Ghrelin action on GnRH neurons and pituitary gonadotropes might be mediated by GnIH-GPR147 system

2016 ◽  
Vol 25 (2) ◽  
Author(s):  
Onder Celik ◽  
Nilufer Celik ◽  
Suleyman Aydin ◽  
Banu Kumbak Aygun ◽  
Esra Tustas Haberal ◽  
...  
Keyword(s):  
Inhibitory Effect ◽  
Wide Distribution ◽  
Gonadotropin Secretion ◽  
Ghrelin Receptor ◽  
Gnrh Neurons ◽  
The Status ◽  
Potential Impact ◽  
Gonadotropin Inhibitory Hormone ◽  
Reproductive Events ◽  
G Protein Coupled

AbstractAcylated ghrelin (AG) effect on GnRH secretion is mediated, at least in part, by GH secreta-gogue receptor (GHS-R) which is present in the GnRH neurons. As the acylation is mandatory for binding to GHS-R, unacylated isoform of ghrelin (UAG) action on gonadotropin secretion is likely to be mediated by other receptors or mediators that have not been identified yet. UAG, therefore, may act partially via a GHS-R-independent mechanism and inhibitory impact of UAG on GnRH neurons may be executed via modulation of other neuronal networks. Ghrelin and gonadotropin inhibitory hormone (GnIH), two agonistic peptides, have been known as important regulators of reproductive events. Potential impact of ghrelin on the activity of GnIH neurons is not exactly known. Both GnIH and ghrelin are potent stimulators of food intake and inhibitors of gonadotropin release. By binding G-protein coupled GnIH receptor (GnIH-R), GPR147, which is located in the human gonadotropes and GnRh neurons, GnIH exerts an inhibitory effect on both GnRH neurons and the gonadotropes. The GnIH-GPR147 system receives information regarding the status of energy reservoir of body from circulating peptides and then transfers them to the kisspeptin-GnIH-GnRH network. Due to wide distribution of this network in brain GnIH neurons may project on ghrelin neurons in the arcuate nucleus and contribute to the regulation of UAG’s central effects or vice versa. Together, the unidentified ghrelin receptor in the hypothalamus and hypophysis may be GnIH-R. Therefore, it is reasonable that ghrelin may act on both hypothalamus and hypophysis via GnIH-GPR147 system to block gonadotropin synthesis and secretion.

scholarly journals RFamide-Related Peptide-3 Receptor Gene Expression in GnRH and Kisspeptin Neurons and GnRH-Dependent Mechanism of Action

Endocrinology ◽  
2012 ◽  
Vol 153 (8) ◽  
pp. 3770-3779 ◽  
Author(s):  
Mohammed Z. Rizwan ◽  
Matthew C. Poling ◽  
Maggie Corr ◽  
Pamela A. Cornes ◽  
Rachael A. Augustine ◽  
...  
Keyword(s):  
Neuronal Network ◽  
Receptor Gene ◽  
Male Rats ◽  
Gonadotropin Secretion ◽  
Female Mice ◽  
Related Peptide ◽  
Gnrh Neurons ◽  
Lh Secretion ◽  
G Protein Coupled

RFamide-related peptide-3 (RFRP-3) is known to inhibit the activity of GnRH neurons. It is not yet clear whether its G protein-coupled receptors, GPR147 and GPR74, are present on GnRH neurons or on afferent inputs of the GnRH neuronal network or whether RFRP-3 can inhibit gonadotropin secretion independently of GnRH. We tested the following: 1) whether GnRH is essential for the effects of RFRP-3 on LH secretion; 2) whether RFRP-3 neurons project to GnRH and rostral periventricular kisspeptin neurons in mice, and 3) whether Gpr147 and Gpr74 are expressed by these neurons. Intravenous treatment with the GPR147 antagonist RF9 increased plasma LH concentration in castrated male rats but was unable to do so in the presence of the GnRH antagonist cetrorelix. Dual-label immunohistochemistry revealed that approximately 26% of GnRH neurons from male and diestrous female mice were apposed by RFRP-3 fibers, and 19% of kisspeptin neurons from proestrous female mice were apposed by RFRP-3 fibers. Using immunomagnetic purification of GnRH and kisspeptin cells, single-cell nested RT-PCR, and in situ hybridization, we showed that 33% of GnRH neurons and 9–16% of rostral periventricular kisspeptin neurons expressed Gpr147, whereas Gpr74 was not expressed in either population. These data reveal that RFRP-3 can act at two levels of the GnRH neuronal network (i.e. the GnRH neurons and the rostral periventricular kisspeptin neurons) to modulate reproduction but is unable to inhibit gonadotropin secretion independently of GnRH.

