It is a member of the seven-transmembrane, rhodopsin likeG-protein coupled receptor (GPCR) family[1] and is activated by the peptide hormone gonadotropin-releasing hormone (GnRH) or the rhodopsin likesynthetic agonist). The GnRHR is expressed on the surface of pituitary gonadotrope cells as well as lymphocytes, breast, ovary, and prostate [2]. Its activity is critical for successful reproductive function. Several diseases are associated with a dysfunction of this receptor or the corresponding signaling cascade.
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. [3].
Structure
General structure
GnRH1R has the overall architecture of seven canonical transmembrane (TM) helices with connecting extra- and intracellular loop domains (ECL/ICL) similar to rhodopsin like receptors. However, it lacks the typically occurring cytoplasmic C-terminal helix and has an unusual ligand binding mode. The structural variation between existing GnRHR Typ I, II and III in different species has been analyzed [4]. First crystallographic structure analysis of human GnGH1R serve the investigation of the molecular mechanism of the receptor[5]. In this analysis the GnRH1R contains certain modifications: ICL3 (aa 243-256) is replaced by the , it is in a complex with the antagonistic drug , and remains in inactive conformation in respect to G protein coupling.
In this conformation, the ECL2 of GnRH1R forms an and is anchored to the extracellular tip of TM3 through a conserved disulfide bond between residues C1143.25 and C196 in ECL2.
Following structural highlights are different to receptors of this family: The conserved D138-R183-Y3.51 motif is in fact the in GnRH1R. An intrahelical salt bridge is observed between D138 and R139, as well as a polar interaction between R139 and T265 6.33 (This restricts the outward movement of those TMs associated with GPCR activation). The (aa 18–33) before TM1 is well folded and appears inserted into the orthostatic binding cavity.
Ligand binding
The overall pocket in GnRH1R is defined by the N terminus, TM2, TM3, TM5, TM6, and TM7, forming a highly hydrophobic binding site with a few polar residues (D982.61, N1022.65, K1213.32, and N3057.35
The orthosteric binding pocket of GnRH1R is solvent-accessible, appears relatively shallow and a plasticity is indicated with respect to different ligands. Structural analysis provides the possibility to design orally deliverable small molecules with activity towards the receptor.
A detailed interaction network for elagolix has been described (Structure1) in which The N-terminus, residue Y2836.51 and a polar interaction network formed by residues D98 and K121 are of particular importance for ligand recognition.
N terminus: fits in cavity (contact to surrounding ressiudues: N1022.65, Q1744.60, and F1784.64 from TM2 and TM4) indicating a distinct roles in mediating binding of different ligands. However, it is not engaged in GnRH activation of wild-type GnRH1R.
Y283: engaged in the ligand recognition and activation of GnRH1R29 together with Y2846.52 and M1253.36 are suggested to form the bottom wall
Signal transduction
Conformational rearrangements of common microswitches38,39 are characteristically influenced by the unusual ligand recognition and the absence of the cytoplasmic C-terminal helix.
The transition of different GPCR conformation states is known to be mediated by water molecules by rearranging the conserved hydrophilic network formed by conserved amino acids in different helices43
Different motifs have already been identified to be critical for signal transmission in GnH1R. Noteworthy the hydrophobic Y6.51-Y6.52(TM6)-W6.48-F6.44 motif in TM6 and residues F2726.40 and Y3237.53.
Gonadotrophin releasing hormone
Hormone
GnRH is a decapeptid that was isolated and characterised by the groups of A V Schally and R C L Guillemin, the 1977 Nobel laureates.
GnRH is the pivotal hypothalamic hormone regulating reproduction. Over 20 forms of the decapeptide have been identified in which the NH2- and COOH-terminal sequences, which are essential for receptor binding and activation, are conserved.
In most vertebrates there are at least two, and usually three, forms of GnRH. In mammals, there are two forms, GnRH I which regulates gonadotropin and GnRH II which appears to be a neuromodulator and stimulates sexual behaviour.
Antagonist
Like GnRH, peptide antagonists of the GnRH receptor are decapeptides, but with 50–70% of amino acids substituted , and they exhibit classical competitive antagonism ;
Blockade of GnRH effects may be wanted for a variety of reasons—eg, to prevent untimely luteinisation during assisted reproduction or in the treatment of sex-hormone-dependent disorders
Unlike the agonists, GnRH antagonists do not induce an initial stimulation of gonadotropin release, but cause an immediate and rapid, reversible suppression of gonadotropin secretion. The principal mechanism of action of GnRH antagonists is competitive receptor occupancy of GnRH-r. [6]
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. [7] 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 [8].
Moreover, the activity the pathways related to the receptor and its localisation can cause cancer. [9]
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 [10]. In addition it is a promising therapeutic target for the treatment of conditions including uterine fibroids [11], endometriosis [12], and prostate cancer [13].
GnRH agonists and antagonists also have promise as novel contraceptives. Indeed, concerning animals, the GnRH receptor could be a good target for contraception with a DNA vaccine [14]
Besides, on pharmacological grounds the primary indications for GnRH antagonists will be in any situation in which chemical gonadotropic hypophysectomy is required.
References
- ↑ Stojilkovic SS, Reinhart J, Catt KJ. Gonadotropin-releasing hormone receptors: structure and signal transduction pathways. Endocr Rev. 1994 Aug;15(4):462-99. doi: 10.1210/edrv-15-4-462. PMID:7988482 doi:http://dx.doi.org/10.1210/edrv-15-4-462
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ Yan W, Cheng L, Wang W, Wu C, Yang X, Du X, Ma L, Qi S, Wei Y, Lu Z, Yang S, Shao Z. Structure of the human gonadotropin-releasing hormone receptor GnRH1R reveals an unusual ligand binding mode. Nat Commun. 2020 Oct 20;11(1):5287. doi: 10.1038/s41467-020-19109-w. PMID:33082324 doi:http://dx.doi.org/10.1038/s41467-020-19109-w
- ↑ doi: https://dx.doi.org/10.1016/S0140-6736(01)06797-6
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
