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Revision as of 10:11, 13 January 2021

This Sandbox is Reserved from 26/11/2020, through 26/11/2021 for use in the course "Structural Biology" taught by Bruno Kieffer at the University of Strasbourg, ESBS. This reservation includes Sandbox Reserved 1643 through Sandbox Reserved 1664.

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Gonadotropin releasing hormone 1 receptor (GnRHR)

spinqualitylabelsall models PDB ID 7BR3 Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image It is a member of the seven-transmembrane, G-protein coupled receptor (GPCR) family and is activated by the peptide hormone gonadotropin-releasing hormone (GnRH) or the synthetic agonist. The GnRHR is expressed on the surface of pituitary gonadotrope cells as well as lymphocytes, breast, ovary, and prostate [1]. Its activity is critical for successful reproductive function. Several diseases are associated with a dysfunction of this receptor or the corresponding signaling cascade. Contents 1 Biological Function 2 Disease 3 Relevance 4 Structural highlights Biological Function The gonadotropin releasing hormone 1 receptor is located in the plasmic membrane of pituitary gonadotrope cells in the anterior pituitary, a major organ of the endocrine system in the brain. It is activated by the gonadotropin releasing hormone (GnRH) which acts upon GnRHRs as the key regulator of puberty and reproduction. This peptide hormone is produced in the hypothalamus but gets secreted and acts upon GnRHRs in the anterior pituitary to exert its effects on reproductive maturation. The activation of the receptor, associates with G-proteins, leads to the releasing of gonadotropic luteinizing hormone (LH) and follicle stimulating hormone (FSH) by activating several signaling cascades. These pathways mainly corresponds to the inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG), MAPK, and adenyl cyclase pathways. [2]. Disease A mutation or a dysfonctionnement of the receptor could cause diseases impacting the reproduction function. More generally, the dysfonctionnement of the pathways involving GnRH and its receptor leads to endocrine pathologies called hypogonadism. [3] It exits many types of hypogonadism but the one involving the mutation of the receptor is the idiopatic hypogonadotropic hypogonadism (IHH). In this case, the mutation leads to failure of detectable ligand binding causing the decreased efficiency of the inisitol pathway and consequently leading to the decrease of the LH, FSH, and sex steroid secretions [4]. Moreover, the activity the pathways related to the receptor and its localisation can cause cancer. [5] Relevance The main uses of the couple GnRH - GnRHR in the medicine field are to cure hormone-dependent diseases and assisted reproductive techniques. For instance, an agonist of GnRH is used for fertility preservation as an alternative of cryopreservation [6]. In addition it is a promising therapeutic target for the treatment of conditions including uterine fibroids [7], endometriosis [8], and prostate cancer [9]. Besides, concerning animals, the GnRH receptor could be a good target for contraception with a DNA vaccine [10] Structural highlights [11] (PGS) domain

References

1. ↑ Cheung LW, Wong AS. Gonadotropin-releasing hormone: GnRH receptor signaling in extrapituitary tissues. FEBS J. 2008 Nov;275(22):5479-95. doi: 10.1111/j.1742-4658.2008.06677.x. PMID:18959738 doi:http://dx.doi.org/10.1111/j.1742-4658.2008.06677.x
2. ↑ Aguilar-Rojas A, Huerta-Reyes M. Human gonadotropin-releasing hormone receptor-activated cellular functions and signaling pathways in extra-pituitary tissues and cancer cells (Review). Oncol Rep. 2009 Nov;22(5):981-90. doi: 10.3892/or_00000525. PMID:19787210 doi:http://dx.doi.org/10.3892/or_00000525
3. ↑ Richard-Eaglin A. Male and Female Hypogonadism. Nurs Clin North Am. 2018 Sep;53(3):395-405. doi: 10.1016/j.cnur.2018.04.006. PMID:30100005 doi:http://dx.doi.org/10.1016/j.cnur.2018.04.006
4. ↑ Meysing AU, Kanasaki H, Bedecarrats GY, Acierno JS Jr, Conn PM, Martin KA, Seminara SB, Hall JE, Crowley WF Jr, Kaiser UB. GNRHR mutations in a woman with idiopathic hypogonadotropic hypogonadism highlight the differential sensitivity of luteinizing hormone and follicle-stimulating hormone to gonadotropin-releasing hormone. J Clin Endocrinol Metab. 2004 Jul;89(7):3189-98. doi: 10.1210/jc.2003-031808. PMID:15240592 doi:http://dx.doi.org/10.1210/jc.2003-031808
5. ↑ Harrison GS, Wierman ME, Nett TM, Glode LM. Gonadotropin-releasing hormone and its receptor in normal and malignant cells. Endocr Relat Cancer. 2004 Dec;11(4):725-48. doi: 10.1677/erc.1.00777. PMID:15613448 doi:http://dx.doi.org/10.1677/erc.1.00777
6. ↑ Torrealday S, Lalioti MD, Guzeloglu-Kayisli O, Seli E. Characterization of the gonadotropin releasing hormone receptor (GnRHR) expression and activity in the female mouse ovary. Endocrinology. 2013 Oct;154(10):3877-87. doi: 10.1210/en.2013-1341. Epub 2013 Aug, 2. PMID:23913446 doi:http://dx.doi.org/10.1210/en.2013-1341
7. ↑ Ali M, Chaudhry ZT, Al-Hendy A. Successes and failures of uterine leiomyoma drug discovery. Expert Opin Drug Discov. 2018 Feb;13(2):169-177. doi:, 10.1080/17460441.2018.1417381. Epub 2017 Dec 18. PMID:29254389 doi:http://dx.doi.org/10.1080/17460441.2018.1417381
8. ↑ Perricos A, Wenzl R. Efficacy of elagolix in the treatment of endometriosis. Expert Opin Pharmacother. 2017 Sep;18(13):1391-1397. doi:, 10.1080/14656566.2017.1359258. Epub 2017 Jul 28. PMID:28737050 doi:http://dx.doi.org/10.1080/14656566.2017.1359258
9. ↑ Schally AV, Block NL, Rick FG. Discovery of LHRH and development of LHRH analogs for prostate cancer treatment. Prostate. 2017 Jun;77(9):1036-1054. doi: 10.1002/pros.23360. Epub 2017 Apr 27. PMID:28449236 doi:http://dx.doi.org/10.1002/pros.23360
10. ↑ Samoylov A, Napier I, Morrison N, Cochran A, Schemera B, Wright J, Cattley R, Samoylova T. DNA Vaccine Targeting Gonadotropin-Releasing Hormone Receptor and Its Application in Animal Contraception. Mol Biotechnol. 2019 Feb;61(2):73-83. doi: 10.1007/s12033-018-0137-9. PMID:30448908 doi:http://dx.doi.org/10.1007/s12033-018-0137-9
11. ↑ Millar RP, Lu ZL, Pawson AJ, Flanagan CA, Morgan K, Maudsley SR. Gonadotropin-releasing hormone receptors. Endocr Rev. 2004 Apr;25(2):235-75. doi: 10.1210/er.2003-0002. PMID:15082521 doi:http://dx.doi.org/10.1210/er.2003-0002