Editing Steroid hormone receptor (section)

== Types ==
Steroid hormone receptors can be categorized into several types based on their specific ligands and functions:

1.[[Estrogen receptor|Estrogen Receptors]] (ER): There are two subtypes, ERα and ERβ, which bind to the hormone estrogen. They regulate gene expression in response to estrogen, playing essential roles in reproductive tissues, bone metabolism, and cardiovascular health.

2.	[[Progesterone receptor|Progesterone Receptors]] (PR): PRs bind to the hormone progesterone and regulate gene expression in response to its signaling. They are critical for various reproductive processes, including menstruation, pregnancy, and mammary gland development.

3.	[[Androgen receptor|Androgen Receptors]] (AR): These receptors bind to androgens such as testosterone and dihydrotestosterone (DHT). They play key roles in the development and function of male reproductive organs, as well as in secondary sexual characteristics and muscle growth.

4.	[[Glucocorticoid receptor|Glucocorticoid Receptors]] (GR): GRs bind to glucocorticoids like cortisol and regulate gene expression in response to stress and metabolic signals. They are involved in processes such as immune response, metabolism, and stress adaptation.

5.	[[Mineralocorticoid receptor|Mineralocorticoid Receptors]] (MR): MRs primarily bind to mineralocorticoids such as aldosterone and regulate electrolyte balance and blood pressure by controlling ion transport in epithelial cells of the kidney and other tissues.<ref>Evans RM. The steroid and thyroid hormone receptor superfamily. Science. 1988 Nov 18;240(4859):889-95. doi: 10.1126/science.3283939. PMID 3283939.</ref>

===Nuclear receptors===
{{Main|nuclear receptor}}
Steroid receptors of the nuclear receptor family are all [[transcription factor]]s. Depending upon the type of receptor, they are either located in the [[cytosol]] and move to the [[cell nucleus]] 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]] (NLS) found in the hinge region of the receptor. This region of the receptor is covered up by [[heat shock protein]]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.

<!-- Please compare with mirror list at [[Intracellular receptor#Members]]-->
* [[Nuclear receptor]]s
** Subfamily 3: Estrogen Receptor-like
***Group A: [[Estrogen receptor]]	([[Sex hormone]]s: [[Estrogen]])
****1: Estrogen receptor-α	([[estrogen receptor alpha|ERα]]; NR3A1, {{Gene|ESR1}})
****2: Estrogen receptor-β	([[estrogen receptor beta|ERβ]]; NR3A2, {{Gene|ESR2}})
***Group C: 3-Ketosteroid receptors
****1: Glucocorticoid receptor	([[glucocorticoid receptor|GR]]; {{Gene|NR3C1}})	([[Cortisol]])
****2: Mineralocorticoid receptor	([[mineralocorticoid receptor|MR]]; {{Gene|NR3C2}})	([[Aldosterone]])
****3: Progesterone receptor	([[progesterone receptor|PR]]; NR3C3, {{Gene|PGR}})	([[Sex hormone]]s: [[Progesterone]])
****4: Androgen receptor	([[androgen receptor|AR]]; NR3C4, {{Gene|AR}})	([[Sex hormone]]s: [[Testosterone]])

