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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 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 protein family, group of evoluti ...
(GPCR) family. It is the receptor of
gonadotropin-releasing hormone Gonadotropin-releasing hormone (GnRH) is a releasing hormone responsible for the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary. GnRH is a tropic peptide hormone synthesized and rele ...
(GnRH). Agonist binding to the GnRH receptor activates the Gq/11 family of heterotrimeric G proteins. The GnRHR is expressed on the surface of
pituitary The pituitary gland or hypophysis is an endocrine gland in vertebrates. In humans, the pituitary gland is located at the base of the brain, protruding off the bottom of the hypothalamus. The pituitary gland and the hypothalamus control much of th ...
gonadotrope cells as well as
lymphocyte A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include T cells (for cell-mediated and cytotoxic adaptive immunity), B cells (for humoral, antibody-driven adaptive immunity), an ...
s,
breast The breasts are two prominences located on the upper ventral region of the torso among humans and other primates. Both sexes develop breasts from the same embryology, embryological tissues. The relative size and development of the breasts is ...
,
ovary The ovary () is a gonad in the female reproductive system that produces ova; when released, an ovum travels through the fallopian tube/ oviduct into the uterus. There is an ovary on the left and the right side of the body. The ovaries are end ...
, and
prostate The prostate is an male accessory gland, accessory gland of the male reproductive system and a muscle-driven mechanical switch between urination and ejaculation. It is found in all male mammals. It differs between species anatomically, chemica ...
. This receptor is a 60
kDa The dalton or unified atomic mass unit (symbols: Da or u, respectively) is a unit of mass defined as of the mass of an unbound neutral atom of carbon-12 in its nuclear and electronic ground state and at rest. It is a non-SI unit accepted f ...
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 ...
and resides primarily in the
pituitary The pituitary gland or hypophysis is an endocrine gland in vertebrates. In humans, the pituitary gland is located at the base of the brain, protruding off the bottom of the hypothalamus. The pituitary gland and the hypothalamus control much of th ...
and is responsible for eliciting the actions of GnRH after its release from the
hypothalamus The hypothalamus (: hypothalami; ) is a small part of the vertebrate brain that contains a number of nucleus (neuroanatomy), nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrin ...
. 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 Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...
s.


Function

Following binding of GnRH, the GnRHR associates with G-proteins that activate a
phosphatidylinositol Phosphatidylinositol or inositol phospholipid is a biomolecule. It was initially called "inosite" when it was discovered by Léon Maquenne and Johann Joseph von Scherer in the late 19th century. It was discovered in bacteria but later also found ...
(PtdIns)-
calcium Calcium is a chemical element; it has symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar to it ...
second messenger Second messengers are intracellular signaling molecules released by the cell in response to exposure to extracellular signaling molecules—the first messengers. (Intercellular signals, a non-local form of cell signaling, encompassing both first m ...
system. Activation of the GnRHR ultimately causes the release of
follicle stimulating hormone Follicle-stimulating hormone (FSH) is a gonadotropin, a glycoprotein polypeptide hormone. FSH is synthesized and secreted by the gonadotropic cells of the anterior pituitary gland and regulates the development, growth, pubertal maturation, ...
(FSH) and
luteinizing hormone Luteinizing hormone (LH, also known as luteinising hormone, lutropin and sometimes lutrophin) is a hormone produced by gonadotropic cells in the anterior pituitary gland. The production of LH is regulated by gonadotropin-releasing hormone (G ...
(LH).


Genes

There are two major forms of the GNRHR, each encoded by a separate gene (''
GNRHR Gonadotropin-releasing hormone receptor is a protein that in humans is encoded by the ''GNRHR'' gene. This gene encodes the receptor for type 1 gonadotropin-releasing hormone. This receptor is a member of the seven-transmembrane, G-protein coupl ...
'' and '' GNRHR2''). Alternative splicing of the GNRHR gene, ''GNRHR'', results in multiple
transcript Transcript may refer to: * Transcript (biology), a molecule of RNA transcribed from DNA * Transcript (education), a copy of a student's permanent academic record * Transcript (law), a written record of spoken language in court proceedings * Transc ...
variants encoding different
isoform A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene and are the result of genetic differences. While many perform the same or similar biological roles, some isoforms have uniqu ...
s. More than 18
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, often th ...
initiation sites in the 5' region and multiple
polyA Polyadenylation is the addition of a poly(A) tail to an RNA transcript, typically a messenger RNA (mRNA). The poly(A) tail consists of multiple adenosine monophosphates; in other words, it is a stretch of RNA that has only adenine bases. In euka ...
signals in the 3' region have been identified for ''GNRHR''.


Regulation

The GnRHR responds to GnRH as well as to synthetic
GnRH agonist A gonadotropin-releasing hormone agonist (GnRH agonist) is a type of medication which affects gonadotropins and sex hormones. They are used for a variety of indications including in fertility medicine and to lower sex hormone levels in the treat ...
s. Agonists stimulate the receptor, however prolonged exposure leads to a
downregulation In biochemistry, in the biology, biological context of organisms' regulation of gene expression and production of gene products, downregulation is the process by which a cell (biology), cell decreases the production and quantities of its cellular ...
effect resulting in hypogonadism, an effect that is often medically utilized.
GnRH antagonist Gonadotropin-releasing hormone antagonists (GnRH antagonists) are a class of medications that receptor antagonist, antagonize the gonadotropin-releasing hormone receptor (GnRH receptor) and thus the action of gonadotropin-releasing hormone (GnRH ...
s block the receptor and inhibit gonadotropin release. GnRHRs are further regulated by the presence of
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 a ...
s as well as
activin and inhibin Activin and inhibin are two closely related protein complexes that have almost directly opposite biological effects. Identified in 1986, activin enhances FSH biosynthesis and secretion, and participates in the regulation of the menstrual c ...
.


