View source for Gonadotropin-releasing hormone receptor

{{Short description|G-protein coupled receptor}}
{{Infobox protein
 |Name= [[GNRHR|Gonadotropin-releasing hormone receptor]]
 |Symbol=[[GNRHR]]
 |AltSymbols=GnRH-R; LRHR;
 |HGNCid=4421
 |Chromosome=4
 |Arm=q
 |Band=21.2
 |LocusSupplementaryData=
 |ECnumber=
 |OMIM=138850
 |EntrezGene=2798
 |RefSeq=NM_000406
 |UniProt=P30968
}}
{{Infobox protein
| Name = [[GNRHR2|Gonadotropin-releasing hormone (type 2) receptor 2]]
| caption =
| image =
| width =
| HGNCid = 16341
| Symbol = [[GNRHR2]]
| AltSymbols =
| EntrezGene = 114814
| OMIM =
| RefSeq = NR_002328
| UniProt = Q96P88
| PDB =
| ECnumber =
| Chromosome = 1
| Arm = q
| Band = 12
| LocusSupplementaryData =
}}

The '''gonadotropin-releasing hormone receptor''' ('''GnRHR'''), also known as the [[luteinizing hormone releasing hormone]] receptor ('''LHRHR'''), is a member of the seven-transmembrane, [[G-protein coupled receptor]] (GPCR) family. It is the receptor of [[gonadotropin-releasing hormone]] (GnRH). Agonist binding to the GnRH receptor activates the Gq/11 family of heterotrimeric G proteins.<ref name="Flanagan2017">{{cite journal
 | last1 = Flanagan
 | first1 = Colleen A.
 | last2 = Manilall
 | first2 = Ashmeetha
 | title = Gonadotropin-releasing hormone (GnRH) receptor structure and GnRH binding
 | journal = Frontiers in Endocrinology
 | volume = 8
 | pages = 274
 | doi = 10.3389/fendo.2017.00274
 | pmid = 29123501
 | year = 2017
| doi-access = free
 | pmc = 5662886
 }}</ref> The GnRHR is expressed on the surface of [[pituitary]] gonadotrope cells as well as [[lymphocyte]]s, [[breast]], [[ovary]], and [[prostate]].

This receptor is a 60 [[kDa]] [[G protein-coupled receptor]] and resides primarily in the [[pituitary]] and is responsible for eliciting the actions of GnRH after its release from the [[hypothalamus]].<ref name="pmid16140177">{{cite journal | author = Millar RP | title = GnRHs and GnRH receptors | journal = [[Anim. Reprod. Sci.]] | volume = 88 | issue = 1–2 | pages = 5–28 | year = 2005 | pmid = 16140177 | doi = 10.1016/j.anireprosci.2005.05.032 }}</ref> Upon activation, the LHRHr stimulates [[tyrosine phosphatase]] and elicits the release of LH from the pituitary.

Evidence exists showing the presence of GnRH and its receptor in extrapituitary tissues as well as a role in progression of some [[cancer]]s.<ref name="pmid15613448">{{cite journal |vauthors=Harrison GS, Wierman ME, Nett TM, Glode LM | title = Gonadotropin-releasing hormone and its receptor in normal and malignant cells | journal = Endocr. Relat. Cancer | volume = 11 | issue = 4 | pages = 725–48 | year = 2004 | pmid = 15613448 | doi = 10.1677/erc.1.00777 | doi-access = free }}</ref>

{{TOC limit|3}}

==Function==
Following binding of GnRH, the GnRHR associates with G-proteins that activate a [[phosphatidylinositol]] (PtdIns)-[[calcium]] [[second messenger]] system. Activation of the GnRHR ultimately causes the release of [[follicle stimulating hormone]] (FSH) and [[luteinizing hormone]] (LH).