Characterization of a cDNA encoding a novel avian hypothalamic neuropeptide exerting an inhibitory effect on gonadotropin release

2001 ◽  
Vol 354 (2) ◽  
pp. 379-385 ◽  
Author(s):  
Honoo SATAKE ◽  
Miki HISADA ◽  
Tsuyoshi KAWADA ◽  
Hiroyuki MINAKATA ◽  
Kazuyoshi UKENA ◽  
...  
Keyword(s):  
Amino Acid ◽  
Basic Amino Acid ◽  
Inhibitory Effect ◽  
Gene Encoding ◽  
Specific Expression ◽  
Gonadotropin Secretion ◽  
Putative Gene ◽  
Gonadotropin Release ◽  
Pcr Products ◽  
Gonadotropin Inhibitory Hormone

We previously isolated a novel dodecapeptide containing a C-terminal -Arg-Phe-NH2 sequence, SIKPSAYLPLRF-NH2 (RFamide peptide), from the quail brain. This quail RFamide peptide was shown to decrease gonadotropin release from the cultured anterior pituitary and to be located at least in the quail hypothalamo-hypophysial system. We therefore designated this RFamide peptide gonadotropin inhibitory hormone (GnIH). In the present study we characterized the GnIH cDNA from the quail brain by a combination of 3′ and 5′ rapid amplification of cDNA ends (‘RACE’). The deduced GnIH precursor consisted of 173 amino acid residues, encoding one GnIH and two putative gene-related peptide (GnIH-RP-1 and GnIH-RP-2) sequences that included -LPXRF (X = L or Q) at their C-termini. All these peptide sequences were flanked by a glycine C-terminal amidation signal and a single basic amino acid on each end as an endoproteolytic site. Southern blotting analysis of reverse-transcriptase-mediated PCR products demonstrated a specific expression of the gene encoding GnIH in the diencephalon including the hypothalamus. Furthermore, mass spectrometric analyses detected the mass numbers for matured GnIH and GnIH-RP-2, revealing that both peptides are produced from the precursor in the diencephalon as an endogenous ligand. Taken together, these results lead to the conclusion that GnIH is a hypothalamic factor responsible for the negative regulation of gonadotropin secretion. Furthermore, the presence of a novel RFamide peptide family containing a C-terminal -LPXRF-NH2 sequence has been revealed.

scholarly journals RFamide-Related Peptide-3, a Mammalian Gonadotropin-Inhibitory Hormone Ortholog, Regulates Gonadotropin-Releasing Hormone Neuron Firing in the Mouse

Endocrinology ◽  
2009 ◽  
Vol 150 (6) ◽  
pp. 2799-2804 ◽  
Author(s):  
Eric Ducret ◽  
Greg M. Anderson ◽  
Allan E. Herbison
Keyword(s):  
Firing Rate ◽  
Fluorescent Protein ◽  
Suppressive Effect ◽  
Small Population ◽  
Neuron Activity ◽  
Gonadotropin Secretion ◽  
Gnrh Neurons ◽  
Gonadotropin Inhibitory Hormone ◽  
Green Fluorescent ◽  
Prolactin Releasing Peptide

The recent discovery that an RFamide termed gonadotropin-inhibitory hormone is likely to be a hypophysiotrophic gonadotropin release-inhibiting hormone in birds has generated interest into the role of LPXRFamide neuropeptides in the control of gonadotropin secretion in mammals. Recent immunocytochemical studies in birds and mammals have suggested that neurons expressing the mammalian LPXRFamides, RFamide-related peptides (RFRPs) 1 and 3, may innervate and regulate GnRH neurons directly. We used cell-attached electrophysiology in adult male and female GnRH-green fluorescent protein-tagged neurons to examine whether RFRP-3 modulated the electrical excitability of GnRH neurons. RFRP-3 was found to exhibit rapid and repeatable inhibitory effects on the firing rate of 41% of GnRH neurons. A small population of GnRH neurons (12%) increased their firing rate in response to RFRP-3, and the remainder was unaffected. No difference was detected in the RFRP-3 responses of GnRH neurons from male, diestrous, or proestrus female mice. The suppressive effect of RFRP-3 was maintained when amino acid transmission was blocked, suggesting a possible direct effect of RFRP-3 upon GnRH neurons. To evaluate the effects of other RFamide neuropeptides on GnRH neurons, we tested the actions of prolactin-releasing peptide-20 and -31. Neither compounds altered the firing rate of GnRH neurons. These studies demonstrate that RFRP-3 has a likely direct suppressive action on the excitability of GnRH neurons, indicating a role for RFRPs in the regulation of gonadotropin secretion in mammals through modulation of GnRH neuron activity.

