Peptides (v.30, #1)

Editorial by Manuel Tena-Sempere; Hubert Vaudry (1-3).

From KISS1 to kisspeptins: An historical perspective and suggested nomenclature by Michelle L. Gottsch; Donald K. Clifton; Robert A. Steiner (4-9).
The cancer suppressor gene, KISS1, was initially described as having an important role in inhibiting cancer metastasis. Since then, KISS1 and its receptor, KISS1R, have been shown to play a key role in controlling the onset of puberty of reproductive physiology in the human and other species. Recent studies have also linked KISS1/kisspeptin/KISS1R to other processes, such as vasoconstriction, aging, adipocyte physiology, and perhaps as a molecular conduit linking metabolism and reproduction. This article highlights the history of KISS1/kisspeptin/KISS1R biology and proposes a consensus for nomenclature of the key molecules in this signaling pathway.
Keywords: KISS1; Kisspeptin; Kisspeptin receptor; Metastin;

Intracellular signaling pathways activated by kisspeptins through GPR54: Do multiple signals underlie function diversity? by Justo P. Castaño; Antonio J. Martínez-Fuentes; Ester Gutiérrez-Pascual; Hubert Vaudry; Manuel Tena-Sempere; María M. Malagón (10-15).
Kisspeptins, a family of peptide products derived from the KiSS-1 gene, activate their cognate receptor GPR54 in various target tissues to exert disparate functions, including inhibition of tumor metastasis and control of reproductive function. In contrast to the plethora of studies that have analyzed in recent years the regulatory functions of the KiSS-1/GPR54 system, only a limited number of reports have been primarily focused on delineating the intracellular signaling pathways involved. Nevertheless, there is solid evidence indicating that kisspeptin can activate a wide variety of signals via GPR54. These include typical G-protein (Gαq/11)-coupled cascades, such as activation of phospholipase C (PLC), and subsequent accumulation of inositol-(1,4,5)-triphosphate (IP3), intracellular Ca2+ mobilization, and activation of protein kinase C. However, kisspeptin also activates pathways related to mitogen activated protein kinases (MAPK), especially ERK1/2, and p38 and phosphatidylinositol-3-kinase (PI3K)/Akt. Additionally, the kisspeptin/GPR54 pair can also influence cell signaling by interacting with other receptors, such as chemokine receptor CXCR4, and GnRH receptor. Kisspeptin can also affect other signaling events, like expression of matrix metalloproteinase 9 (via NFκB), and that of calcineurin. The information gathered hitherto clearly indicates that activation of a specific set of interconnected signals is selectively triggered by kisspeptin via GPR54 in a cell type-dependent manner to precisely regulate functions as distinct as hormone release and cell migration. In this scenario, it will be important to decipher kisspeptin/GPR54 signaling mechanisms in reproductive and non-reproductive tissues by studying additional models, especially on natural kisspeptin targets expressing endogenous GPR54.
Keywords: KiSS-1; Kisspeptin; Metastin; GPR54; Signaling; Ca2+; MAPK;

The granule cells of the dentate gyrus form the input stage of the hippocampal trisynaptic circuit and their function is strongly influenced by peptidergic systems. GPR54 is highly and discretely expressed in these cells. We have found that activation of GPR54 with kisspeptin-10 causes a rapid and large increase in the amplitude of excitatory synaptic responses in granule cells, without changing membrane properties. The effect was suppressed by the G-protein inhibitor GDP-β-S and the calcium chelator BAPTA, and analysis of miniature EPSCs revealed an increase in mean amplitude but not event frequency, indicating that GPR54 and the mechanisms for enhancing EPSCs are postsynaptic, possibly involving changes in AMPA receptor number or conductance. The kisspeptin-induced synaptic potentiation was abolished by inhibitors of ERK1/2, tyrosine kinase, and CaMKII. RT-PCR experiments showed that KiSS-1 is expressed in the dentate gyrus. KiSS-1 mRNA was significantly increased by seizure activity in rats and when neuronal activity in organotypic hippocampal slice cultures was enhanced by kainate or picrotoxin, while mRNA for GPR54 remained essentially unchanged. These results suggest that kisspeptin may be locally synthesized and act as an autocrine factor. In separate experiments, hippocampal KiSS-1 mRNA in male rats was increased after gonadectomy. In summary, kisspeptin is a novel endogenous factor which is dynamically regulated by neuronal activity and which, in marked distinction from other neuropeptides, increases synaptic transmission in dentate granule cells through signaling cascades possibly linked to the MAP kinase system. This novel peptide system may play a role in cognition and in the pathogenesis of epilepsy.
Keywords: Dentate gyrus; EPSC; Excitatory synaptic transmission; KiSS-1; Gene expression;

