Editing Hormone receptor

{{short description|Group of proteins}}
A '''hormone receptor''' is a [[receptor (biochemistry)|receptor]] molecule that binds to a specific [[hormone]]. Hormone receptors are a wide family of proteins made up of receptors for thyroid and steroid hormones, retinoids and [[Vitamin D]], and a variety of other receptors for various ligands, such as [[fatty acids]] and [[prostaglandins]].<ref name=":0">{{Cite journal|last1=Aranda|first1=A.|last2=Pascual|first2=A.|date=2001-07-01|title=Nuclear hormone receptors and gene expression|journal=Physiological Reviews|volume=81|issue=3|pages=1269–1304|issn=0031-9333|pmid=11427696|doi=10.1152/physrev.2001.81.3.1269|hdl=10261/79944|s2cid=5972234 }}</ref> Hormone receptors are of mainly two classes. Receptors for [[peptide hormones]] tend to be [[cell surface receptor]]s built into the [[cell membrane|plasma membrane]] of cells and are thus referred to as [[Transmembrane protein|trans membrane]] receptors. An example of this is [[Actrapid]].<ref name=":1">{{Cite journal|last=Gammeltoft|first=S.|date=1984-10-01|title=Insulin receptors: binding kinetics and structure-function relationship of insulin|journal=Physiological Reviews|language=en|volume=64|issue=4|pages=1321–1378|issn=0031-9333|pmid=6387730|doi=10.1152/physrev.1984.64.4.1321}}</ref> Receptors for [[steroid hormone]]s are usually found within the [[protoplasm]] and are referred to as intracellular or [[nuclear receptor]]s, such as testosterone.<ref>{{Cite journal|last1=McEwen|first1=B. S.|last2=Kloet|first2=E. R. De|last3=Rostene|first3=W.|date=1986-10-01|title=Adrenal steroid receptors and actions in the nervous system|journal=Physiological Reviews|language=en|volume=66|issue=4|pages=1121–1188|issn=0031-9333|pmid=3532143|doi=10.1152/physrev.1986.66.4.1121}}</ref> Upon hormone binding, the receptor can initiate multiple signaling pathways, which ultimately leads to changes in the behavior of the target cells.

Hormonal therapy and hormone receptors play a very large part in breast cancer treatment (therapy is not limited to only breast cancer). By influencing the hormones, the cells' growth can be changed along with its function. These hormones can cause cancer to not survive in the human body.<ref>{{Cite news|url=http://www.breastcancer.org/symptoms/diagnosis/hormone_status/understanding|title=Understanding Hormone Receptors and What They Do|work=Breastcancer.org|access-date=2017-04-06|language=en}}</ref>

== General ligand binding ==
[[File:Hormone Receptor Binding.png|thumb|Signal molecule binds to its hormone receptor, inducing a conformational change in the receptor to begin a signaling cascade that induces a cellular response.]]
Hormone receptor proteins bind to a hormone as a result of an accumulation of weak interactions. Because of the relatively large size of enzymes and receptors, the large amount of surface area provides the basis for these weak interactions to occur. This binding is actually highly specific because of the complementarity of these interactions between polar, non-polar, charged, neutral, hydrophilic, or hydrophobic residues. Upon binding, the receptor often undergoes a conformational change and may bind further, signaling ligands to activate a signaling pathway. Because of these highly specific and high affinity interactions between hormones and their receptors, very low concentrations of hormone can produce significant cellular response.<ref name=":2">{{Cite book|title=Principles of Biochemistry|last=Nelson 1, Cox 2, Lehninger 3|publisher=Worth|location=New York|pages=81}}</ref> Receptors can have various different structures depending on the function of the hormone and the structure of its ligand. Therefore, hormone binding to its receptor is a complex process that can be mediated by cooperative binding, reversible and irreversible interactions, and multiple binding sites.<ref name=":1"/>

