steroid receptor that is capable of transmitting signals to the interior of cells.
Cytosol
The cytosol or intracellular fluid is the liquid found inside cells, that is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondrion into compartments....
and also in the 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...
of target cells. They are generally intracellular receptor
Intracellular receptor
Intracellular 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...
s (typically cytoplasmic) and initiate signal transduction
Signal transduction
Signal transduction occurs when an extracellular signaling molecule activates a cell surface receptor. In turn, this receptor alters intracellular molecules creating a response...
for steroid hormone
Steroid hormone
A steroid hormone is a steroid that acts as a hormone. Steroid hormones can be grouped into five groups by the receptors to which they bind: glucocorticoids, mineralocorticoids, androgens, estrogens, and progestogens...
s which lead to changes in gene expression over a time period of hours to days. The best studied steroid hormone 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...
are members of the nuclear receptor
Nuclear receptor
In the field of molecular biology, nuclear receptors are a class of proteins found within cells that are responsible for sensing steroid and thyroid hormones and certain other molecules...
subfamily 3 (NR3) that include receptors for 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...
(group NR3A) and 3-ketosteroids (group NR3C).
Nuclear receptors
Steroid receptors of the nuclear receptor family are all transcription factorTranscription 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. Depending upon the intracellular steroid hormone that they bind, they are either located in the cytosol
Cytosol
The cytosol or intracellular fluid is the liquid found inside cells, that is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondrion into compartments....
and move to 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...
upon activation, or spend their life in the nucleus waiting for the steroid hormone to enter and activate them. This uptake into the nucleus has to do with Nuclear Localization Signal
Nuclear localization signal
A nuclear localization signal or sequence is an amino acid sequence which 'tags' a protein for import into the cell nucleus by nuclear transport. Typically, this signal consists of one or more short sequences of positively charged lysines or arginines exposed on the protein surface. Different...
s (NLS) found in a region of the receptor. In most cases this signal is covered up by heat shock proteins (hsp) which bind the receptor until the hormone is present. Upon binding by the hormone the receptor undergoes a conformational change, the hsp come off, and the receptor together with the bound hormone enter the nucleus to act upon transcription.
- Nuclear receptorNuclear receptorIn the field of molecular biology, nuclear receptors are a class of proteins found within cells that are responsible for sensing steroid and thyroid hormones and certain other molecules...
s- Subfamily 3: Estrogen Receptor-like
- Group A: 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...
(Sex hormones: 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...
)- 1: Estrogen receptor-α (ERαEstrogen receptor alphaEstrogen receptor alpha , also known as NR3A1 , is a nuclear receptor that is activated by the sex hormone estrogen...
; NR3A1) - 2: Estrogen receptor-β (ERβEstrogen receptor betaEstrogen 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 :...
; NR3A2)
- 1: Estrogen receptor-α (ERα
- Group B: Estrogen related receptorEstrogen related receptorThere 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....
- 1: Estrogen-related receptor-α (ERRαEstrogen-related receptor alphaEstrogen-related receptor alpha , also known as NR3B1 , is a nuclear receptor that in humans is encoded by the ESRRA gene.-Tissue distribution:...
; NR3B1) - 2: Estrogen-related receptor-β (ERRβEstrogen-related receptor betaEstrogen-related receptor beta , also known as NR3B2 , is a nuclear receptor that in humans is encoded by the ESRRB gene .- Function :...
; NR3B2) - 3: Estrogen-related receptor-γ (ERRγEstrogen-related receptor gammaEstrogen-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...
; NR3B3)
- 1: Estrogen-related receptor-α (ERRα
- Group C: 3-Ketosteroid receptors
- 1: Glucocorticoid receptor (GRGlucocorticoid receptorThe glucocorticoid receptor also known as NR3C1 is the receptor to which cortisol and other glucocorticoids bind....
; ) (CortisolCortisolCortisol 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,...
) - 2: Mineralocorticoid receptor (MRMineralocorticoid receptorThe 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...
; ) (AldosteroneAldosteroneAldosterone 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...
) - 3: Progesterone receptor (PRProgesterone receptorThe progesterone receptor also known as NR3C3 , is an intracellular steroid receptor that specifically binds progesterone...
; NR3C3) (Sex hormones: ProgesteroneProgesteroneProgesterone also known as P4 is a C-21 steroid hormone involved in the female menstrual cycle, pregnancy and embryogenesis of humans and other species...
) - 4: Androgen receptor (ARAndrogen receptorThe 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...
; NR3C4) (Sex hormones: TestosteroneTestosteroneTestosterone 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...