The neuroanatomy of the kisspeptin system in the mammalian brain by Jens D. Mikkelsen; Valerie Simonneaux (26-33).
The kisspeptin precursor is the protein transcribed from the Kiss-1 gene and the kisspeptins are the peptides that are posttranslationally processed from the precursor. The kisspeptins activate the G-protein coupled receptor GPR54 and are strongly implicated in puberty onset and in regulation of the hypothalamo–pituitary gonadal axis in mammals. Physiological studies have indicated that these effects occur via a direct activation of the GnRH neurons, and at an unknown site in the median eminence or directly on the gonadotropes. Paradoxically, while the function of kisspeptin is relatively well understood, little data are available about the localization of kisspeptin neurons in the brain, and in particular the projection patterns of kisspeptin containing axons implicated in regulation of the hypothalamo–pituitary gonadal axis. This review covers the current information about the localization of kisspeptin neurons in the mammalian brain and discusses the facts and artifacts of the methods of their detection. The available data suggest that kisspeptins are synthesized in neurons in the anteroventral periventricular nucleus and the arcuate nucleus. Both populations are considered to be involved in control of gonadotropes. In addition, kisspeptin nerve terminals and receptors are found in other hypothalamic area suggesting that kisspeptins are involved in regulation of other yet unknown homeostatic or neuroendocrine functions.
Keywords: Arcuate nucleus; AVPV; Puberty; Immunohistochemistry; Metastin; RFRP;

Four transgenic mouse lines have been generated with mutations in the Gpr54 gene and two lines with mutations in the Kiss1 gene. In general, the phenotypes of all these mutant mice are very similar and provide evidence that these molecules constitute an authentic receptor/ligand pair with no obvious redundancy or overlap with other signaling pathways. The mutant mice all fail to undergo pubertal maturation and show poor development of the gonads and infertility with low sex steroid and gonadotrophic hormone levels (hypogonadotrophic hypogonadism). Spermatogenesis and ovulation are severely impaired and mutant females do not show estrous cycling. The gonads and the anterior pituitary retain functional responses to hormonal stimulation however, consistent with the primary defect being a failure to secrete gonadotrophin releasing hormone (GnRH) from the hypothalamus. Slight differences between the phenotype of some of the mutant lines may reflect the type of mutation carried by each line. These mutant mice are being used to interrogate the function of Gpr54 and Kiss1 in key aspects of mammalian reproduction in vivo including the role of these proteins in the generation of the pre-ovulatory luteinizing hormone (LH) surge and aspects of sexual behavior. They provide a useful resource to further understand the hypothalamic regulation of mammalian reproduction, its integration with the pituitary–gonadal axis and to study the potential function of Gpr54 and Kiss1 in peripheral tissues.
Keywords: Transgenic mice; Hypogonadotrophic hypogonadism; Gpr54; Kiss1;

Reproductive functions of kisspeptin and Gpr54 across the life cycle of mice and men by Yee-Ming Chan; Sarabeth Broder-Fingert; Stephanie B. Seminara (42-48).
The reproductive phenotypes of nearly two dozen patients with mutations in GPR54 have been reported, as have the phenotypes of four mouse lines mutant for Gpr54 and two lines mutant for Kiss1. These phenotypes demonstrate that kisspeptin/Gpr54 function is required at all phases of the life cycle when the secretion of gonadotropin-releasing hormone (GnRH) is robust. Furthermore, there is phenotypic variability ranging from severe hypogonadism to partial sexual development. Collectively, these findings suggest that kisspeptin and Gpr54 serve as an essential conduit for relaying developmental information to the GnRH neuron.
Keywords: GPR54; KISS1; Kisspeptin; Reproduction; Idiopathic hypogonadotropic hypogonadism;

Physiological role of metastin/kisspeptin in regulating gonadotropin-releasing hormone (GnRH) secretion in female rats by Satoshi Ohkura; Yoshihisa Uenoyama; Shunji Yamada; Tamami Homma; Kenji Takase; Naoko Inoue; Kei-ichiro Maeda; Hiroko Tsukamura (49-56).
Various studies have attempted to unravel the physiological role of metastin/kisspeptin in the control of gonadotropin-releasing hormone (GnRH) release. A number of evidences suggested that the population of metastin/kisspeptin neurons in the anteroventral periventricular nucleus (AVPV) is involved in generating a GnRH surge to induce ovulation in rodents, and thus the target of estrogen positive feedback. Females have an obvious metastin/kisspeptin neuronal population in the AVPV, but males have only a few cell bodies in the nucleus, suggesting that the absence of the surge-generating mechanism or positive feedback action in males is due to the limited AVPV metastin/kisspeptin neuronal population. On the other hand, the arcuate nucleus (ARC) metastin/kisspeptin neuronal population is considered to be involved in the regulation of tonic GnRH release. The ARC metastin/kisspeptin neurons show no sex difference in their expression, which is suppressed by gonadal steroids in both sexes. Thus, the ARC population of metastin/kisspeptin neurons is a target of estrogen negative feedback action on tonic GnRH release. The lactating rat model provided further evidence indicating that ARC metastin/kisspeptin neurons are involved in GnRH pulse generation, because pulsatile release of luteinizing hormone (LH) is profoundly suppressed by suckling stimulus and the LH pulse suppression is well associated with the suppression of ARC metastin/kisspeptin and KiSS-1 gene expression in lactating rats.
Keywords: Pulse; Surge; Estrous cycle; Estrogen; Lactation; Suckling stimulus;

