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Besides, on pharmacological grounds, the primary indications for GnRH antagonists will be in any situation in which chemical gonadotropic hypophysectomy is required. | Besides, on pharmacological grounds, the primary indications for GnRH antagonists will be in any situation in which chemical gonadotropic hypophysectomy is required. | ||
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== References == | == References == | ||
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Gonadotropin releasing hormone 1 receptor (GnRHR)
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 FunctionThe 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 correspond to the inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG), MAPK, and adenyl cyclase pathways. [3]. StructureGeneral structureGnRH1R has the overall architecture of seven canonical transmembranes (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 serves 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 Pyrococcus abysi , 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 C114 and C196. Following structural highlights are different to receptors of this family: The well-known conserved D-R-Y motif is in fact the motif in GnRH1R. An intrahelical salt bridge is observed between D138 and R139, as well as a polar interaction between R139 and T265 (This interaction 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 bindingThe overall pocket in GnRH1R is defined by the N terminus, TM2, TM3, TM5, TM6, and TM7, forming a highly with a few polar residues (D98, N102, K121, and N305) The orthosteric binding pocket of GnRH1R is solvent-accessible, appears relatively shallow and 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[6] in which the N-terminus, residue Y283 and a polar formed by residues D98 and K121 are of particular importance for ligand recognition. Fits in cavity (contact to surrounding residues: N102, Q174, and F178 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. Engaged in the ligand recognition and activation of GnRH1R29 together with Y284 and M125 are suggested to form the bottom wall. Signal transductionConformational rearrangements of common microswitches[7] 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 helices[8]. Different motifs have 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 F272 and Y323[9]. Gonadotropin releasing hormoneHormoneGnRH is a decapeptide that was isolated and characterized 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 behavior. AntagonistLike 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 luteinization 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. [10] DiseaseA mutation or dysfunction of the receptor could cause diseases impacting the reproduction function. More generally, the dysfunction of the pathways involving GnRH and its receptor leads to endocrine pathologies called hypogonadism. [11] It exits many types of hypogonadism but the one involving the mutation of the receptor is the idiopathic hypogonadotropic hypogonadism (IHH). In this case, the mutation leads to failure of detectable ligand binding causing the decreased efficiency of the inositol pathway and consequently leading to the decrease of the LH, FSH, and sex steroid secretions [12]. Moreover, the activity of the pathways related to the receptor and its localization can cause cancer. [13] RelevanceThe main uses of the couple GnRH - GnRHR in the medical field is to cure hormone-dependent diseases and assisted reproductive techniques. For instance, an agonist of GnRH is used for fertility preservation as an alternative to cryopreservation [14]. In addition it is a promising therapeutic target for the treatment of conditions including uterine fibroids [15], endometriosis [16], and prostate cancer [17]. 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 [18] Besides, on pharmacological grounds, the primary indications for GnRH antagonists will be in any situation in which chemical gonadotropic hypophysectomy is required. References
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