Steroid hormone receptors are found in the

nucleus Nucleus ( : nuclei) is a Latin word for the seed inside a fruit. It most often refers to: *Atomic nucleus, the very dense central region of an atom *Cell nucleus, a central organelle of a eukaryotic cell, containing most of the cell's DNA Nucle ...

cytosol The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells (intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...

, and also on the

plasma membrane The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment (t ...

of target cells. They are generally

intracellular receptor Intracellular receptors are Globular protein receptors located inside the cell rather than on its cell membrane. The word ''intracellular'' means "within or inside a cell". Molecules that cross a cell membrane to bind with a receptor are generally ...

s (typically cytoplasmic or nuclear) and initiate

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 ...

for

steroid hormone A steroid hormone is a steroid that acts as a hormone. Steroid hormones can be grouped into two classes: corticosteroids (typically made in the adrenal cortex, hence ''cortico-'') and sex steroids (typically made in the gonads or placenta). Wi ...

s which lead to changes in gene expression over a time period of hours to days. The best studied steroid hormone

receptors Receptor may refer to: *Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a n ...

are members of the

nuclear receptor In the field of molecular biology, nuclear receptors are a class of proteins responsible for sensing steroids, thyroid hormones, vitamins, and certain other molecules. These receptors work with other proteins to regulate the expression of speci ...

subfamily 3 (NR3) that include receptors for

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 acti ...

(group NR3A) and 3-ketosteroids (group NR3C). In addition to nuclear receptors, several

G protein-coupled receptor G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...

s and

ion channel Ion channels are pore-forming membrane proteins that allow ions to pass through the channel pore. Their functions include establishing a resting membrane potential, shaping action potentials and other electrical signals by gating the flow of io ...

s act as

cell surface receptor Cell surface receptors (membrane receptors, transmembrane receptors) are receptors that are embedded in the plasma membrane of cells. They act in cell signaling by receiving (binding to) extracellular molecules. They are specialized integral m ...

s for certain steroid hormones.

Types

Nuclear receptors

Steroid receptors of the nuclear receptor family are all

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 fu ...

s. Depending upon the type of receptor, they are either located in the

and move to 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 ...

upon activation, or remain in the nucleus waiting for the steroid hormone to enter and activate them. This uptake into the nucleus is facilitated by

nuclear localization signal A nuclear localization signal ''or'' sequence (NLS) is an amino acid sequence that '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 o ...

(NLS) found in the hinge region of the receptor. This region of the receptor is covered up by

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 (HSPs) which bind the receptor until the hormone is present. Upon binding by the hormone the receptor undergoes a conformational change releasing the HSP, and the receptor together with the bound hormone enter the nucleus to act upon transcription. *

Nuclear receptor In the field of molecular biology, nuclear receptors are a class of proteins responsible for sensing steroids, thyroid hormones, vitamins, and certain other molecules. These receptors work with other proteins to regulate the expression of speci ...

s ** Subfamily 3: Estrogen Receptor-like ***Group A:

Estrogen receptor Estrogen receptors (ERs) are a group of proteins found inside cells. They are receptors that are activated by the hormone estrogen ( 17β-estradiol). Two classes of ER exist: nuclear estrogen receptors (ERα and ERβ), which are members of the ...

(

Sex hormone Sex hormones, also known as sex steroids, gonadocorticoids and gonadal steroids, are steroid hormones that interact with vertebrate steroid hormone receptors. The sex hormones include the androgens, estrogens, and progestogens. Their effects ar ...

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 acti ...

) ****1: Estrogen receptor-α (

ERα Estrogen receptor alpha (ERα), also known as NR3A1 (nuclear receptor subfamily 3, group A, member 1), is one of two main types of estrogen receptor, a nuclear receptor (mainly found as a chromatin-binding protein) that is activated by the sex ...

; NR3A1, ) ****2: Estrogen receptor-β (

ERβ Estrogen receptor beta (ERβ) also known as NR3A2 (nuclear receptor subfamily 3, group A, member 2) is one of two main types of estrogen receptor—a nuclear receptor which is activated by the sex hormone estrogen. In humans ERβ is encoded by ...

; NR3A2, ) ***Group C: 3-Ketosteroid receptors ****1: Glucocorticoid receptor ( GR; ) (

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 gland ...