==Genes==
There are two major forms of the GNRHR, each encoded by a separate gene (''[[GNRHR]]'' and ''[[GNRHR2]]'').<ref name="pmid15380810">{{cite journal |vauthors=Neill JD, Musgrove LC, Duck LW | title = Newly recognized GnRH receptors: function and relative role | journal = Trends Endocrinol. Metab. | volume = 15 | issue = 8 | pages = 383–92 | year = 2004 | pmid = 15380810 | doi = 10.1016/j.tem.2004.08.005 | s2cid = 26829807 }}</ref><ref name="pmid15561800">{{cite journal |vauthors=Cheng CK, Leung PC | title = Molecular biology of gonadotropin-releasing hormone (GnRH)-I, GnRH-II, and their receptors in humans | journal = Endocr. Rev. | volume = 26 | issue = 2 | pages = 283–306 | year = 2005 | pmid = 15561800 | doi = 10.1210/er.2003-0039 | doi-access = free }}</ref>

Alternative splicing of the GNRHR gene, ''GNRHR'', results in multiple [[Transcription (genetics)|transcript]] variants encoding different [[isoform]]s. More than 18 [[Transcription (genetics)|transcription]] initiation sites in the 5' region and multiple [[polyA]] signals in the 3' region have been identified for ''GNRHR''.

==Regulation==
The GnRHR responds to GnRH as well as to synthetic [[GnRH agonist]]s. Agonists stimulate the receptor, however prolonged exposure leads to a [[downregulation]] effect resulting in hypogonadism, an effect that is often medically utilized. [[GnRH antagonist]]s block the receptor and inhibit gonadotropin release. GnRHRs are further regulated by the presence of [[sex hormone]]s as well as [[activin and inhibin]].

==Ligands==

===Agonists===

====Peptides====
* [[Azagly-nafarelin]]
* [[Buserelin]]
* [[Deslorelin]]
* [[Fertirelin]]
* [[Gonadotropin-releasing hormone|GnRH]]
* [[Gonadorelin]]
* [[Goserelin]]
* [[Histrelin]]
* [[Lecirelin]]
* [[Leuprorelin]]
* [[Nafarelin]]
* [[Peforelin]]
* [[Triptorelin]]

===Antagonists===

====Peptides====
* [[Abarelix]]
* [[Cetrorelix]]
* [[Degarelix]]
* [[Ganirelix]]
* [[Ozarelix]]

====Non-peptides====
* [[Elagolix]]
* [[Linzagolix]]
* [[Opigolix]]
* [[Relugolix]]
* [[Sufugolix]]

===Pharmacoperones===
Current research is looking into pharmacoperones, or chemical chaparones that promote the shuttling of mature Gonadotropin-releasing hormone receptor (GNRHR) protein to the cell surface, leading to a functional protein. Gonadotropin-releasing hormone receptor function has been shown to be deleteriously effected by point mutations in its gene. Some of these mutations, when expressed, cause the receptor to remain in the cytosol. An approach to rescue receptor function utilizes pharmacoperones or molecular chaperones, which are typically small molecules that rescue misfolded proteins to the cell surface. These interact with the receptor to restore cognate receptor function devoid of antagonist or agonist activity. This approach, when effective, should increase therapeutic reach. Pharmacoperones have been identified that restore function of Gonadotropin-releasing hormone receptor.<ref name="pmid32601341">{{cite journal | vauthors = Smith E, Janovick JA, Bannister T, Shumate J, Ganapathy V, Scampavia L, Spicer TP | title = Rescue of mutant gonadotropin-releasing hormone receptor function independent of cognate receptor activity | journal = Scientific Reports | volume = 10 | issue = 1 | pages = 10579 | date = June 2020 | pmid = 32601341 | doi = 10.1038/s41598-020-67473-w | pmc = 7324376 | bibcode = 2020NatSR..1010579S }}</ref><ref name="pmid24831790">{{cite journal | vauthors = Conn PM, Smith E, Spicer TP, Chase P, Scampavia L, Janovick JA | title = A Phenotypic High Throughput Screening Assay for the Identification of Pharmacoperones for the Gonadotropin Releasing Hormone Receptor | journal = Assay and Drug Development Technologies | volume = 12 | issue = 4 | pages = 238–246 | date = May 2014 | pmid = 24831790 | doi = 10.1089/adt.2014.576 | pmc = 4025569 }}</ref>

