Gonadotropin-releasing hormone receptor

Gonadotropin-releasing hormone receptor
Identifiers
Symbol	GNRHR
Alt. symbols	GnRH-R; LRHR;
Entrez	2798
HUGO	4421
OMIM	138850
RefSeq	NM_000406
UniProt	P30968
Other data
Locus	Chr. 4 q21.2

Gonadotropin-releasing hormone (type 2) receptor 2
Identifiers
Symbol	GNRHR2
Entrez	114814
HUGO	16341
RefSeq	NR_002328
UniProt	Q96P88
Other data
Locus	Chr. 1 q12

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 expressed on the surface of pituitary gonadotrope cells as well as lymphocytes, 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 LHRH after its release from the hypothalamus.^[1] Upon activation, the LHRHr stimulates tyrosine phosphatase and elicits the release of LH from the pituitary.

Evidence exists showing the presence of LHRH and its receptor in extrapituitary tissues as well as a role in progression of some cancers.^[2]

Function

Following binding of Gonadotropin releasing hormone (GNRH), GNRHR associates with G-proteins that activate a phosphatidylinositol (PtdIns)-calcium second messenger system. Activation of 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).^[3][4]

Alternative splicing of the GNRHR gene, GNRHR, results in multiple transcript variants encoding different isoforms. More than 18 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 agonists. Agonists stimulate the receptor, however prolonged exposure leads to a downregulation effect resulting in hypogonadism, an effect that is often medically utilized. GNRH antagonists block the receptor and inhibit gonadotropin release. GNRHRs are further regulated by the presence of sex hormones as well as activin and inhibin.

Clinical implications

Defects in the GNRHR are a cause of hypogonadotropic hypogonadism (HH).^[5]

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 or much later or in many cases 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 the gonadotropin-releasing hormone (GnRH). GnRH is produced in the hypothalamus but gets secreted and acts upon receptors (GnRH-R) on the anterior pituitary to exert its effects on reproductive maturation.

Understanding how GnRH-R functions has been key to developing clinical strategies to treat reproductive-related disorders.^[6][7][8]

References

1. Millar RP (2005). "GnRHs and GnRH receptors". Anim. Reprod. Sci. 88 (1–2): 5–28. doi:10.1016/j.anireprosci.2005.05.032. PMID 16140177.
2. Harrison GS, Wierman ME, Nett TM, Glode LM (2004). "Gonadotropin-releasing hormone and its receptor in normal and malignant cells". Endocr. Relat. Cancer 11 (4): 725–48. doi:10.1677/erc.1.00777. PMID 15613448.
3. Neill JD, Musgrove LC, Duck LW (2004). "Newly recognized GnRH receptors: function and relative role". Trends Endocrinol. Metab. 15 (8): 383–92. doi:10.1016/j.tem.2004.08.005. PMID 15380810.
4. Cheng CK, Leung PC (2005). "Molecular biology of gonadotropin-releasing hormone (GnRH)-I, GnRH-II, and their receptors in humans". Endocr. Rev. 26 (2): 283–306. doi:10.1210/er.2003-0039. PMID 15561800.
5. Layman LC (2007). "Hypogonadotropic hypogonadism". Endocrinol. Metab. Clin. North Am. 36 (2): 283–96. doi:10.1016/j.ecl.2007.03.010. PMID 17543719.
6. Re M, Pampillo M, Savard M, Dubuc C, McArdle CA, Millar RP, Conn PM, Gobeil F, Bhattacharya M, Babwah AV (2010). Koch, Karl-Wilhelm, ed. "The human gonadotropin releasing hormone type I receptor is a functional intracellular GPCR expressed on the nuclear membrane". PLoS ONE 5 (7): e11489. doi:10.1371/journal.pone.0011489. PMC 2900216. PMID 20628612.
7. Balasubramanian R, Dwyer A, Seminara SB, Pitteloud N, Kaiser UB, Crowley WF (2010). "Human GnRH deficiency: a unique disease model to unravel the ontogeny of GnRH neurons". Neuroendocrinology 92 (2): 81–99. doi:10.1159/000314193. PMC 3214927. PMID 20606386.
8. Viswanathan V, Eugster EA (December 2009). "Etiology and treatment of hypogonadism in adolescents". Endocrinol. Metab. Clin. North Am. 38 (4): 719–38. doi:10.1016/j.ecl.2009.08.004. PMID 19944289.

External links

• "Gonadotrophin-Releasing Hormone Receptors". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.
• GNRHR protein, human at the US National Library of Medicine Medical Subject Headings (MeSH)