Ligands


Agonists


Peptides

*
Azagly-nafarelin Azagly-nafarelin, sold under the brand name Gonazon, is a gonadotropin-releasing hormone agonist (GnRH agonist) medication which is used in veterinary medicine in Europe. It is a GnRH analogue and a synthetic peptide, specifically a decapeptide. ...
*
Buserelin Buserelin, sold under the brand name Suprefact among others, is a medication which is used primarily in the treatment of prostate cancer and endometriosis. It is also used for other indications such as the treatment of premenopausal breast canc ...
*
Deslorelin Deslorelin, sold under the brand name Suprelorin among others, is an injectable gonadotropin releasing hormone superagonist (GnRH agonist) which is used in veterinary medicine for various indications. Uses Veterinary Deslorelin is used in ve ...
* Fertirelin *
GnRH Gonadotropin-releasing hormone (GnRH) is a releasing hormone responsible for the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary. GnRH is a tropic peptide hormone synthesized and released ...
*
Gonadorelin Gonadorelin is a gonadotropin-releasing hormone agonist (GnRH agonist) which is used in fertility medicine and to treat amenorrhea and hypogonadism. It is also used in veterinary medicine. The medication is a form of the endogenous GnRH and is ...
*
Goserelin Goserelin, sold under the brand name Zoladex among others, is a medication which is used to suppress production of the sex hormones (testosterone and estrogen), particularly in the treatment of breast cancer and prostate cancer. It is an injectab ...
*
Histrelin Histrelin acetate, sold under the brand name Supprelin among others, is a nonapeptide analogue of gonadotropin-releasing hormone (GnRH) with added potency. When present in the bloodstream, it acts on particular cells of the pituitary gland cal ...
* Lecirelin *
Leuprorelin Leuprorelin, also known as leuprolide, is a manufactured version of a hormone used to treat prostate cancer, breast cancer, endometriosis, uterine fibroids, for early puberty, as part of transgender hormone therapy, or to perform chemical ca ...
*
Nafarelin Nafarelin, sold under the brand name Synarel among others, is a gonadotropin-releasing hormone agonist (GnRH agonist) medication which is used in the treatment of endometriosis and early puberty. It is also used to treat uterine fibroids, to c ...
* Peforelin *
Triptorelin Triptorelin, sold under the brand name Decapeptyl among others, is a medication that acts as an agonist analog of gonadotropin-releasing hormone, repressing expression of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). It is a ...


Antagonists


Peptides

* Abarelix *
Cetrorelix Cetrorelix (, ), or cetrorelix acetate (, ), sold under the brand name Cetrotide, is an injectable gonadotropin-releasing hormone (GnRH) gonadotropin-releasing hormone antagonist, antagonist. A synthetic compound, synthetic decapeptide, it is us ...
*
Degarelix Degarelix, sold under the brand name Firmagon among others, is a hormonal therapy used in the treatment of prostate cancer. Testosterone is a male hormone that promotes growth of many prostate tumours and therefore reducing circulating testost ...
* Ganirelix * Ozarelix


Non-peptides

*
Elagolix Elagolix, sold under the brand name Orilissa, is a gonadotropin-releasing hormone antagonist (GnRH antagonist) medication which is used in the treatment of pain associated with endometriosis in women. It is also under development for the treatme ...
* Linzagolix * Opigolix *
Relugolix Relugolix, sold under the brand names Orgovyx and Relumina among others, is a gonadotropin-releasing hormone antagonist (GnRH receptor antagonist) medication which is used in the treatment of prostate cancer, uterine fibroids and endometriosis. ...
* 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.


Clinical implications

Defects in the GnRHR are a cause of
hypogonadotropic hypogonadism Hypogonadotropic hypogonadism (HH), is due to problems with either the hypothalamus or pituitary gland affecting the hypothalamic-pituitary-gonadal axis (HPG axis). Hypothalamic disorders result from a deficiency in the release of gonadotropic ...
(HH). Normal
puberty Puberty is the process of physical changes through which a child's body matures into an adult body capable of sexual reproduction. It is initiated by hormonal signals from the brain to the gonads: the ovaries in a female, the testicles i ...
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 In medicine, precocious puberty is puberty occurring at an unusually early age. In most cases, the process is normal in every aspect except the unusually early age and simply represents a variation of normal development. There is early developm ...
) or much later (
delayed puberty Delayed puberty is when a person lacks or has incomplete development of specific sexual characteristics past the usual age of onset of puberty. The person may have no physical or hormone, hormonal signs that puberty has begun. In the United States ...
). In some cases puberty never occurs and thereby contributes to the estimated 35-70 million infertile couples worldwide. 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 The anterior pituitary (also called the adenohypophysis or pars anterior) is a major Organ (anatomy), organ of the endocrine system. The anterior pituitary is the glandular, Anatomical terms of location#Usage in human anatomy, anterior lobe that t ...
to exert its effects on reproductive maturation. Understanding how GnRHR functions has been key to developing clinical strategies to treat reproductive-related disorders.


See also

*
GnRH modulator A GnRH modulator, or GnRH receptor modulator, also known as an LHRH modulator or LHRH receptor modulator, is a type of medication which modulates the GnRH receptor, the biological target of the hypothalamic hormone gonadotropin-releasing horm ...


References


External links

* * {{DEFAULTSORT:Gonadotropin-Releasing Hormone Receptor G protein-coupled receptors Gonadotropin-releasing hormone and gonadotropins