==== 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<ref name="pmid8221895">{{PDB|1HCQ}}; {{cite journal | vauthors = Schwabe JW, Chapman L, Finch JT, Rhodes D | title = The crystal structure of the estrogen receptor DNA-binding domain bound to DNA: how receptors discriminate between their response elements | journal = Cell | volume = 75 | issue = 3 | pages = 567–78 | date = Nov 1993 | pmid = 8221895 | doi = 10.1016/0092-8674(93)90390-C | s2cid = 20795587 }}</ref> where zinc is coordinated with four [[cysteine]] and no [[histidine]] residues. Their secondary and tertiary structure is distinct from that of classic [[zinc finger]]s.<ref name="pmid3283939">{{cite journal | vauthors = Evans RM | title = The steroid and thyroid hormone receptor superfamily | journal = Science | volume = 240 | issue = 4854 | pages = 889–95 | date = May 1988 | pmid = 3283939 | pmc = 6159881 | doi = 10.1126/science.3283939 | bibcode = 1988Sci...240..889E }}</ref> This region controls which gene will be activated. On DNA it interacts with the [[hormone response element]] (HRE).
# ''Hinge region'': This area controls the movement of the receptor to the nucleus.
# ''Hormone binding domain'': The moderately conserved [[ligand]]-binding domain (LBD) can include a [[nuclear localization signal]], amino-acid sequences capable of binding chaperones and parts of dimerization interfaces. Such receptors are closely related to [[Chaperone (protein)|chaperone]]s (namely heat shock proteins [[hsp90]] and [[FKBP4|hsp56]]), which are required to maintain their inactive (but receptive) cytoplasmic [[Protein structure|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.<ref name="Mangelsdorf_1995">{{cite journal | vauthors = Mangelsdorf DJ, Thummel C, Beato M, Herrlich P, Schütz G, Umesono K, Blumberg B, Kastner P, Mark M, Chambon P, Evans RM | title = The nuclear receptor superfamily: the second decade | journal = Cell | volume = 83 | issue = 6 | pages = 835–9 | date = Dec 1995 | pmid = 8521507 | pmc = 6159888 | doi = 10.1016/0092-8674(95)90199-X }}</ref><ref name="Novac_2004">{{cite journal | vauthors = Novac N, Heinzel T | title = Nuclear receptors: overview and classification | journal = Current Drug Targets. Inflammation and Allergy | volume = 3 | issue = 4 | pages = 335–46 | date = Dec 2004 | pmid = 15584884 | doi = 10.2174/1568010042634541 }}</ref> 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. It is also related to EAATs.

After binding to the [[ligand]] (steroid hormone), steroid receptors often form [[protein dimer|dimer]]s. In the nucleus, the complex acts as a [[transcription factor]], augmenting or suppressing [[Transcription (genetics)|transcription]] particular [[gene]]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 [[mineralocorticoid receptor|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 cells.<ref name="pmid15288769">{{cite journal | vauthors = Luconi M, Francavilla F, Porazzi I, Macerola B, Forti G, Baldi E | title = Human spermatozoa as a model for studying membrane receptors mediating rapid nongenomic effects of progesterone and estrogens | journal = Steroids | volume = 69 | issue = 8–9 | pages = 553–9 | date = Aug 2004 | pmid = 15288769 | doi = 10.1016/j.steroids.2004.05.013 | s2cid = 25453428 }}</ref>

Steroid hormone receptors can also function outside the nucleus and couple to cytoplasmic signal transduction proteins such as [[phosphoinositide 3-kinase|PI3k]] and [[AKT|Akt kinase]].<ref name="pmid15001646">{{cite journal | vauthors = Aquila S, Sisci D, Gentile M, Middea E, Catalano S, Carpino A, Rago V, Andò S | title = Estrogen receptor (ER)alpha and ER beta are both expressed in human ejaculated spermatozoa: evidence of their direct interaction with phosphatidylinositol-3-OH kinase/Akt pathway | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 89 | issue = 3 | pages = 1443–51 | date = Mar 2004 | pmid = 15001646 | doi = 10.1210/jc.2003-031681 | doi-access = free }}</ref>

===Other===

Steroid hormone receptors exert their effects through several mechanisms, including:

1.	[[Gene regulation|Gene Regulation]]: Upon ligand binding, steroid hormone receptors translocate to the nucleus, where they bind to specific DNA sequences called hormone response elements (HREs) within the regulatory regions of target genes. This binding either activates or suppresses gene transcription, leading to changes in mRNA levels and ultimately protein synthesis.

2.	Transcriptional Coactivators and Corepressors: Steroid hormone receptors recruit coactivator or corepressor proteins to the gene promoter regions, which modulate the activity of RNA polymerase and other transcriptional machinery, thereby influencing [[gene expression]].

3.	[[Chromatin remodeling|Chromatin Remodeling]]: Steroid hormone receptors can also induce changes in chromatin structure through the recruitment of chromatin remodeling complexes. This allows for accessibility of the transcriptional machinery to specific gene regulatory regions, facilitating or inhibiting gene transcription.

4.	Non-Genomic Signaling: In addition to classical genomic actions, steroid hormone receptors can initiate rapid, non-genomic signaling pathways in the cytoplasm or at the cell membrane. These pathways involve activation of various protein kinases and other signaling molecules, leading to rapid cellular responses such as ion fluxes, cytoskeletal rearrangements, and activation of second messenger systems.