) ****2: Mineralocorticoid receptor ( MR; ) (

Aldosterone Aldosterone is the main mineralocorticoid steroid hormone produced by the zona glomerulosa of the adrenal cortex in the adrenal gland. It is essential for sodium conservation in the kidney, salivary glands, sweat glands, and colon. It plays a c ...

) ****3: Progesterone receptor ( PR; NR3C3, ) (

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 m ...

) ****4: Androgen receptor ( AR; NR3C4, ) (

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 system, male reproductive tissues such as testes and prostate, as well as promoting secondar ...

)

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

cysteine Cysteine (symbol Cys or C; ) is a semiessential proteinogenic amino acid with the formula . The thiol side chain in cysteine often participates in enzymatic reactions as a nucleophile. When present as a deprotonated catalytic residue, sometime ...

and no

histidine Histidine (symbol His or H) is an essential amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated –NH3+ form under biological conditions), a carboxylic acid group (which is in the de ...

residues. Their secondary and tertiary structure is distinct from that of classic

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. This region controls which gene will be activated. On DNA it interacts with the

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 binds ...

(HRE). # ''Hinge region'': This area controls the movement of the receptor to the nucleus. # ''Hormone binding domain'': The moderately conserved

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 electr ...

-binding domain (LBD) can include a

, amino-acid sequences capable of binding chaperones and parts of dimerization interfaces. Such receptors are closely related to chaperones (namely heat shock proteins

hsp90 Hsp90 (heat shock protein 90) is a chaperone protein that assists other proteins to fold properly, stabilizes proteins against heat stress, and aids in protein degradation. It also stabilizes a number of proteins required for tumor growth, ...

and hsp56), which are required to maintain their inactive (but receptive) cytoplasmic conformation. 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.

Mechanism of action

= 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

(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 In biochemistry, a protein dimer is a macromolecular complex formed by two protein monomers, or single proteins, which are usually non-covalently bound. Many macromolecules, such as proteins or nucleic acids, form dimers. The word ''dimer'' ha ...

heterodimer In biochemistry, a protein dimer is a macromolecular complex formed by two protein monomers, or single proteins, which are usually non-covalently bound. Many macromolecules, such as proteins or nucleic acids, form dimers. The word ''dimer'' has ...

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. It is also related to EAATs After binding to the

(steroid hormone), steroid receptors often form

dimer Dimer may refer to: * Dimer (chemistry), a chemical structure formed from two similar sub-units ** Protein dimer, a protein quaternary structure ** d-dimer * Dimer model, an item in statistical mechanics, based on ''domino tiling'' * Julius Dimer ( ...

s. In the nucleus, the complex acts as a

, augmenting or suppressing

transcription Transcription refers to the process of converting sounds (voice, music etc.) into letters or musical notes, or producing a copy of something in another medium, including: Genetics * Transcription (biology), the copying of DNA into RNA, the fir ...

particular

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 ba ...

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

= Non-genomic

= The cell membrane aldosterone receptor has shown to increase the activity of the basolateral Na/K ATPase, ENaC sodium channels and ROMK potassium channels of the

principal cell The collecting duct system of the kidney consists of a series of tubules and ducts that physically connect nephrons to a minor calyx or directly to the renal pelvis. The collecting duct system is the last part of nephron and participates in elect ...

in the

distal tubule The distal convoluted tubule (DCT) is a portion of kidney nephron between the loop of Henle and the collecting tubule. Physiology It is partly responsible for the regulation of potassium, sodium, calcium, and pH. On its apical surface (lumen ...

and

cortical collecting duct The collecting duct system of the kidney consists of a series of tubules and ducts that physically connect nephrons to a minor calyx or directly to the renal pelvis. The collecting duct system is the last part of nephron and participates in elect ...

nephron The nephron is the minute or microscopic structural and functional unit of the kidney. It is composed of a renal corpuscle and a renal tubule. The renal corpuscle consists of a tuft of capillaries called a glomerulus and a cup-shaped structure ca ...

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 cells. Steroid hormone receptors can also function outside the nucleus and couple to cytoplasmic signal transduction proteins such as

PI3k Phosphoinositide 3-kinases (PI3Ks), also called phosphatidylinositol 3-kinases, are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which i ...

and Akt kinase.