Kisspeptins and the control of gonadotropin secretion in male and female rodents by J. Roa; J.M. Castellano; V.M. Navarro; D.J. Handelsman; L. Pinilla; M. Tena-Sempere (57-66).
Kisspeptins, the products of KiSS-1 gene acting via G protein-coupled receptor 54 (GPR54), have recently emerged as fundamental gatekeepers of gonadal function by virtue of their ability to stimulate gonadotropin secretion. Indeed, since the original disclosure of the reproductive facet of the KiSS-1/GPR54 system, an ever-growing number of studies have substantiated the extraordinary potency of kisspeptins to elicit gonadotropin secretion in different mammalian species, under different physiologic and experimental conditions, and through different routes of administration. In this context, studies conducted in laboratory rodents have been enormously instrumental to characterize: (i) the primary mechanisms of action of kisspeptins in the control of gonadotropin secretion; (ii) the pharmacological consequences of acute vs. continuous activation of GPR54; (iii) the roles of specific populations of kisspeptin-producing neurons at the hypothalamus in mediating the feedback effects of sex steroids; (v) the function of kisspeptins in the generation of the pre-ovulatory surge of gonadotropins; and (iv) the influence of sex steroids on GnRH/gonadotropin responsiveness to kisspeptins. While some of those aspects of kisspeptin function will be covered elsewhere in this Special Issue, we summarize herein the most salient data, obtained in laboratory rodents, that have helped to define the physiologic roles and putative pharmacological implications of kisspeptins in the control of male and female gonadotropic axis.
Keywords: Kisspeptins; KiSS-1; GPR54; GnRH; Gonadotropins; LH; FSH; Mouse; Rat;

The present article reviews recent studies of monkeys and, in some cases, humans that have been conducted to examine the role of kisspeptin-GPR54 signaling in the regulation of the hypothalamic–pituitary–gonadal axis in higher primates. This area of peptide biology was initiated in 2003 by the discovery that loss of function mutations of GPR54 in man were associated with hypogonadotropic hypogonadism and absent or delayed puberty. Puberty in the monkey, an experimental model commonly used to study this fundamental developmental stage, is first described. This is followed by a review of the role of kisspeptin in the regulation of the postnatal ontogeny of GnRH pulsatility. The roles of kisspeptin in GnRH pulse generation and in the feedback loops governing gonadotropin secretion in primates are then discussed. A brief section on kisspeptin-GPR54 signaling at the pituitary and gonadal levels is also included. The review concludes with a discussion of the phenomenon of GPR54 downregulation by continuous exposure to kisspeptin and its therapeutic implications.
Keywords: Rhesus monkey; Puberty; GnRH pulse generator; Feedback loops; GPR54 downregulation;

Kisspeptins and the control of gonadotropin secretion in humans by C.N. Jayasena; W.S. Dhillo; S.R. Bloom (76-82).
The kisspeptin hormones are a family of peptides encoded by the KiSS-1 gene, which bind to the G-protein coupled receptor-54 (GPR54). Interactions between kisspeptin and GPR54 are thought to play a critical role in reproduction. In agreement with animal data, kisspeptin-54 administration acutely stimulates the release of gonadotrophins in both male and female healthy subjects, with no observed adverse effects. Furthermore, its potency is comparable to those of other gonadotrophin secretagogues studied. The kisspeptin-GPR54 system thus offers a novel means of therapeutically manipulating the hypothalamo-pituitary-gonadal (HPG) axis in humans. This article aims to provide a focused review of the experimental data which inform us how kisspeptin influences the HPG axis in humans.
Keywords: Kisspeptin; Human; GPR54; Gonadotrophin; LH; FSH;

