Gonadotropin-Releasing Hormone and GnRH Receptor: Structure, Function and Drug Development

2020 ◽  
Vol 27 (36) ◽  
pp. 6136-6158 ◽  
Author(s):  
Haralambos Tzoupis ◽  
Agathi Nteli ◽  
Maria-Eleni Androutsou ◽  
Theodore Tselios
Keyword(s):  
Hormone Receptors ◽  
Gnrh Receptor ◽  
Gonadotropin Releasing Hormone ◽  
Human Organism ◽  
Valuable Insight ◽  
Pituitary Cells ◽  
Treatment Protocols ◽  
Gnrh Analogues ◽  
Releasing Hormone ◽  
Functional Studies

Background: Gonadotropin-Releasing Hormone (GnRH) is a key element in sexual maturation and regulation of the reproductive cycle in the human organism. GnRH interacts with the pituitary cells through the activation of the Gonadotropin Releasing Hormone Receptors (GnRHR). Any impairments/dysfunctions of the GnRH-GnRHR complex lead to the development of various cancer types and disorders. Furthermore, the identification of GnRHR as a potential drug target has led to the development of agonist and antagonist molecules implemented in various treatment protocols. The development of these drugs was based on the information derived from the functional studies of GnRH and GnRHR. Objective: This review aims at shedding light on the versatile function of GnRH and GnRH receptor and offers an apprehensive summary regarding the development of different agonists, antagonists and non-peptide GnRH analogues. Conclusion: The information derived from these studies can enhance our understanding of the GnRH-GnRHR versatile nature and offer valuable insight into the design of new more potent molecules.

scholarly journals Acute desensitization of phospholipase C-coupled muscarinic M3 receptors but not gonadotropin-releasing hormone receptors co-expressed in αT3-1 cells: implications for mechanisms of rapid desensitization

1998 ◽  
Vol 333 (2) ◽  
pp. 301-308 ◽  
Author(s):  
Gary B. WILLARS ◽  
Craig A. McARDLE ◽  
Stefan R. NAHORSKI
Keyword(s):  
Phospholipase C ◽  
Cell Line ◽  
Hormone Receptors ◽  
State Level ◽  
Structural Features ◽  
Gnrh Receptor ◽  
Gonadotropin Releasing Hormone ◽  
Releasing Hormone ◽  
M3 Receptors ◽  
M3 Receptor

In the present study we have expressed the muscarinic M3 receptor in an immortalized mouse pituitary cell line (αT3-1), which expresses an endogenous gonadotropin-releasing hormone (GnRH) receptor, to examine potential differences in acute receptor regulation. Both of these receptors couple to the activation of phosphoinositide-specific phospholipase C (PLC) in these cells and we demonstrate that, despite expression in the same cell background, acute desensitization is a feature of muscarinic M3 receptors but not of GnRH receptors. We show that, when the concentrations of GnRH and methacholine are matched to give approximately equivalent maximal elevations of Ins(1,4,5)P3, the GnRH receptor is able to sustain PLC activity at the initial rate, whereas the muscarinic M3 receptor cannot. Thus PLC-activating G-protein-coupled receptors are able to undergo rapid desensitization in this cell line, indicating that the desensitization profile is receptor-specific rather than cell-specific. This argues strongly that post-receptor regulatory features do not have a prominent role in mediating rapid desensitization in these cells. Furthermore GnRH receptor-mediated PLC activity is sustained despite a marked and persistent depletion in the steady-state level of PtdIns(4,5)P2. In contrast, activation of muscarinic receptors is not sustained despite only a transient decrease in PtdIns(4,5)P2 concentration. Thus, whereas the contribution of PtdIns(4,5)P2 depletion to the temporal profile of receptor-mediated PLC signalling has been difficult to assess, the present results demonstrate that this is unlikely to be of importance in these cells. We suggest that unique structural features of the GnRH receptor result in a lack of appropriate regulatory phospho-acceptor sites and that the absence of agonist-dependent phosphorylation might underlie the lack of acute regulation.

scholarly journals Gonadotrophin-releasing hormone receptors in GtoPdb v.2021.3

2021 ◽  
Vol 2021 (3) ◽  
Author(s):  
Laura H. Heitman ◽  
Adriaan P. IJzerman ◽  
Craig A. McArdle ◽  
Adam J Pawson
Keyword(s):  
Hormone Receptors ◽  
Gnrh Receptor ◽  
Type I ◽  
Gonadotropin Secretion ◽  
Gnrh Analogues ◽  
Releasing Hormone ◽  
Hormone Synthesis ◽  
Consequent Reduction ◽  
Gonadotrophin Releasing Hormone ◽  
Ancient Gene

