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GNRHR

Official Full Name
gonadotropin releasing hormone receptor
Organism
Homo sapiens
GeneID
2798
Background
This gene encodes the receptor for type 1 gonadotropin-releasing hormone. This receptor 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. Following binding of gonadotropin-releasing hormone, the receptor associates with G-proteins that activate a phosphatidylinositol-calcium second messenger system. Activation of the receptor ultimately causes the release of gonadotropic luteinizing hormone (LH) and follicle stimulating hormone (FSH). Defects in this gene are a cause of hypogonadotropic hypogonadism (HH). Alternative splicing 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 this gene. [provided by RefSeq, Jul 2008]
Synonyms
HH7; GRHR; LRHR; LHRHR; GNRHR1;
Bio Chemical Class
GPCR rhodopsin
Protein Sequence
MANSASPEQNQNHCSAINNSIPLMQGNLPTLTLSGKIRVTVTFFLFLLSATFNASFLLKLQKWTQKKEKGKKLSRMKLLLKHLTLANLLETLIVMPLDGMWNITVQWYAGELLCKVLSYLKLFSMYAPAFMMVVISLDRSLAITRPLALKSNSKVGQSMVGLAWILSSVFAGPQLYIFRMIHLADSSGQTKVFSQCVTHCSFSQWWHQAFYNFFTFSCLFIIPLFIMLICNAKIIFTLTRVLHQDPHELQLNQSKNNIPRARLKTLKMTVAFATSFTVCWTPYYVLGIWYWFDPEMLNRLSDPVNHFFFLFAFLNPCFDPLIYGYFSL
Open
Disease
Coronavirus infection, Endometriosis, Esophageal cancer, Female infertility, Mature B-cell lymphoma, Ovarian developmental anomaly, Ovarian dysfunction, Pituitary gland disorder, Prostate cancer, Prostate disease, Prostate hyperplasia, Solid tumour/cancer, Uterine fibroid
Approved Drug
10 +
Clinical Trial Drug
10 +
Discontinued Drug
9 +

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Detailed Information

Gonadotropin-releasing hormone (GnRH), a decapeptide hormone secreted by the hypothalamus, exists in two subtypes in humans. The commonly referenced GnRH, specifically GnRH I, is located on the short arm of chromosome 8 (8p11.2 ~ 8p21) with the protein sequence pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2, mainly distributed in the brain. The GnRH II gene is located on the short arm of chromosome 20 (20p13), with the protein sequence pGlu-His-Trp-Ser-His-Gly-Trp-Tyr-Pro-Gly-NH2, prevalent outside the brain, such as in the uterus and ovaries.

The gonadotropin-releasing hormone receptor (GnRHR) is a seven-transmembrane G protein-coupled receptor, consisting of a single polypeptide chain featuring an extracellular N-terminus, seven transmembrane domains, and three extracellular and three intracellular loops. Two receptor types are known. In humans, the GnRHR I gene is located on the long arm of chromosome 4 (4q13) and is the predominant type expressed in the body, mainly in the pituitary and placenta, with less presence in the ovaries, uterus, breast, and prostate. Conversely, the GnRHR II gene is found on the long arm of chromosome 1 (1q12), but due to a premature termination codon, no functional protein exists in humans.

Gonadotropin-releasing hormone analogs (GnRHa) can competitively bind to GnRHR in pituitary cells, thereby inhibiting gonadal function and exerting significant therapeutic effects. GnRHa can be divided into two categories: GnRH agonists (GnRH-a) and GnRH antagonists (GnRH-ant), both of which bind specifically to GnRHR and effectively block its action, showing similar ovarian function suppression. Common GnRH-a medications include goserelin, triptorelin, and leuprorelin, while GnRH-ant drugs comprise degarelix, cetrorelix, and abarelix.

GnRHR expression is also observed in various tumors. Basic studies indicate that GnRHR on breast cancer cell surfaces, when combined with GnRHa, can activate downstream molecular signaling pathways, inhibit cell proliferation and invasion, and promote apoptosis, thus exhibiting antitumor effects. Several novel targeted drugs with GnRHR as a target are under clinical and preclinical investigation. The expression and role of GnRHR in breast cancer, alongside the antitumor molecular mechanisms mediated by it, will be introduced, as well as an overview of various GnRH conjugate drugs targeting tumor surface GnRHR.