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

GPCR linked proteins most likely interact with steroid hormones through an amino acid consensus sequence traditionally thought of as a cholesterol recognition and interaction site. About a third of Class A GPCRs contain this sequence. The steroid hormones themselves are different enough from one another that they do not all affect all of the GPCR linked proteins; however, the similarities between the steroid hormones and between the receptors make plausible the argument that each receptor may respond to multiple steroid hormones or that each hormone could affect multiple receptors. This is contrary to the traditional model of having a unique receptor for each unique ligand. At least four different GPCR-linked proteins are known to respond to steroid hormones. G Protein-Coupled Receptor 30 (GPR30) binds estrogen, Membrane Progestin Receptor (mPR) binds progesterone, G Protein-Coupled Receptor Family C Group 6 Member A (GPRC6A) binds androgens, and Thyroid Hormone and Trace Amine Associated Receptor 1 (TAAR1) binds Thyroid hormone (though not technically steroid hormones, thyroid hormones can be grouped here because their receptors belong to the nuclear receptor superfamily). As an example of the effects of these GPCR-linked proteins consider GPR30. GPR30 binds estrogen, and upon binding estrogen this pathway activates

adenylyl cyclase Adenylate cyclase (EC 4.6.1.1, also commonly known as adenyl cyclase and adenylyl cyclase, abbreviated AC) is an enzyme with systematic name ATP diphosphate-lyase (cyclizing; 3′,5′-cyclic-AMP-forming). It catalyzes the following reaction: :A ...

and epidermal growth factor receptor. It results in vasodilation, renoprotection, mammary gland development, etc. Sulfated steroids and

bile acids Bile acids are steroid acids found predominantly in the bile of mammals and other vertebrates. Diverse bile acids are synthesized in the liver. Bile acids are conjugated with taurine or glycine residues to give anions called bile salts. Primary b ...

are also detected by

vomeronasal receptors Vomeronasal receptors are a class of olfactory receptors that putatively function as receptors for pheromones. Pheromones have evolved in all animal phyla, to signal sex and dominance status, and are responsible for stereotypical social and sexua ...

, specifically the V1 family.

Ion channels

Neuroactive steroid Neurosteroids, also known as neuroactive steroids, are endogenous or exogenous steroids that rapidly alter neuronal excitability through interaction with ligand-gated ion channels and other cell surface receptors. The term ''neurosteroid'' was coin ...

s bind to and modulate the activity of several ion channels including the GABA_A,

NMDA ''N''-methyl--aspartic acid or ''N''-methyl--aspartate (NMDA) is an amino acid derivative that acts as a specific agonist at the NMDA receptor mimicking the action of glutamate, the neurotransmitter which normally acts at that receptor. Unlike ...

, and

sigma receptor Sigma receptors (σ-receptors) are protein cell surface receptors that bind ligands such as 4-PPBP (4-phenyl-1-(4-phenylbutyl) piperidine), SA 4503 (cutamesine), ditolylguanidine, dimethyltryptamine, and siramesine. There are two subtypes, ...

s. The steroid

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 m ...

has been found to modulate the activity of

CatSper 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 tha ...

(cation channels of sperm)

voltage-gated Voltage-gated ion channels are a class of transmembrane proteins that form ion channels that are activated by changes in the electrical membrane potential near the channel. The membrane potential alters the conformation of the channel proteins ...

Ca²⁺ channels. Since eggs release progesterone, sperm may use progesterone as a homing signal to swim toward eggs (

chemotaxis Chemotaxis (from '' chemo-'' + ''taxis'') is the movement of an organism or entity in response to a chemical stimulus. Somatic cells, bacteria, and other single-cell or multicellular organisms direct their movements according to certain chemica ...

). *

SHBG/SHBG-R complex

Sex hormone-binding globulin Sex hormone-binding globulin (SHBG) or sex steroid-binding globulin (SSBG) is a glycoprotein that binds to androgens and estrogens. When produced by the Sertoli cells in the seminiferous tubules of the testis, it has also been called androgen-bi ...

(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

and synthesis of the

cAMP Camp may refer to: Outdoor accommodation and recreation * Campsite or campground, a recreational outdoor sleeping and eating site * a temporary settlement for nomads * Camp, a term used in New England, Northern Ontario and New Brunswick to descri ...

second messenger. Hence the SHBG/SHBG-R complex appears to act as a

transmembrane A transmembrane protein (TP) is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequentl ...

steroid receptor that is capable of transmitting signals to the interior of cells.

References

External links

* * {{Receptor/signaling modulators Intracellular receptors