Review: neuroestrogen regulation of socio-sexual behavior of males

It is thought that estrogen (neuroestrogen) synthesized by the action of aromatase in the brain from testosterone activates male socio-sexual behaviors, such as aggression and sexual behavior in birds. We recently found that gonadotropin-inhibitory hormone (GnIH), a hypothalamic neuropeptide, inhibits socio-sexual behaviors of male quail by directly activating aromatase and increasing neuroestrogen synthesis in the preoptic area (POA). The POA is thought to be the most critical site of aromatization and neuroestrogen action for the regulation of socio-sexual behavior of male birds. We concluded that GnIH inhibits socio-sexual behaviors of male quail by increasing neuroestrogen concentration beyond its optimal concentration in the brain for expression of socio-sexual behavior. On the other hand, it has been reported that dopamine and glutamate, which stimulate male socio-sexual behavior in birds and mammals, inhibit the activity of aromatase in the POA. Multiple studies also report that the activity of aromatase or neuroestrogen is negatively correlated with changes in male socio-sexual behavior in fish, birds, and mammals including humans. Here, we review previous studies that investigated the role of neuroestrogen in the regulation of male socio-sexual behavior and reconsider the hypothesis that neuroestrogen activates male socio-sexual behavior in vertebrates. It is considered that basal concentration of neuroestrogen is required for the maintenance of male socio-sexual behavior but higher concentration of neuroestrogen may inhibit male socio-sexual behavior

Comparative and Evolutionary Aspects of Gonadotropin-Inhibitory Hormone and FMRFamide-Like Peptide Systems

Gonadotropin-inhibitory hormone (GnIH) is a hypothalamic neuropeptide that was found in the brain of Japanese quail when investigating the existence of RFamide peptides in birds. GnIH was named because it decreased gonadotropin release from cultured anterior pituitary, which was located in the hypothalamo-hypophysial system. GnIH and GnIH precursor gene related peptides have a characteristic C-terminal LPXRFamide (X = L or Q) motif that is conserved in jawed vertebrates. Orthologous peptides to GnIH are also named RFamide related peptide or LPXRFamide peptide from their structure. A G-protein coupled receptor GPR147 is the primary receptor for GnIH. Similarity-based clustering of neuropeptide precursors in metazoan species indicates that GnIH precursor of vertebrates is evolutionarily related to FMRFamide precursor of mollusk and nematode. FMRFamide peptide is the first RFamide peptide that was identified from the ganglia of the venus clam. In order to infer the evolutionary history of the GnIH-GnIH receptor system we investigate the structural similarities between GnIH and its receptor and well-studied nematode Caenorhabditis elegans (C. elegans) FMRFamide-like peptides (FLPs) and their receptors. We also compare the functions of FLPs of nematode with GnIH of chordates. A multiple sequence alignment and phylogenetic analyses of GnIH, neuropeptide FF (NPFF), a paralogous peptide of GnIH, and FLP precursors have shown that GnIH and NPFF precursors belong to different clades and some FLP precursors have structural similarities to either precursor. The peptide coding regions of FLP precursors in the same clade align well with those of GnIH or NPFF precursors. Alignment of GnIH (LPXRFa) peptides of chordates and FLPs of C. elegans grouped the peptides into five groups according to the last C-terminal amino acid sequences, which were MRFa, LRFa, VRFa, IRFa, and PQRFa. Phylogenetic analysis of receptors suggested that GPR147 has evolutionary relationships with FLP receptors, which regulate reproduction, aggression, locomotion, and feeding. GnIH and some FLPs mediate the effect of stress on reproduction and behavior, which may also be a conserved property of these peptide systems. Future studies are needed to investigate the mechanism of how neuropeptide precursor genes are mutated to evolve new neuropeptides and their inheritance

Neuropeptide FF/neuropeptide AF receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