GnRH1 and GnRH2 receptors (provisonal nomenclature [39], also called Type I and Type II GnRH receptor, respectively [85]) have been cloned from numerous species, most of which express two or three types of GnRH receptor [85, 84, 114]. GnRH I (p-Glu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2) is a hypothalamic decapeptide also known as luteinizing hormone-releasing hormone, gonadoliberin, luliberin, gonadorelin or simply as GnRH. It is a member of a family of similar peptides found in many species [85, 84, 114] including GnRH II (pGlu-His-Trp-Ser-His-Gly-Trp-Tyr-Pro-Gly-NH2 (which is also known as chicken GnRH-II). Receptors for three forms of GnRH exist in some species but only GnRH I and GnRH II and their cognate receptors have been found in mammals [85, 84, 114]. GnRH1 receptors are expressed by pituitary gonadotrophs, where they mediate the effects of GnRH on gonadotropin hormone synthesis and secretion that underpin central control of mammalian reproduction. GnRH analogues are used in assisted reproduction and to treat steroid hormone-dependent conditions [58]. Notably, agonists cause desensitization of GnRH-stimulated gonadotropin secretion and the consequent reduction in circulating sex steroids is exploited to treat hormone-dependent cancers of the breast, ovary and prostate [58]. GnRH1 receptors are selectively activated by GnRH I and all lack the COOH-terminal tails found in other GPCRs. GnRH2 receptors do have COOH-terminal tails and (where tested) are selective for GnRH II over GnRH I. GnRH2 receptors are expressed by some primates but not by humans [88]. Phylogenetic classifications divide GnRH receptors into three [85] or five groups [129] and highlight examples of gene loss through evolution, with humans retaining only one ancient gene. The structure of the GnRH1 receptor in complex with elagolix has been elucidated [132].

scholarly journals Gonadotrophin-releasing hormone receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

2019 ◽  
Vol 2019 (4) ◽  
Author(s):  
Laura H. Heitman ◽  
Adriaan P. IJzerman ◽  
Craig A. McArdle ◽  
Adam J. Pawson
Keyword(s):  
Hormone Receptors ◽  
Gnrh Receptor ◽  
Type I ◽  
Gonadotropin Secretion ◽  
Gnrh Analogues ◽  
Releasing Hormone ◽  
Hormone Synthesis ◽  
Consequent Reduction ◽  
Gonadotrophin Releasing Hormone ◽  
Ancient Gene

GnRH1 and GnRH2 receptors (provisonal nomenclature [35], also called Type I and Type II GnRH receptor, respectively [78]) have been cloned from numerous species, most of which express two or three types of GnRH receptor [78, 77, 107]. GnRH I (p-Glu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2) is a hypothalamic decapeptide also known as luteinizing hormone-releasing hormone, gonadoliberin, luliberin, gonadorelin or simply as GnRH. It is a member of a family of similar peptides found in many species [78, 77, 107] including GnRH II (pGlu-His-Trp-Ser-His-Gly-Trp-Tyr-Pro-Gly-NH2 (which is also known as chicken GnRH-II). Receptors for three forms of GnRH exist in some species but only GnRH I and GnRH II and their cognate receptors have been found in mammals [78, 77, 107]. GnRH1 receptors are expressed by pituitary gonadotrophs, where they mediate the effects of GnRH on gonadotropin hormone synthesis and secretion that underpin central control of mammalian reproduction. GnRH analogues are used in assisted reproduction and to treat steroid hormone-dependent conditions [53]. Notably, agonists cause desensitization of GnRH-stimulated gonadotropin secretion and the consequent reduction in circulating sex steroids is exploited to treat hormone-dependent cancers of the breast, ovary and prostate [53]. GnRH1 receptors are selectively activated by GnRH I and all lack the COOH-terminal tails found in other GPCRs. GnRH2 receptors do have COOH-terminal tails and (where tested) are selective for GnRH II over GnRH I. GnRH2 receptors are expressed by some primates but not by humans [81]. Phylogenetic classifications divide GnRH receptors into three [78] or five groups [122] and highlight examples of gene loss through evolution, with humans retaining only one ancient gene.

scholarly journals Endocrine and molecular milieus of ovarian follicles are diversely affected by human chorionic gonadotropin and gonadotropin-releasing hormone in prepubertal and mature gilts

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Adam J. Ziecik ◽  
Jan Klos ◽  
Katarzyna Gromadzka-Hliwa ◽  
Mariola A. Dietrich ◽  
Mariola Slowinska ◽  
...  
Keyword(s):  
Chorionic Gonadotropin ◽  
Human Chorionic Gonadotropin ◽  
Hormone Receptors ◽  
Cell Function ◽  
Ovarian Follicle ◽  
Molecular Transport ◽  
Gonadotropin Releasing Hormone ◽  
Matrix Remodeling ◽  
Releasing Hormone ◽  
Serum Gonadotropin

AbstractDifferent strategies are used to meet optimal reproductive performance or manage reproductive health. Although exogenous human chorionic gonadotropin (hCG) and gonadotropin-releasing hormone (GnRH) agonists (A) are commonly used to trigger ovulation in estrous cycle synchronization, little is known about their effect on the ovarian follicle. Here, we explored whether hCG- and GnRH-A-induced native luteinizing hormone (LH) can affect the endocrine and molecular milieus of ovarian preovulatory follicles in pigs at different stages of sexual development. We collected ovaries 30 h after hCG/GnRH-A administration from altrenogest and pregnant mare serum gonadotropin (eCG)-primed prepubertal and sexually mature gilts. Several endocrine and molecular alternations were indicated, including broad hormonal trigger-induced changes in follicular fluid steroid hormones and prostaglandin levels. However, sexual maturity affected only estradiol levels. Trigger- and/or maturity-dependent changes in the abundance of hormone receptors (FSHR and LHCGR) and proteins associated with lipid metabolism and steroidogenesis (e.g., STAR, HSD3B1, and CYP11A1), prostaglandin synthesis (PTGS2 and PTGFS), extracellular matrix remodeling (MMP1 and TIMP1), protein folding (HSPs), molecular transport (TF), and cell function and survival (e.g., VIM) were observed. These data revealed different endocrine properties of exogenous and endogenous gonadotropins, with a potent progestational/androgenic role of hCG and estrogenic/pro-developmental function of LH.

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