scholarly journals Molecular Basis for the Activation of Gonadotropin-Inhibitory Hormone Gene Transcription by Corticosterone

Endocrinology ◽  
2014 ◽  
Vol 155 (5) ◽  
pp. 1817-1826 ◽  
Author(s):  
You Lee Son ◽  
Takayoshi Ubuka ◽  
Misato Narihiro ◽  
Yujiro Fukuda ◽  
Itaru Hasunuma ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Transcriptional Activation ◽  
Molecular Basis ◽  
Neuronal Cell ◽  
Reproductive Function ◽  
Inhibitory Effect ◽  
Coding Region ◽  
Gonadotropin Secretion ◽  
High Concentrations ◽  
Gonadotropin Inhibitory Hormone

The inhibitory effect of stress on reproductive function is potentially mediated by high concentrations of circulating glucocorticoids (GCs) acting via the GC receptor (GR). Gonadotropin-inhibitory hormone (GnIH) is a hypothalamic neuropeptide that inhibits gonadotropin secretion. GnIH may mediate stress-induced reproductive dysfunction. However, it is not yet known whether GC-bound GR is directly involved in GnIH transcription. Here, we demonstrated the localization of GR mRNA in GnIH neurons in the paraventricular nucleus of quail, suggesting that GC can directly regulate GnIH transcription. We next showed that 24 hours of treatment with corticosterone (CORT) increase GnIH mRNA expression in the quail diencephalon. We further investigated the mechanism of activation of GnIH transcription by CORT using a GnIH-expressing neuronal cell line, rHypoE-23, derived from rat hypothalamus. We found the expression of GR mRNA in rHypoE-23 cells and increased GnIH mRNA expression by 24 hours of CORT treatment. We finally characterized the promoter activity of rat GnIH gene stimulated by CORT. Through DNA deletion analysis, we identified a CORT-responsive region at 2000–1501 bp upstream of GnIH precursor coding region. This region included 2 GC response elements (GREs) at −1665 and −1530 bp. Mutation of −1530 GRE abolished CORT responsiveness. We also found CORT-stimulated GR recruitment at the GnIH promoter region containing the −1530 GRE. These results provide a putative molecular basis for transcriptional activation of GnIH under stress by demonstrating that CORT directly induces GnIH transcription by recruitment of GR to its promoter.

scholarly journals Gonadotropin Inhibitory Hormone and Its Receptor: Potential Key to the Integration and Coordination of Metabolic Status and Reproduction

2022 ◽  
Vol 12 ◽  
Author(s):  
Grégoy Y. Bédécarrats ◽  
Charlene Hanlon ◽  
Kazuyoshi Tsutsui
Keyword(s):  
Receptor Potential ◽  
Inhibitory Effect ◽  
Wide Distribution ◽  
Metabolic Status ◽  
Stress Axis ◽  
Inhibitory Peptide ◽  
Glucose And Lipid Metabolism ◽  
Reproductive Axis ◽  
Gonadotropin Inhibitory Hormone ◽  
The Impact

Since its discovery as a novel gonadotropin inhibitory peptide in 2000, the central and peripheral roles played by gonadotropin-inhibiting hormone (GnIH) have been significantly expanded. This is highlighted by the wide distribution of its receptor (GnIH-R) within the brain and throughout multiple peripheral organs and tissues. Furthermore, as GnIH is part of the wider RF-amide peptides family, many orthologues have been characterized across vertebrate species, and due to the promiscuity between ligands and receptors within this family, confusion over the nomenclature and function has arisen. In this review, we intend to first clarify the nomenclature, prevalence, and distribution of the GnIH-Rs, and by reviewing specific localization and ligand availability, we propose an integrative role for GnIH in the coordination of reproductive and metabolic processes. Specifically, we propose that GnIH participates in the central regulation of feed intake while modulating the impact of thyroid hormones and the stress axis to allow active reproduction to proceed depending on the availability of resources. Furthermore, beyond the central nervous system, we also propose a peripheral role for GnIH in the control of glucose and lipid metabolism at the level of the liver, pancreas, and adipose tissue. Taken together, evidence from the literature strongly suggests that, in fact, the inhibitory effect of GnIH on the reproductive axis is based on the integration of environmental cues and internal metabolic status.