5.	Cross-Talk with Other Signaling Pathways: Steroid hormone receptors can also interact with and modulate the activity of other signaling pathways, such as growth factor signaling pathways, thereby integrating hormonal and growth factor signals to regulate cellular processes.<ref>Mangelsdorf DJ, Thummel C, Beato M, Herrlich P, Schütz G, Umesono K, Blumberg B, Kastner P, Mark M, Chambon P, Evans RM. The nuclear receptor superfamily: the second decade. Cell. 1995 Dec 15;83(6):835-9. doi: 10.1016/0092-8674(95)90199-x. PMID 8521507.</ref>

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.<ref name="pmid14708019">{{cite journal | vauthors = Norman AW, Mizwicki MT, Norman DP | title = Steroid-hormone rapid actions, membrane receptors and a conformational ensemble model | journal = Nature Reviews. Drug Discovery | volume = 3 | issue = 1 | pages = 27–41 | date = Jan 2004 | pmid = 14708019 | doi = 10.1038/nrd1283 | s2cid = 17487277 }}</ref>

==== 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.<ref name="Wang_2014">{{cite journal | vauthors = Wang C, Liu Y, Cao JM | title = G protein-coupled receptors: extranuclear mediators for the non-genomic actions of steroids | journal = International Journal of Molecular Sciences | volume = 15 | issue = 9 | pages = 15412–25 | year = 2014 | pmid = 25257522 | pmc = 4200746 | doi = 10.3390/ijms150915412 | doi-access = free }}</ref>

At least four different GPCR-linked proteins are known to respond to steroid hormones. [[GPR30]] binds estrogen, [[membrane progestin receptor]] (mPR) binds progesterone, and [[GPRC6A]] binds androgens. 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]] and epidermal growth factor receptor. It results in vasodilation, renoprotection, mammary gland development, etc.<ref name="Wang_2014"/>

Sulfated steroids and [[bile acids]] are also detected by [[vomeronasal receptors]], specifically the V1 family.<ref name="pmid31831669">{{cite journal | vauthors = Lee D, Kume M, Holy TE | title = Sensory coding mechanisms revealed by optical tagging of physiologically defined neuronal types | journal = Science | volume = 366 | issue = 6471 | pages = 1384–1389 | date = December 2019 | pmid = 31831669 | doi = 10.1126/science.aax8055 | bibcode = 2019Sci...366.1384L | s2cid = 209339279 | pmc = 7591936 }}</ref><ref name="pmid25073926">{{cite journal | vauthors = Haga-Yamanaka S, Ma L, He J, Qiu Q, Lavis LD, Looger LL, Yu CR | title = Integrated action of pheromone signals in promoting courtship behavior in male mice | journal = eLife | volume = 3 | pages = e03025 | date = July 2014 | pmid = 25073926 | pmc = 4107909 | doi = 10.7554/eLife.03025 | doi-access = free }}</ref><ref name="pmid32523992">{{cite journal | vauthors = Wong WM, Cao J, Zhang X, Doyle WI, Mercado LL, Gautron L, Meeks JP | title = Physiology-forward identification of bile acid-sensitive vomeronasal receptors | journal = Sci Adv | volume = 6 | issue = 22 | pages = eaaz6868 | date = May 2020 | pmid = 32523992 | pmc = 7259934 | doi = 10.1126/sciadv.aaz6868 | bibcode = 2020SciA....6.6868W }}</ref>