==Clinical implications==

Defects in the GnRHR are a cause of [[hypogonadotropic hypogonadism]] (HH).<ref name="pmid17543719">{{cite journal | author = Layman LC | title = Hypogonadotropic hypogonadism | journal = Endocrinol. Metab. Clin. North Am. | volume = 36 | issue = 2 | pages = 283–96 | year = 2007 | pmid = 17543719 | doi = 10.1016/j.ecl.2007.03.010 }}</ref>

Normal [[puberty]] begins between ages 8 and 14 in girls and between 9 and 14 in boys. Puberty, however, for some children can come much sooner ([[precocious puberty]]) or much later ([[delayed puberty]]). In some cases puberty never occurs and thereby contributes to the estimated 35-70 million infertile couples worldwide.{{Cn|date=August 2023}} Among children, the abnormally early or late onset of puberty exerts intense emotional and social stress that too often goes untreated.

The timely onset of puberty is regulated by many factors and one factor that is often referred to as the master regulator of puberty and reproduction is GnRH. This peptide hormone is produced in the hypothalamus but gets secreted and acts upon GnRHRs in the [[anterior pituitary]] to exert its effects on [[sexual maturity|reproductive maturation]].

Understanding how GnRHR functions has been key to developing clinical strategies to treat reproductive-related disorders.<ref name="pmid20628612">{{cite journal | vauthors = Re M, Pampillo M, Savard M, Dubuc C, McArdle CA, Millar RP, Conn PM, Gobeil F, Bhattacharya M, Babwah AV | title = The human gonadotropin releasing hormone type I receptor is a functional intracellular GPCR expressed on the nuclear membrane | journal = PLOS ONE | volume = 5 | issue = 7 | pages = e11489 | year = 2010 | pmid = 20628612 | pmc = 2900216 | doi = 10.1371/journal.pone.0011489 | bibcode = 2010PLoSO...511489R | editor1-last = Koch | editor1-first = Karl-Wilhelm | doi-access = free }}</ref><ref name="pmid20606386">{{cite journal |vauthors=Balasubramanian R, Dwyer A, Seminara SB, Pitteloud N, Kaiser UB, Crowley WF | title = Human GnRH deficiency: a unique disease model to unravel the ontogeny of GnRH neurons | journal = Neuroendocrinology | volume = 92 | issue = 2 | pages = 81–99 | year = 2010 | pmid = 20606386 | doi = 10.1159/000314193 | pmc=3214927}}</ref><ref name="pmid19944289">{{cite journal |vauthors=Viswanathan V, Eugster EA | title = Etiology and treatment of hypogonadism in adolescents | journal = Endocrinol. Metab. Clin. North Am. | volume = 38 | issue = 4 | pages = 719–38 |date=December 2009 | pmid = 19944289 | doi = 10.1016/j.ecl.2009.08.004 | pmc = 4102132 }}</ref>

==See also==
* [[GnRH modulator]]

==References==
{{Reflist|2}}

==External links==
*{{cite web | url = http://www.iuphar-db.org/GPCR/ChapterMenuForward?chapterID=1357 | title = Gonadotrophin-Releasing Hormone Receptors | work = IUPHAR Database of Receptors and Ion Channels | publisher = International Union of Basic and Clinical Pharmacology | access-date = 2008-12-04 | archive-date = 2016-03-03 | archive-url = https://web.archive.org/web/20160303192543/http://www.iuphar-db.org/GPCR/ChapterMenuForward?chapterID=1357 | url-status = dead }}
* {{MeshName|GNRHR+protein,+human}}

{{G protein-coupled receptors}}
{{Neuropeptide receptors}}
{{GnRH and gonadotropins}}
{{GnRH and gonadotropin receptor modulators}}

{{DEFAULTSORT:Gonadotropin-Releasing Hormone Receptor}}
[[Category:G protein-coupled receptors]]
[[Category:Gonadotropin-releasing hormone and gonadotropins]]