scholarly journals An inhibitory circuit from brainstem to GnRH neurons in male mice: a new role for the RFRP receptor

Endocrinology ◽  
2021 ◽  
Author(s):  
Stephanie Constantin ◽  
Katherine Pizano ◽  
Kaya Matson ◽  
Yufei Shan ◽  
Daniel Reynolds ◽  
...  
Keyword(s):  
Neuropeptide Y ◽  
Fluorescent Protein ◽  
Nucleus Tractus Solitarius ◽  
Brain Slices ◽  
Adult Brain ◽  
Energy Deficit ◽  
Gonadotropin Secretion ◽  
Gnrh Neurons ◽  
Gonadotropin Inhibitory Hormone ◽  
Green Fluorescent

Abstract RFamide-related peptides (RFRPs, mammalian orthologs of gonadotropin-inhibitory hormone) convey circadian, seasonal and social cues to the reproductive system. They regulate gonadotropin secretion by modulating gonadotropin-releasing hormone (GnRH) neurons via the RFRP receptor. Mice lacking this receptor are fertile but exhibit abnormal gonadotropin responses during metabolic challenges such as acute fasting, when the normal drop in gonadotropin levels is delayed. Although it is known that these food intake signals to the reproductive circuit originate in the nucleus tractus solitarius (NTS) in the brainstem, the phenotype of the neurons conveying the signal remains unknown. Given that neuropeptide FF (NPFF), another RFamide peptide, resides in the NTS and can bind to the RFRP receptor, we hypothesized that NPFF may regulate GnRH neurons. To address this question, we used a combination of techniques: cell-attached electrophysiology on GnRH-driven green fluorescent protein-tagged neurons in acute brain slices; calcium imaging on cultured GnRH neurons; and immunostaining on adult brain tissue. We found 1) NPFF inhibits GnRH neuron excitability via the RFRP receptor and its canonical signaling pathway (Gi/o protein and G protein-coupled inwardly-rectifying potassium channels), 2) NPFF-like fibers in the vicinity of GnRH neurons coexpress neuropeptide Y, 3) the majority of NPFF-like cell bodies in the NTS also coexpress neuropeptide Y, and 4) acute fasting increased NPFF-like immunoreactivity in the NTS. Together these data indicate that NPFF neurons within the NTS inhibit GnRH neurons, and thus reproduction, during fasting but prior to the energy deficit.

scholarly journals The inhibitory effect of Gβγ and Gβ isoform specificity on ENaC activity

2013 ◽  
Vol 305 (9) ◽  
pp. F1365-F1373 ◽  
Author(s):  
Ling Yu ◽  
Otor Al-Khalili ◽  
Billie Jeanne Duke ◽  
James D. Stockand ◽  
Douglas C. Eaton ◽  
...  
Keyword(s):  
Single Channel ◽  
Inhibitory Effect ◽  
G Protein Coupled Receptors ◽  
Open Probability ◽  
A6 Cells ◽  
Kinase C ◽  
Downstream Effectors ◽  
Isoform Specificity ◽  
Low Levels ◽  
G Protein Coupled

Epithelial Na+ channel (ENaC) activity, which determines the rate of renal Na+ reabsorption, can be regulated by G protein-coupled receptors. Regulation of ENaC by Gα-mediated downstream effectors has been studied extensively, but the effect of Gβγ dimers on ENaC is unclear. A6 cells endogenously contain high levels of Gβ1 but low levels of Gβ3, Gβ4, and Gβ5 were detected by Q-PCR. We tested Gγ2 combined individually with Gβ1 through Gβ5 expressed in A6 cells, after which we recorded single-channel ENaC activity. Among the five β and γ2 combinations, β1γ2 strongly inhibits ENaC activity by reducing both ENaC channel number ( N) and open probability ( Po) compared with control cells. In contrast, the other four β-isoforms combined with γ2 have no significant effect on ENaC activity. By using various inhibitors to probe Gβ1γ2 effects on ENaC regulation, we found that Gβ1γ2-mediated ENaC inhibition involved activation of phospholipase C-β and its enzymatic products that induce protein kinase C and ERK1/2 signaling pathways.