==== Ion channels ====

[[Neuroactive steroid]]s bind to and modulate the activity of several ion channels including the [[GABAA receptor|GABA<sub>A</sub>]],<ref name="pmid2422758">{{cite journal | vauthors = Majewska MD, Harrison NL, Schwartz RD, Barker JL, Paul SM | title = Steroid hormone metabolites are barbiturate-like modulators of the GABA receptor | journal = Science | volume = 232 | issue = 4753 | pages = 1004–7 | date = May 1986 | pmid = 2422758 | doi = 10.1126/science.2422758 | url = https://zenodo.org/record/1230988 }}</ref><ref name="pmid17531325">{{cite journal | vauthors = Herd MB, Belelli D, Lambert JJ | title = Neurosteroid modulation of synaptic and extrasynaptic GABA(A) receptors | journal = Pharmacology & Therapeutics | volume = 116 | issue = 1 | pages = 20–34 | date = Oct 2007 | pmid = 17531325 | doi = 10.1016/j.pharmthera.2007.03.007 | arxiv = 1607.02870 }}</ref><ref name="pmid17108970">{{cite journal | vauthors = Hosie AM, Wilkins ME, da Silva HM, Smart TG | title = Endogenous neurosteroids regulate GABAA receptors through two discrete transmembrane sites | journal = Nature | volume = 444 | issue = 7118 | pages = 486–9 | date = Nov 2006 | pmid = 17108970 | doi = 10.1038/nature05324 | bibcode = 2006Natur.444..486H | s2cid = 4382394 }}</ref><ref name="pmid2160838">{{cite journal | vauthors = Puia G, Santi MR, Vicini S, Pritchett DB, Purdy RH, Paul SM, Seeburg PH, Costa E | title = Neurosteroids act on recombinant human GABAA receptors | journal = Neuron | volume = 4 | issue = 5 | pages = 759–65 | date = May 1990 | pmid = 2160838 | doi = 10.1016/0896-6273(90)90202-Q | s2cid = 12626366 }}</ref> [[NMDA receptor|NMDA]],<ref name="pmid1654510">{{cite journal | vauthors = Wu FS, Gibbs TT, Farb DH | title = Pregnenolone sulfate: a positive allosteric modulator at the N-methyl-D-aspartate receptor | journal = Molecular Pharmacology | volume = 40 | issue = 3 | pages = 333–6 | date = Sep 1991 | pmid = 1654510 | url = http://molpharm.aspetjournals.org/cgi/content/abstract/40/3/333 | format = abstract }}</ref> and [[sigma receptor]]s.<ref name="pmid9062676">{{cite journal | vauthors = Maurice T, Junien JL, Privat A | title = Dehydroepiandrosterone sulfate attenuates dizocilpine-induced learning impairment in mice via sigma 1-receptors | journal = Behavioural Brain Research | volume = 83 | issue = 1–2 | pages = 159–64 | date = Feb 1997 | pmid = 9062676 | doi = 10.1016/S0166-4328(97)86061-5 | s2cid = 3979800 }}</ref>

The steroid [[progesterone]] has been found to modulate the activity of [[cation channels of sperm|CatSper]] (cation channels of sperm) [[Voltage-gated ion channel|voltage-gated]] Ca<sup>2+</sup> channels. Since eggs release progesterone, sperm may use progesterone as a homing signal to swim toward eggs ([[chemotaxis]]).<ref name="pmid21412338">{{cite journal | vauthors = Strünker T, Goodwin N, Brenker C, Kashikar ND, Weyand I, Seifert R, Kaupp UB | title = The CatSper channel mediates progesterone-induced Ca2+ influx in human sperm | journal = Nature | volume = 471 | issue = 7338 | pages = 382–6 | date = Mar 2011 | pmid = 21412338 | doi = 10.1038/nature09769 | bibcode = 2011Natur.471..382S | s2cid = 4431334}}
*{{cite journal |author=Ewen Callaway |date=16 March 2011 |title=Female hormone could be key to male contraceptive |journal=Nature |doi=10.1038/news.2011.163 |doi-access=free}}</ref><ref name="pmid21412339">{{cite journal | vauthors = Lishko PV, Botchkina IL, Kirichok Y | title = Progesterone activates the principal Ca2+ channel of human sperm | journal = Nature | volume = 471 | issue = 7338 | pages = 387–91 | date = Mar 2011 | pmid = 21412339 | doi = 10.1038/nature09767 | bibcode = 2011Natur.471..387L | s2cid = 4340309 }}</ref>

==== 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 [[cyclic adenosine monophosphate|cAMP]] second messenger.<ref name="pmid19698759">{{cite journal | vauthors = Rosner W, Hryb DJ, Kahn SM, Nakhla AM, Romas NA | title = Interactions of sex hormone-binding globulin with target cells | journal = Molecular and Cellular Endocrinology | volume = 316 | issue = 1 | pages = 79–85 | date = Mar 2010 | pmid = 19698759 | doi = 10.1016/j.mce.2009.08.009 | s2cid = 27912941 }}</ref>  Hence the SHBG/SHBG-R complex appears to act as a [[membrane receptor|transmembrane]] steroid receptor that is capable of transmitting signals to the interior of cells.