The Neuropeptide FF receptor family contains two subtypes, NPFF1 and NPFF2 (provisional nomenclature [10]), which exhibit high affinities for neuropeptide FF (NPFF, O15130) and RFamide related peptides (RFRP: precursor gene symbol NPVF, Q9HCQ7). NPFF1 is broadly distributed in the central nervous system with the highest levels found in the limbic system and the hypothalamus. NPFF2 is present in high density in the superficial layers of the mammalian spinal cord where it is involved in nociception and modulation of opioid functions

Neuropeptide FF/neuropeptide AF receptors in GtoPdb v.2023.1

The Neuropeptide FF receptor family contains two subtypes, NPFF1 and NPFF2 (provisional nomenclature [12]), which exhibit high affinities for neuropeptide FF (NPFF, O15130) and RFamide related peptides (RFRP: precursor gene symbol NPVF, Q9HCQ7). NPFF1 is broadly distributed in the central nervous system with the highest levels found in the limbic system and the hypothalamus. NPFF2 is present in high density in the superficial layers of the mammalian spinal cord where it is involved in nociception and modulation of opioid functions

Molecular Mechanisms of Gonadotropin-Inhibitory Hormone (GnIH) Actions in Target Cells and Regulation of GnIH Expression

Since gonadotropin-inhibitory hormone (GnIH) was discovered in 2000 as the first hypothalamic neuropeptide that actively inhibits gonadotropin release, researches conducted for the last 18 years have demonstrated that GnIH acts as a pronounced negative regulator of reproduction. Inhibitory effect of GnIH on reproduction is mainly accomplished at hypothalamic-pituitary levels; gonadotropin-releasing hormone (GnRH) neurons and gonadotropes are major targets of GnIH action based on the morphological interaction with GnIH neuronal fibers and the distribution of GnIH receptor. Here, we review molecular studies mainly focusing on the signal transduction pathway of GnIH in target cells, GnRH neurons, and gonadotropes. The use of well-defined cellular model systems allows the mechanistic study of signaling pathway occurring in target cells by demonstrating the direct cause-and-effect relationship. The insights gained through studying molecular mechanism of GnIH action contribute to deeper understanding of the mechanism of how GnIH communicates with other neuronal signaling systems to control our reproductive function. Reproductive axis closely interacts with other endocrine systems, thus GnIH expression levels would be changed by adrenal and thyroid status. We also briefly review molecular studies investigating the regulatory mechanisms of GnIH expression to understand the role of GnIH as a mediator between adrenal, thyroid and gonadal axes

Gonadotropin-inhibitory hormone inhibits GnRH-induced gonadotropin subunit gene transcriptions by inhibiting AC/cAMP/PKA-dependent ERK pathway in LβT2 cells

A neuropeptide that directly inhibits gonadotropin secretion from the pituitary was discovered in quail and named gonadotropin-inhibitory hormone (GnIH). The presence and functional roles of GnIH orthologs, RF-amide-related peptides (RFRP), that possess acommonC-terminal LPXRF-amide (X L or Q) motif have also been demonstrated in mammals. GnIH orthologs inhibit gonadotropin synthesis and release by acting on pituitary gonadotropes and GnRH neurons in the hypothalamus via its receptor (GnIH receptor). It is becoming increasingly clear that GnIH is an important hypothalamic neuropeptide controlling reproduction, but the detailed signaling pathway mediating the inhibitory effect of GnIH on target cells is still unknown. In the present study, we investigated the pathway of GnIH cell signaling and its possible interaction with GnRH signaling using a mouse gonadotrope cell line, LβT2 . First, we demonstrated the expression of GnIH receptormRNAin L T2 cells by RT-PCR. We then examined the inhibitory effects of mouse GnIH orthologs [mouse RFRP (mRFRP)] on GnRH-induced cell signaling events. We showed that mRFRP effectively inhibited GnRH-induced cAMP signaling by using a cAMP-sensitive reporter system and measuring cAMP levels, indicating that mRFRP function as an inhibitor of adenylate cyclase.Wefurther showed that mRFRP inhibited GnRH-stimulated ERK phosphorylation, and this effect was mediated by the inhibition of the protein kinase A pathway. Finally, we demonstrated that mRFRP inhibited GnRH stimulated gonadotropin subunit gene transcriptions and also LH release. Taken together, the results indicate that mRFRP function as GnIH to inhibit GnRH-induced gonadotropin subunit gene transcriptions by inhibiting adenylate cyclase/cAMP/protein kinase A-dependent ERK activation in LβT2 cells.http://endo.endojournals.orgnf201