scholarly journals The apelin receptor: physiology, pathology, cell signalling, and ligand modulation of a peptide-activated class A GPCR

2014 ◽  
Vol 92 (6) ◽  
pp. 431-440 ◽  
Author(s):  
Nigel A. Chapman ◽  
Denis J. Dupré ◽  
Jan K. Rainey
Keyword(s):  
G Protein ◽  
Cell Signalling ◽  
Wide Distribution ◽  
Peptide Ligand ◽  
Cellular Effects ◽  
Class A ◽  
Promising Therapeutic Target ◽  
Apelin Receptor ◽  
Obesity And Cancer ◽  
G Protein Coupled

The apelin receptor (AR or APJ) is a class A (rhodopsin-like) G-protein-coupled receptor with wide distribution throughout the human body. Activation of the AR by its cognate peptide ligand, apelin, induces diverse physiological effects including vasoconstriction and dilation, strengthening of heart muscle contractility, angiogenesis, and regulation of energy metabolism and fluid homeostasis. Recently, another endogenous peptidic activator of the AR, Toddler/ELABELA, was identified as having a crucial role in zebrafish (Danio rerio) embryonic development. The AR is also implicated in pathologies including cardiovascular disease, diabetes, obesity, and cancer, making it a promising therapeutic target. Despite its established importance, the precise roles of AR signalling remain poorly understood. Moreover, little is known about the mechanisms of peptide–AR activation. Additional complexity arises from modulation of the AR by 2 endogenous peptide ligands, both with multiple bioactive isoforms of variable length and distribution. The various apelin and Toddler/ELABELA isoforms may also produce distinct cellular effects. Further complexity arises through formation of functionally distinct heterodimers between the AR and other G-protein-coupled receptors. This minireview outlines key (patho)physiological actions of the AR, addresses what is known about signal transduction downstream of AR activation, and concludes by discussing unique properties of the endogenous peptidic ligands of the AR.

Caffeine does not inhibit substance P-evoked intracellular Ca2+ mobilization in rat salivary acinar cells

1999 ◽  
Vol 276 (4) ◽  
pp. C915-C922 ◽  
Author(s):  
J. T. Seo ◽  
H. Sugiya ◽  
S. I. Lee ◽  
M. C. Steward ◽  
A. C. Elliott
Keyword(s):  
Signal Transduction ◽  
Substance P ◽  
G Protein ◽  
Acinar Cells ◽  
Inhibitory Effect ◽  
Structural Motif ◽  
Stimulus Response ◽  
Inhibit Substance ◽  
Prior Application ◽  
G Protein Coupled

We used the Ca2+-sensitive fluorescent dye fura 2, together with measurements of intracellulard- myo-inositol 1,4,5-trisphosphate [Ins(1,4,5) P 3], to assess the inhibitory effects of caffeine on signal transduction via G protein-coupled receptor pathways in isolated rat mandibular salivary acinar cells. ACh, norepinephrine (NE), and substance P (SP) all evoked substantial increases in the intracellular free Ca2+ concentration ([Ca2+]i). Responses to ACh and NE were markedly inhibited by prior application of 20 mM caffeine. The inhibitory effect of caffeine was not reproduced by phosphodiesterase inhibition with IBMX or addition of cell-permeant dibutyryl cAMP. In contrast to the ACh and NE responses, the [Ca2+]iresponse to SP was unaffected by caffeine. Despite this, SP and ACh appeared to mobilize Ca2+ from a common intracellular pool. Measurements of agonist-induced changes in Ins(1,4,5) P 3levels confirmed that caffeine inhibited the stimulus-response coupling pathway at a point before Ins(1,4,5) P 3generation. Caffeine did not, however, inhibit [Ca2+]iresponses evoked by direct activation of G proteins with 40 mM F−. These data show that caffeine inhibits G protein-coupled signal transduction in these cells at some element that is common to the muscarinic and α-adrenergic signaling pathways but is not shared by the SP signaling pathway. We suggest that this element might be a specific structural motif on the G protein-coupled muscarinic and α-adrenergic receptors.

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