== Functions ==

=== Transmission of signal ===
The presence of hormone or multiple hormones enables a response in the receptor, which begins a cascade of signaling. The hormone receptor interacts with different molecules to induce a variety of changes, such as an increase or decrease of nutrient sources, growth, and other metabolic functions. These signaling pathways are complex mechanisms mediated by feedback loops where different signals activate and inhibit other signals. If a signaling pathway ends with the increase in production of a nutrient, that nutrient is then a signal back to the receptor that acts as a competitive inhibitor to prevent further production.<ref>{{Cite journal|last1=Mullur|first1=Rashmi|last2=Liu|first2=Yan-Yun|last3=Brent|first3=Gregory A.|date=2014-04-01|title=Thyroid Hormone Regulation of Metabolism|journal=Physiological Reviews|language=en|volume=94|issue=2|pages=355–382|doi=10.1152/physrev.00030.2013|issn=0031-9333|pmc=4044302|pmid=24692351}}</ref> Signaling pathways regulate cells through activating or inactivating gene expression, transport of metabolites, and controlling enzymatic activity to manage growth and functions of metabolism.<ref>{{Cite journal|last1=Argetsinger|first1=L. S.|last2=Carter-Su|first2=C.|date=1996-10-01|title=Mechanism of signaling by growth hormone receptor|journal=Physiological Reviews|language=en|volume=76|issue=4|pages=1089–1107|issn=0031-9333|pmid=8874495|doi=10.1152/physrev.1996.76.4.1089}}</ref>

==== Intracellular receptors ====
[[Intracellular receptor|Intracellular ]] and [[nuclear receptor]]s are a direct way for the cell to respond to internal changes and signals. Intracellular receptors are activated by hydrophobic ligands that pass through the cellular membrane. All nuclear receptors are very similar in structure, and are described with intrinsic transcriptional activity. Intrinsic transcriptional involves the three following domains:<ref>{{Cite web|url=http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/moaction/intracell.html|title=Mechanism of Action: Hormones with Intracellular Receptors|website=www.vivo.colostate.edu|language=en|access-date=2017-04-06}}</ref> transcription-activating,<ref>{{Cite web|url=http://www.uh.edu/~phardin/MolBioCh12-04.html|title=Molecular Biology|website=www.uh.edu|access-date=2017-04-06}}</ref> DNA-binding,<ref>{{Cite journal|last1=Follis|first1=Ariele Viacava|last2=Llambi|first2=Fabien|last3=Ou|first3=Li|last4=Baran|first4=Katherine|last5=Green|first5=Douglas R.|last6=Kriwacki|first6=Richard W.|date=2014-06-01|title=The DNA-binding domain mediates both nuclear and cytosolic functions of p53|journal=Nature Structural & Molecular Biology|language=en|volume=21|issue=6|pages=535–543|doi=10.1038/nsmb.2829|issn=1545-9993|pmc=4134560|pmid=24814347}}</ref> and ligand-binding.<ref>{{Cite web|url=http://www.ks.uiuc.edu/Research/smd_imd/rar_dna/|title=Ligand Binding Domain|website=www.ks.uiuc.edu|access-date=2017-04-06}}</ref> These domains and ligands are hydrophobic and are able to travel through the membrane.<ref>{{Cite news|url=http://www.open.edu/openlearn/science-maths-technology/cell-signalling/content-section-2.5#|title=Cell signalling|work=OpenLearn|access-date=2017-04-06}}</ref> The movement of macromolecules and ligand molecules into the cell enables a complex transport system of intracellular signal transfers through different cellular environments until response is enabled.<ref>{{Cite journal|last=Stockert|first=R. J.|date=1995-07-01|title=The asialoglycoprotein receptor: relationships between structure, function, and expression|journal=Physiological Reviews|language=en|volume=75|issue=3|pages=591–609|issn=0031-9333|pmid=7624395|doi=10.1152/physrev.1995.75.3.591}}</ref> Nuclear receptors are a special class of intracellular receptor that specifically aid the needs of the cell to express certain genes. Nuclear receptors often bind directly to DNA by targeting specific DNA sequences in order to express or repress transcription of nearby genes.<ref name=":0" />

==== Cell surface receptors ====
The extracellular environment is able to induce changes within the cell. Hormones, or other extracellular signals, are able to induce changes within the cell by binding to [[cell surface receptor]]s also known as transmembrane receptors.<ref name=":2" /> This interaction allows the hormone receptor to produce second messengers within the cell to aid response. Second messengers may also be sent to interact with intracellular receptors in order to enter the complex signal transport system that eventually changes cellular function.<ref name=":1" />