RNA interference of gonadotropin-inhibitory hormone gene induces arousal in songbirds.

Gonadotropin-inhibitory hormone (GnIH) was originally identified in quail as a hypothalamic neuropeptide inhibitor of pituitary gonadotropin synthesis and release. However, GnIH neuronal fibers do not only terminate in the median eminence to control anterior pituitary function but also extend widely in the brain, suggesting it has multiple roles in the regulation of behavior. To identify the role of GnIH neurons in the regulation of behavior, we investigated the effect of RNA interference (RNAi) of the GnIH gene on the behavior of white-crowned sparrows, a highly social songbird species. Administration of small interfering RNA against GnIH precursor mRNA into the third ventricle of male and female birds reduced resting time, spontaneous production of complex vocalizations, and stimulated brief agonistic vocalizations. GnIH RNAi further enhanced song production of short duration in male birds when they were challenged by playbacks of novel male songs. These behaviors resembled those of breeding birds during territorial defense. The overall results suggest that GnIH gene silencing induces arousal. In addition, the activities of male and female birds were negatively correlated with GnIH mRNA expression in the paraventricular nucleus. Density of GnIH neuronal fibers in the ventral tegmental area was decreased by GnIH RNAi treatment in female birds, and the number of gonadotropin-releasing hormone neurons that received close appositions of GnIH neuronal fiber terminals was negatively correlated with the activity of male birds. In summary, GnIH may decrease arousal level resulting in the inhibition of specific motivated behavior such as in reproductive contexts

Identification of Human GnIH Homologs, RFRP-1 and RFRP-3, and the Cognate Receptor, GPR147 in the Human Hypothalamic Pituitary Axis

The existence of a hypothalamic gonadotropin-inhibiting system has been elusive. A neuropeptide named gonadotropin-inhibitory hormone (GnIH, SIKPSAYLPLRF-NH2) which directly inhibits gonadotropin synthesis and release from the pituitary was recently identified in quail hypothalamus. Here we identify GnIH homologs in the human hypothalamus and characterize their distribution and biological activity. GnIH homologs were isolated from the human hypothalamus by immunoaffinity purification, and then identified as MPHSFANLPLRF-NH2 (human RFRP-1) and VPNLPQRF-NH2 (human RFRP-3) by mass spectrometry. Immunocytochemistry revealed GnIH-immunoreactive neuronal cell bodies in the dorsomedial region of the hypothalamus with axonal projections to GnRH neurons in the preoptic area as well as to the median eminence. RT-PCR and subsequent DNA sequencing of the PCR products identified human GnIH receptor (GPR147) mRNA expression in the hypothalamus as well as in the pituitary. In situ hybridization further identified the expression of GPR147 mRNA in luteinizing hormone producing cells (gonadotropes). Human RFRP-3 has recently been shown to be a potent inhibitor of gonadotropin secretion in cultured sheep pituitary cells by inhibiting Ca2+ mobilization. It also directly modulates GnRH neuron firing. The identification of two forms of GnIH (RFRP-1 and RFRP-3) in the human hypothalamus which targets human GnRH neurons and gonadotropes and potently inhibit gonadotropin in sheep models provides a new paradigm for the regulation of hypothalamic-pituitary-gonadal axis in man and a novel means for manipulating reproductive functions