)
- 1: Glucocorticoid receptor (GR
- Group A: Estrogen receptor
- Subfamily 3: Estrogen Receptor-like
Structure
Intracellular steroid hormone receptors share a common structure of four units that are functionally homologous, so-called "domains":- Variable domain: It begins at the N-terminal and is the most variable domain between the different receptors.
- DNA binding domain: This centrally located highly conserved DNA binding domain (DBD) consists of two non-repetitive globular motifs where zinc is coordinated with four cysteineCysteineCysteine is an α-amino acid with the chemical formula HO2CCHCH2SH. It is a non-essential amino acid, which means that it is biosynthesized in humans. Its codons are UGU and UGC. The side chain on cysteine is thiol, which is polar and thus cysteine is usually classified as a hydrophilic amino acid...
and no histidineHistidineHistidine Histidine, an essential amino acid, has a positively charged imidazole functional group. It is one of the 22 proteinogenic amino acids. Its codons are CAU and CAC. Histidine was first isolated by German physician Albrecht Kossel in 1896. Histidine is an essential amino acid in humans...
residues. Their secondary and tertiary structure is distinct from that of classic 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. This region controls which gene will be activated. On DNA it interacts with the 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...
(HRE). - Hinge region: This area controls the movement of the receptor to the nucleus.
- Hormone binding domain: The moderately conserved ligandLigandIn coordination chemistry, a ligand is an ion or molecule that binds to a central metal atom to form a coordination complex. The bonding between metal and ligand generally involves formal donation of one or more of the ligand's electron pairs. The nature of metal-ligand bonding can range from...
-binding domain (LBD) can include a nuclear localization signalNuclear localization signalA nuclear localization signal or sequence is an amino acid sequence which 'tags' a protein for import into the cell nucleus by nuclear transport. Typically, this signal consists of one or more short sequences of positively charged lysines or arginines exposed on the protein surface. Different...
, amino-acid sequences capable of binding chaperones and parts of dimerization interfaces. Such receptors are closely related to chaperones (namely heat shock proteins hsp90Hsp90Hsp90 is a molecular chaperone and is one of the most abundant proteins expressed in cells. It is a member of the heat shock protein family, which is upregulated in response to stress...
and hsp56), which are required to maintain their inactive (but receptive) cytoplasmic conformationProtein structureProteins are an important class of biological macromolecules present in all organisms. Proteins are polymers of amino acids. Classified by their physical size, proteins are nanoparticles . Each protein polymer – also known as a polypeptide – consists of a sequence formed from 20 possible L-α-amino...
. At the end of this domain is the C-terminal. The terminal connects the molecule to its pair in the homodimer or heterodimer. It may affect the magnitude of the response.
Genomic
Depending on their mechanism of action and subcellular distribution, nuclear receptors may be classified into at least two classes. Nuclear receptors that bind steroid hormones are all classified as type I receptors. Only type I receptors have a 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...
(hsp) associated with the inactive receptor that will be released when the receptor interacts with the ligand. Type I receptors may be found in homodimer or heterodimer forms. Type II nuclear receptors have no hsp, and in contrast to the classical type I receptor are located in the cell nucleus.
Free (that is, unbound) steroids enter the cell cytoplasm and interact with their receptor. In this process heat shock protein is dissociated, and the activated receptor-ligand complex is translocated into the nucleus.
After binding to the ligand
Ligand
In coordination chemistry, a ligand is an ion or molecule that binds to a central metal atom to form a coordination complex. The bonding between metal and ligand generally involves formal donation of one or more of the ligand's electron pairs. The nature of metal-ligand bonding can range from...
(steroid hormone), steroid receptors often form dimer
Protein dimer
In biochemistry, a dimer is a macromolecular complex formed by two, usually non-covalently bound, macromolecules like proteins or nucleic acids...
s. In the nucleus, the complex acts as a 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...
, augmenting or suppressing transcription
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...
particular 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 by its action on DNA.
Type II receptors are located in the nucleus. Thus, their ligands pass through the cell wall and cytoplasm and enter the nucleus where they activate the receptor without release of hsp. The activated receptor interacts with the hormone response element and the transcription process is initiated as with type I receptors.
Non-genomic
The cell membrane aldosterone receptor
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...
has shown to increase the activity of the basolateral Na/K ATPase, ENaC sodium channels and ROMK potassium channels of the principal cell in the distal tubule and cortical collecting duct of nephron
Nephron
The renal tubule is the portion of the nephron containing the tubular fluid filtered through the glomerulus. After passing through the renal tubule, the filtrate continues to the collecting duct system, which is not part of the nephron....
s (as well as in the large bowel and possibly in sweat glands).