G-protein-coupled membrane receptors (GPCR) are a major class of transmembrane receptors. The features of G proteins include GDP/GTP binding, GTP hydrolysis and guanosine nucleotide exchange.<ref name=":02">{{Cite book|title=Principles of endocrinology and hormone action|others=Belfiore, Antonino,, LeRoith, Derek, 1945-|isbn=9783319446752|location=Cham|oclc=1021173479}}</ref><ref name=":12">{{Citation|last1=Kleine|first1=Bernhard|title=Hormone Receptors|date=2016|work=Hormones and the Endocrine System|pages=247–259|publisher=Springer International Publishing|language=en|doi=10.1007/978-3-319-15060-4_8|isbn=9783319150598|last2=Rossmanith|first2=Winfried G.}}</ref> When a ligand binds to a GPCR the receptor changes conformation, which makes the intracellular loops between the different membrane domains of the receptor interact with G proteins. This interaction causes the exchange of GDP for GTP, which triggers structural changes within the alpha subunit of the G protein.<ref name=":22">{{Cite book|title=Molecular endocrinology|last=F.|first=Bolander, Franklyn|date=1989|publisher=Academic Press|isbn=978-0121112301|location=San Diego|oclc=18324100}}</ref><ref name=":12" /><ref name=":02" /> The changes interrupts the interaction of the alpha subunit with the beta–gamma complex and which results in a single alpha subunit with GTP bound and a beta–gamma dimer. The GTP–alpha monomer interacts with a variety of cellular targets. The beta–gamma dimer also can stimulate enzymes within the cells for example, adenylate cyclase but it does not have as many targets as the GTP–alpha complex.<ref name=":12" />

=== Aiding gene expression ===
Hormone receptors can behave as transcription factors by interacting directly with DNA or by cross-talking with signaling pathways.<ref name=":0" /> This process is mediated through co-regulators. In the absence of ligand, receptor molecules bind corepressors to repress gene expression, compacting [[chromatin]] through histone deacetylatase. When a ligand is present, nuclear receptors undergo a conformational change to recruit various coactivators. These molecules work to remodel chromatin. Hormone receptors have highly specific motifs that can interact with coregulator complexes.<ref>{{Cite journal|last1=Vasudevan|first1=Nandini|last2=Ogawa|first2=Sonoko|last3=Pfaff|first3=Donald|date=2002-01-10|title=Estrogen and Thyroid Hormone Receptor Interactions: Physiological Flexibility by Molecular Specificity|journal=Physiological Reviews|language=en|volume=82|issue=4|pages=923–944|doi=10.1152/physrev.00014.2002|issn=0031-9333|pmid=12270948|s2cid=28649627 }}</ref> This is the mechanism through which receptors can induce regulation of gene expression depending on both the extracellular environment and the immediate cellular composition. Steroid hormones and their regulation by receptors are the most potent molecule interactions in aiding gene expression.<ref name=":0" />

Problems with nuclear receptor binding as a result of shortages of ligand or receptors can have drastic effects on the cell. The dependency on the ligand is the most important part in being able to regulate gene expression, so the absence of ligand is drastic to this process. For example, estrogen deficiency is a cause of osteoporosis and the inability to undergo a proper signaling cascade prevents bone growth and strengthening. Deficiencies in nuclear receptor-mediated pathways play a key role in the development of disease, like osteoporosis.<ref>{{Cite journal|last1=Imai|first1=Yuuki|last2=Youn|first2=Min-Young|last3=Inoue|first3=Kazuki|last4=Takada|first4=Ichiro|last5=Kouzmenko|first5=Alexander|last6=Kato|first6=Shigeaki|date=2013-04-01|title=Nuclear Receptors in Bone Physiology and Diseases|journal=Physiological Reviews|language=en|volume=93|issue=2|pages=481–523|doi=10.1152/physrev.00008.2012|issn=0031-9333|pmc=3768103|pmid=23589826}}</ref>

when a ligand binds to a nuclear receptor, the receptor undergoes a conformational change that causes it to become activated, which in turn affects how much gene expression is regulated.

== Classification ==

=== Receptors for water-soluble hormones ===
Water-soluble hormones include [[glycoprotein]]s, [[catecholamine]]s, and [[peptide hormone]]s composed of [[peptides|polypeptides]], e.g. [[thyroid-stimulating hormone]], [[follicle-stimulating hormone]], [[luteinizing hormone]] and [[insulin]]. These molecules are not lipid-soluble and therefore cannot [[molecular diffusion|diffuse]] through cell membranes. Consequently, receptors for peptide hormones are located on the plasma membrane because they have bound to a receptor protein located on the plasma membrane.<ref>{{Cite journal|last=Boundless|date=2016-10-23|title=Mechanisms of Hormone Action|url=https://www.boundless.com/physiology/textbooks/boundless-anatomy-and-physiology-textbook/endocrine-system-16/hormones-150/mechanisms-of-hormone-action-774-807/|archive-url=https://web.archive.org/web/20170407055659/https://www.boundless.com/physiology/textbooks/boundless-anatomy-and-physiology-textbook/endocrine-system-16/hormones-150/mechanisms-of-hormone-action-774-807/|url-status=dead|archive-date=April 7, 2017|journal=Boundless|language=en}}</ref>

