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Gonadotropin-Releasing Hormone Receptor Signaling and Functions

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Endocrinology and Metabolism".

Deadline for manuscript submissions: closed (31 October 2020) | Viewed by 19811

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Special Issue Editor

Prof. Dr. Zvi Naor

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Department of Biochemistry and Neurobiology, Tel Aviv University, Ramat Aviv 69978, Israel
Interests: signal transduction; GnRH receptor; gonadotropins; pituitary; gonadotropes
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

GnRH is the primary hormone which controls the reproductive system in all vertebrates. GnRH binds to its cognate receptor (GnRHR) in pituitary gonadotropes to regulate the synthesis and secretion of the gonadotropins: Luteinizing Hormone (LH) and Follicle Stimulating Hormone (FSH). LH and FSH in turn control gametogenesis and sex hormone production in the gonads. GnRHR signaling is complex and involves interactions with G-proteins: in particular Gq, elevation of cytosolic Ca2+, and activation of selective Protein Kinase C (PKC) isoforms followed by activation of Mitogen activated protein kinase (MAPK) members such as ERK1/2, JNK and p38, culminating in gonadotropin secretion and synthesis. Identification of GnRHR signaling networks is a great challenge in the field. GnRHRs are present not only in pituitary gonadotropes, but also in some sex-hormone dependent cancers, including prostate cancer. Prostate cancer, which is also known as carcinoma of the prostate (CaP), is the second highest death-causing cancer in the western world. While GnRH secretion in a pulsatile manner regulates normal reproductive functions, application of GnRH agonists (GnRH-A), or antagonists in a continuous manner, disrupts this regulation. As a result, the continuous application of GnRH-A causes desensitization of the GnRHR in the pituitary, and termination of production and secretion of LH and FSH which in turn causes reduction in testosterone secretion, known as "Chemical Castration." This is the basis for the clinical use of GnRH analogs in prostate cancer. However, in later stages, CaP may become hormone-independent, therefore, treatment with GnRH-A in a continuous manner is not beneficial for these cancers. Hence, a novel potential treatment for hormone-independent CaP is required. Indeed, direct apoptotic effects of GnRH-A upon hormone-independent CaP cells (DU-145) has been described, but the magnitude of the effect was not sufficient. Since there is no cure to advanced hormone resistant CaP, new vistas for the development of a therapy is required.

Prof. Zvi Naor
Guest Editor

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Keywords

Gonadotropin Releasing Hormone (GnRH)
GnRH Receptor
Pituitary cells
Gonadotropes
Prostate cancer
G proteins interactions

Published Papers (5 papers)

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Research

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25 pages, 4212 KiB

Open AccessArticle

C-Src Is Activated by the EGF Receptor in a Pathway that Mediates JNK and ERK Activation by Gonadotropin-Releasing Hormone in COS7 Cells

by Sarah Kraus, Outhiriaradjou Benard, Zvi Naor and Rony Seger

Int. J. Mol. Sci. 2020, 21(22), 8575; https://doi.org/10.3390/ijms21228575 - 13 Nov 2020

Cited by 6 | Viewed by 2461

Abstract

The key participants in G-protein-coupled receptor (GPCR) signaling are the mitogen-activated protein kinase (MAPK) signaling cascades. The mechanisms involved in the activation of the above cascades by GPCRs are not fully elucidated. The prototypical GPCR is the receptor for gonadotropin-releasing hormone (GnRHR), which serves as a key regulator of the reproductive system. Here, we expressed GnRHR in COS7 cells and found that GnRHR transmits its signals to MAPKs mainly via Gαi and the EGF receptor, without the involvement of Hb-EGF or PKCs. The main pathway that leads to JNK activation downstream of the EGF receptor involves a sequential activation of c-Src and PI3K. ERK activation by GnRHR is mediated by the EGF receptor, which activates Ras either directly or via c-Src. Beside the main pathway, the dissociated Gβγ and β-arrestin may initiate additional (albeit minor) pathways that lead to MAPK activation in the transfected COS7 cells. The pathways detected are significantly different from those in other GnRHR-bearing cells, indicating that GnRH can utilize various signaling mechanisms for MAPK activation. The unique pathway elucidated here, in which c-Src and PI3K are sequentially activated downstream of the EGF receptor, may serve as a prototype of signaling mechanisms by GnRHR and additional GPCRs in various cell types. Full article

(This article belongs to the Special Issue Gonadotropin-Releasing Hormone Receptor Signaling and Functions)

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Review

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23 pages, 9460 KiB

Open AccessReview

Mechanisms of Reciprocal Regulation of Gonadotropin-Releasing Hormone (GnRH)-Producing and Immune Systems: The Role of GnRH, Cytokines and Their Receptors in Early Ontogenesis in Normal and Pathological Conditions

by Liudmila Zakharova, Viktoria Sharova and Marina Izvolskaia

Int. J. Mol. Sci. 2021, 22(1), 114; https://doi.org/10.3390/ijms22010114 - 24 Dec 2020

Cited by 12 | Viewed by 5117

Abstract

Different aspects of the reciprocal regulatory influence on the development of gonadotropin-releasing hormone (GnRH)-producing- and immune systems in the perinatal ontogenesis and their functioning in adults in normal and pathological conditions are discussed. The influence of GnRH on the development of the immune system, on the one hand, and the influence of proinflammatory cytokines on the development of the hypothalamic-pituitary-gonadal system, on the other hand, and their functioning in adult offspring are analyzed. We have focused on the effects of GnRH on the formation and functional activity of the thymus, as the central organ of the immune system, in the perinatal period. The main mechanisms of reciprocal regulation of these systems are discussed. The reproductive health of an individual is programmed by the establishment and development of physiological systems during critical periods. Regulatory epigenetic mechanisms of development are not strictly genetically controlled. These processes are characterized by a high sensitivity to various regulatory factors, which provides possible corrections for disorders. Full article