There is some evidence that certain steroid hormone receptors can extend through lipid bilayer membranes at the surface of cells and might be able to interact with hormones that remain outside of cells.
Steroid hormone receptors can also function outside of the nucleus and couple to cytoplasmic signal transduction proteins such as PI3k
Phosphoinositide 3-kinase
Phosphatidylinositol 3-kinases are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which in turn are involved in cancer. In response to lipopolysaccharide, PI3K phosphorylates p65, inducing...
and Akt kinase
AKT
Akt, also known as Protein Kinase B , is a serine/threonine protein kinase that plays a key role in multiple cellular processes such as glucose metabolism, cell proliferation, apoptosis, transcription and cell migration.-Family members:...
.
Other
A new class of steroid hormone receptors has recently been elucidated and these new receptors are found on the cell membrane. New studies suggest that along with the well documented intracellular receptors that cell membrane receptors are present for several steroid hormones and that their cellular responses are much quicker than the intracellular receptors.G protein-coupled receptors
At least one G protein-coupled receptorG protein-coupled receptor
G protein-coupled receptors , also known as seven-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptor, and G protein-linked receptors , comprise a large protein family of transmembrane receptors that sense molecules outside the cell and activate inside signal...
, GPR30
GPR30
G-protein coupled estrogen receptor 1 also known as the membrane estrogen receptor or G-protein coupled receptor 30 is a G protein-coupled receptor that in humans is encoded by the GPER gene...
has been found to function a steroid receptor. GPR30 binds to and is activated by 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...
.
Ion channels
Neuroactive steroidNeuroactive steroid
Neuroactive steroids rapidly alter neuronal excitability through interaction with neurotransmitter-gated ion channels. In addition, these steroids may also exert effects on gene expression via intracellular steroid hormone receptors...
s bind to and modulate the activity of several ion channels including the GABAA, NMDA
NMDA receptor
The NMDA receptor , a glutamate receptor, is the predominant molecular device for controlling synaptic plasticity and memory function....
, and sigma receptor
Sigma receptor
The sigma receptors σ1 and σ2 bind to ligands such as 4-PPBP, SA 4503, ditolylguanidine, dimethyltryptamine and siramesine.- Classification :...
s.
The steroid 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...
has been found to modulate the activity of CatSper
Cation channels of sperm
The cation channels of sperm also known as Catsper channels or CatSper, are ion channels that are related to the two-pore channels and distantly related to TRP channels. The four members of this family form voltage-gated Ca2+ channels that seem to be specific to sperm. These channels are required...
(cation channels of sperm) voltage-gated
Voltage-gated ion channel
Voltage-gated ion channels are a class of transmembrane ion channels that are activated by changes in electrical potential difference near the channel; these types of ion channels are especially critical in neurons, but are common in many types of cells....
Ca2+ channels. Since eggs release progesterone, sperm may use progesterone as a homing signal to swim toward eggs (chemotaxis
Chemotaxis
Chemotaxis is the phenomenon in which somatic cells, bacteria, and other single-cell or multicellular organisms direct their movements according to certain chemicals in their environment. This is important for bacteria to find food by swimming towards the highest concentration of food molecules,...
).
SHBG/SHBG-R complex
Sex hormone-binding globulin (SHBG) is thought to mainly function as a transporter and reservoir for the estradiol and testosterone sex hormones. However it has also been demonstrated that SHBG can bind to a cell surface receptor (SHBG-R). The SHBG-R has not been completely characterized. A subset of steroids are able to bind to the SHBG/SHBG-R complex resulting in an activation of adenylyl cyclase and synthesis of the cAMPCyclic adenosine monophosphate
Cyclic adenosine monophosphate is a second messenger important in many biological processes...
second messenger. Hence the SHBG/SHBG-R complex appears to act as a transmembrane
Membrane receptor
Cell surface receptors are specialized integral membrane proteins that take part in communication between the cell and the outside world...
steroid receptor that is capable of transmitting signals to the interior of cells.
External links
- MBC 3320 Steroid hormones and receptors, by Dr. William S. Messer, updated on Monday, April 3, 2000 at 6:05 p.m.
- Steroid Hormone Receptor Signaling. Transcript from Ed. Ralph, A. Bradshaw and Edward A. Dennis: Handbook of Cell Signaling. Academic press, CA, chapter 275. ISBN 0-12-124546-2. Retrieved on May 25, 2005 at 7:49 a.m. (UTC).