Water-soluble hormones come from amino acids and are located and stored in endocrine cells until actually needed.<ref>{{Cite web|url=http://e.hormone.tulane.edu/learning/types-of-hormones.html|title=e.hormone {{!}} Endocrine System : Types of Hormones|website=e.hormone.tulane.edu|access-date=2017-04-06}}</ref>

The main two types of [[transmembrane receptor]] hormone receptor are the [[G-protein-coupled receptor]]s and the [[enzyme-linked receptor]]s. These receptors generally function via intracellular [[second messengers]], including  [[cyclic AMP]] (cAMP), cyclic GMP (cGMP), inositol 1,4,5-trisphosphate ([[Inositol triphosphate|IP3]]) and the [[Calcium signaling|calcium]] (Ca<sup>2+</sup>)-[[calmodulin]] system.

===Receptors for lipid-soluble hormones===
[[File:Estrogen Receptor DBD.jpg|thumb|Cartoon representation of the human hormone estrogen receptor DBD. DNA = orange and blue. DBD of estrogen receptor = white. Zinc atoms = green.]]
[[Steroid hormone receptor]]s and related receptors are generally soluble proteins that function through gene activation. Lipid-soluble hormones target specific sequences of DNA by diffusing into the cell. When they have diffused into the cell, they bind to receptors (intracellular), and migrate into the nucleus.<ref>{{Cite web|url=http://classes.midlandstech.edu/carterp/Courses/bio211/chap16/chap16.htm|archive-url=https://web.archive.org/web/20071124091055/http://classes.midlandstech.edu/carterp/Courses/bio211/chap16/chap16.htm|url-status=dead|archive-date=November 24, 2007|title=The Endocrine System|website=classes.midlandstech.edu|access-date=2017-04-06}}</ref> Their response elements are DNA sequences (promoters) that are bound by the complex of the steroid bound to its receptor.  The receptors themselves are [[zinc-finger]] proteins.<ref>{{Cite web |url=http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/S/SteroidREs.html |title=Steroid Hormone Receptors and their Response Elements |access-date=2006-05-01 |archive-url=https://web.archive.org/web/20061230202811/http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/S/SteroidREs.html |archive-date=2006-12-30 |url-status=dead }}</ref>  These receptors include those for [[glucocorticoid]]s ([[glucocorticoid receptor]]s), [[estrogen]]s ([[estrogen receptor]]s), [[androgen]]s ([[androgen receptor]]s), [[thyroid hormone]] (T3) ([[thyroid hormone receptor]]s), [[calcitriol]] (the active form of [[vitamin D]]) ([[calcitriol receptor]]s), and the [[retinoid]]s ([[vitamin A]]) ([[retinoid receptor]]s). Receptor-protein interactions induce the uptake and destruction of their respective hormones in order to regulate their concentration in the body. This is especially important for steroid hormones because many body systems are entirely steroid dependent.<ref>{{Cite journal|last1=Gimpl|first1=Gerald|last2=Fahrenholz|first2=Falk|date=2001-04-01|title=The Oxytocin Receptor System: Structure, Function, and Regulation|journal=Physiological Reviews|language=en|volume=81|issue=2|pages=629–683|issn=0031-9333|pmid=11274341|doi=10.1152/physrev.2001.81.2.629|s2cid=13265083 }}</ref>

== List of hormone receptors ==
{{Expand list|date=March 2016}}

For some of these classes, in any given species (such as, for example, humans), there is a single molecule encoded by a single gene; in other cases, there are several molecules in the class.

* [[Androgen receptor]]s
* [[Calcitriol receptor]]s
* [[Corticotropin-releasing hormone receptor 1]]
* [[Corticotropin releasing hormone receptor 2]]
* [[Estrogen receptor]]s
* [[Follicle-stimulating hormone receptor]]s
* [[Glucagon receptor]]s
* [[Gonadotropin receptor]]s
* [[Gonadotropin-releasing hormone receptor]]s
* [[Growth hormone receptor]]s
*[[Insulin receptor]]
* [[Luteinizing hormone]]
* [[Progesterone receptor]]s
* [[Retinoid receptor]]s
* [[Somatostatin receptor]]s
* [[Thyroid hormone receptor]]s
* [[Thyrotropin receptor]]s

== References ==
{{reflist}}

{{Neuropeptide receptors}}
{{Transcription factors|g2}}

[[Category:Receptors]]
[[Category:Integral membrane proteins]]