(This article belongs to the Special Issue Gonadotropin-Releasing Hormone Receptor Signaling and Functions)

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23 pages, 980 KiB

Open AccessReview

Gonadotropin-Releasing Hormone Receptors in Prostate Cancer: Molecular Aspects and Biological Functions

by Fabrizio Fontana, Monica Marzagalli, Marina Montagnani Marelli, Michela Raimondi, Roberta M. Moretti and Patrizia Limonta

Int. J. Mol. Sci. 2020, 21(24), 9511; https://doi.org/10.3390/ijms21249511 - 14 Dec 2020

Cited by 23 | Viewed by 5483

Abstract

Pituitary Gonadotropin-Releasing Hormone receptors (GnRH-R) mediate the activity of the hypothalamic decapeptide GnRH, thus playing a key role in the regulation of the reproductive axis. Early-stage prostate cancer (PCa) is dependent on serum androgen levels, and androgen-deprivation therapy (ADT), based on GnRH agonists and antagonists, represents the standard therapeutic approach for PCa patients. Unfortunately, the tumor often progresses towards the more aggressive castration-resistant prostate cancer (CRPC) stage. GnRH receptors are also expressed in CRPC tissues, where their binding to both GnRH agonists and antagonists is associated with significant antiproliferative/proapoptotic, antimetastatic and antiangiogenic effects, mediated by the Gαi/cAMP signaling cascade. GnRH agonists and antagonists are now considered as an effective therapeutic strategy for CRPC patients with many clinical trials demonstrating that the combined use of these drugs with standard therapies (i.e., docetaxel, enzalutamide, abiraterone) significantly improves disease-free survival. In this context, GnRH-based bioconjugates (cytotoxic drugs covalently linked to a GnRH-based decapeptide) have been recently developed. The rationale of this treatment is that the GnRH peptide selectively binds to its receptors, delivering the cytotoxic drug to CRPC cells while sparing nontumor cells. Some of these compounds have already entered clinical trials. Full article

(This article belongs to the Special Issue Gonadotropin-Releasing Hormone Receptor Signaling and Functions)

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15 pages, 1200 KiB

Open AccessReview

Invertebrate Gonadotropin-Releasing Hormone Receptor Signaling and Its Relevant Biological Actions

by Tsubasa Sakai, Tatsuya Yamamoto, Shin Matsubara, Tsuyoshi Kawada and Honoo Satake

Int. J. Mol. Sci. 2020, 21(22), 8544; https://doi.org/10.3390/ijms21228544 - 12 Nov 2020

Cited by 25 | Viewed by 2908

Abstract

Gonadotropin-releasing hormones (GnRHs) play pivotal roles in reproduction via the hypothalamus-pituitary-gonad axis (HPG axis) in vertebrates. GnRHs and their receptors (GnRHRs) are also conserved in invertebrates lacking the HPG axis, indicating that invertebrate GnRHs do not serve as “gonadotropin-releasing factors” but, rather, function as neuropeptides that directly regulate target tissues. All vertebrate and urochordate GnRHs comprise 10 amino acids, whereas amphioxus, echinoderm, and protostome GnRH-like peptides are 11- or 12-residue peptides. Intracellular calcium mobilization is the major second messenger for GnRH signaling in cephalochordates, echinoderms, and protostomes, while urochordate GnRHRs also stimulate cAMP production pathways. Moreover, the ligand-specific modulation of signal transduction via heterodimerization between GnRHR paralogs indicates species-specific evolution in Ciona intestinalis. The characterization of authentic or putative invertebrate GnRHRs in various tissues and their in vitro and in vivo activities indicate that invertebrate GnRHs are responsible for the regulation of both reproductive and nonreproductive functions. In this review, we examine our current understanding of and perspectives on the primary sequences, tissue distribution of mRNA expression, signal transduction, and biological functions of invertebrate GnRHs and their receptors. Full article

(This article belongs to the Special Issue Gonadotropin-Releasing Hormone Receptor Signaling and Functions)

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15 pages, 822 KiB

Open AccessReview

Using Aptamers as a Novel Method for Determining GnRH/LH Pulsatility

by Chioma Izzi-Engbeaya, Ali Abbara, Anthony Cass and Waljit S Dhillo

Int. J. Mol. Sci. 2020, 21(19), 7394; https://doi.org/10.3390/ijms21197394 - 7 Oct 2020

Cited by 7 | Viewed by 3157

Abstract

Aptamers are a novel technology enabling the continuous measurement of analytes in blood and other body compartments, without the need for repeated sampling and the associated reagent costs of traditional antibody-based methodologies. Aptamers are short single-stranded synthetic RNA or DNA that recognise and bind to specific targets. The conformational changes that can occur upon aptamer–ligand binding are transformed into chemical, fluorescent, colour changes and other readouts. Aptamers have been developed to detect and measure a variety of targets in vitro and in vivo. Gonadotropin-releasing hormone (GnRH) is a pulsatile hypothalamic hormone that is essential for normal fertility but difficult to measure in the peripheral circulation. However, pulsatile GnRH release results in pulsatile luteinizing hormone (LH) release from the pituitary gland. As such, LH pulsatility is the clinical gold standard method to determine GnRH pulsatility in humans. Aptamers have recently been shown to successfully bind to and measure GnRH and LH, and this review will focus on this specific area. However, due to the adaptability of aptamers, and their suitability for incorporation into portable devices, aptamer-based technology is likely to be used more widely in the future. Full article

(This article belongs to the Special Issue Gonadotropin-Releasing Hormone Receptor Signaling and Functions)

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