Figure 1 depicts the signal transduction of GnRH receptors in endometrial cancer.Figure 1. GnRH receptor signal transduction in endometrial cancer (EC). (Emons G, et al., 2021)

Physiological Role of GnRHR

Under physiological conditions, GnRHR is expressed in adenohypophysis cells and regulated by pulsatile GnRH secretion from the hypothalamus. Pituitary GnRHR couples with Gαq/11 protein when it interacts with GnRH, therefore activating phospholipase Cβ (PLCβ) and raising intracellular inositol triphosphate (IP3) and diacylglycerol (DAG) levels, which then causes Ca2+ release and protein kinase C (PKC) pathway activation, so activating follicle-stimulating hormone (FSH) and luteinizing hormone (LH) subunit gene transcription and more so the hypothalamic-pituitary-ovarian axis (HPOA). In women, this drives pituitary FSH and LH production, hence affecting ovarian function and the menstrual cycle. In men, pituitary GnRHR activation by GnRH secretes LH and FSH, therefore boosting sperm generation and testosterone release. GnRHR expression in the placenta and granulosa cells suggests that GnRH autocrine/paracrine activation of GnRHR may trigger downstream signaling pathways.

Expression of GnRHR in Breast Cancer

In 1994, Kakar et al. discovered GnRHR expression in tumor cells, with a gene sequence identical to that in the pituitary, but with distinct functionality. Using immunohistochemistry, Moriya et al. verified GnRHR in breast cancer cells, observing a positive relationship with ER and PR expression in cancer cells and a greater expression than in neighboring non-cancerous tissues. With rates as high as 54.8% in ER-positive and 50.8% in PR-positive breast cancers, about 50% to 71% of breast tumors express GnRHR. Various research on triple-negative breast cancer (TNBC) show GnRHR positive frequencies between 49% and 73.8%.

Role of GnRHR in Breast Cancer

Kottler et al. detected both GnRHR and GnRH expressions in breast cancer cells, suggesting that tumor cells may be activated through autocrine/paracrine mechanisms. In tumor cells, GnRHR primarily couples with Gi proteins, generating diverse signaling complexes in different cell lines. When GnRHR binds with GnRHa, it can activate downstream molecular signaling pathways via classical mitogen-activated protein kinase (MAPK) pathways, including the phosphorylation of extracellular signal-regulated kinase (ERK) 1/2, p38MAPK, and c-Jun N-terminal kinase (JNK) pathways.

GnRHR interactions with GnRHa also exhibit anti-proliferative effects. Aguilar-Rojas et al. found that in breast cancer cell line MDA-MB-231, GnRHR binding with GnRH-a buserelin reduced cell proliferation by 25%. GnRH-ant cetrorelix can also inhibit the proliferation of TNBC cell line HCC1806 both in vitro and in vivo in mice.

These interactions further inhibit cancer cell invasion. In MDA-MB-231 cells, buserelin reduces the expression of Rho GTPase-activating protein 18 (ARHGAP18), increasing adhesion and reducing tumor metastasis. Aguilar-Rojas observed that GnRHR and buserelin binding activated RhoA GTPase, promoting F-actin polymerization and adhesion, thereby hindering invasion.

Furthermore, research indicates that GnRHR binding with GnRHa downregulates S100 calcium-binding protein A4 (S100A4) and cysteine-rich angiogenic inducer 61 (CYR61) expression, reducing tumor cell invasion, pointing to GnRHR's anti-tumor role potentially linked to reduced cell stemness. Blocking GnRHR can also facilitate tumor cell apoptosis. Binding GnRHR with triptorelin increases levels of cleaved poly ADP-ribose polymerase (PARP) and caspase-9, indicating induced apoptosis in ovarian, breast, and endometrial cancer cells. Treatment with GnRH-ant [(Ac-D2Nal1, D-4Cpa2, D-3Pal3 and 6, Leu8, D-Ala10)GnRH II] on breast cancer cell lines MDA-MB-231 and MCF-7 boosted caspase 3 and p38 activity, decreased mitochondrial membrane potential, and increased apoptosis rates.

In summary, GnRHR in malignancies such as breast cancer can be bound by GnRHa, inhibiting tumor proliferation and invasion and promoting apoptosis, making it a target for precise anti-tumor drugs.

References:

  1. Duan C, Allard J. Gonadotropin-releasing hormone neuron development in vertebrates. Gen Comp Endocrinol. 2020;292:113465.
  2. Tsai PS. Gonadotropin-releasing hormone by any other name would smell as sweet. Gen Comp Endocrinol. 2018;264:58-63.
  3. Emons G, Gründker C. The Role of Gonadotropin-Releasing Hormone (GnRH) in Endometrial Cancer. Cells. 2021;10(2):292.
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