The nervous system (both central and peripheral) is anatomically and physiologically differentiated between the sexes, ranging from gender-based differences in the cerebral cortex to motoneuron number in the spinal cord. Although genetic factors may play a role in the development of some sexually differentiated traits, most identified sex differences in the brain and behavior are produced under the influence of perinatal sex steroid signaling. In many species, the ability to display an estrogen-induced luteinizing hormone (LH) surge is sexually differentiated, yet the specific neural population(s) that allows females but not males to display such estrogen-mediated “positive feedback” has remained elusive. Recently, the Kiss1/kisspeptin system has been implicated in generating the sexually dimorphic circuitry underlying the LH surge. Specifically, Kiss1 gene expression and kisspeptin protein levels in the anteroventral periventricular (AVPV) nucleus of the hypothalamus are sexually differentiated, with females displaying higher levels than males, even under identical hormonal conditions as adults. These findings, in conjunction with accumulating evidence implicating kisspeptins as potent secretagogues of gonadotropin-releasing hormone (GnRH), suggest that the sex-specific display of the LH surge (positive feedback) reflects sexual differentiation of AVPV Kiss1 neurons. In addition, developmental kisspeptin signaling via its receptor GPR54 appears to be critical in males for the proper sexual differentiation of a variety of sexually dimorphic traits, ranging from complex social behavior to specific forebrain and spinal cord neuronal populations. This review discusses the recent data, and their implications, regarding the bi-directional relationship between the Kiss1 system and the process of sexual differentiation.
Keywords: Metastin; Kisspeptin; Kiss1; GPR54; Sexual differentiation; Sex differences; AVPV; Tyrosine hydroxylase; Development;

In recent years, the Kiss1 gene has been cast into the reproductive spotlight. In the short period since the discovered link between kisspeptins, the encoded peptides of Kiss1, and fertility, these peptides are now known to be critical for the neuroendocrine control of reproduction. Kisspeptin producing cells in the hypothalamus are poised to become the ‘missing link’ in the sex steroid feedback control of GnRH secretion. These cells contain all the necessary components to relay information of the sex steroid environment to GnRH neurons, which possess the kisspeptin receptor, GPR54. Sex steroids regulate Kiss1 mRNA, and kisspeptin expression in the hypothalamus, in a manner consistent with both negative and positive feedback control of GnRH. The precise nature of sex steroid effects, in particular those of estrogen, on Kiss1 expression have been extensively studied in the female rodent and ewe. In the arcuate nucleus (ARC) of both species, kisspeptin cells appear to forward signals pertinent to negative feedback regulation of GnRH, although in the ewe it appears this population of Kiss1 cell is also responsible for positive feedback regulation of GnRH at the time of the preovulatory GnRH/LH surge. In rodents, these positive feedback signals appear to be mediated by kisspeptin cells exclusively within the anteroventral periventricular nucleus (AVPV). There are no Kiss1 cells in the ovine AVPV, but there is a population in the preoptic area. The role these preoptic area cells play in the sex steroid feedback regulation of GnRH secretion, if any, is yet to be revealed.
Keywords: KiSS-1; Kiss1; Kisspeptin; Metastin; GPR54; GnRH; Sheep; Reproduction;

The G-protein coupled receptor, GPR54, and its ligand, kisspeptin-54 (a KiSS-1 derived peptide) have been reported to be important players in control of LHRH-1 release. However, the role of the GPR54 signaling in primate reproductive senescence is still unclear. In the present study we investigated whether KiSS-1, GPR54, and LHRH-1 mRNA in the brain change after menopause in female rhesus monkeys using quantitative real-time PCR. Results indicate that KiSS-1, GPR54, and LHRH-1 mRNA levels in the medial basal hypothalamus (MBH) in postmenopausal females (28.3 ± 1.1 years of age, n  = 5) were all significantly higher than that in eugonadal adult females (14.7 ± 2.1 years of age, n  = 9), whereas KiSS-1, GPR54, and LHRH-1 mRNA levels in the preoptic area (POA) did not have any significant changes between the two age groups. To further determine the potential contribution by the absence of ovarian steroids, we compared the changes in KiSS-1, GPR54, and LHRH-1 mRNA levels in young adult ovarian intact vs. young ovariectomized females. Results indicate that KiSS-1 and LHRH-1 mRNA levels in the MBH, not POA, in ovariectomized females were significantly higher than those in ovarian intact females, whereas GPR54 mRNA levels in ovariectomized females had a tendency to be elevated in the MBH, although the values were not quite statistically significant. Collectively, in the primate the reduction in the negative feedback control by ovarian steroids appears to be responsible for the aging changes in kisspeptin-GPR54 signaling and the elevated state of the LHRH-1 neuronal system.
Keywords: LHRH-1 mRNA; KiSS-1 mRNA; GPR54 mRNA; Menopause; Primates;

Menopause is characterized by depletion of ovarian follicles, a reduction of ovarian hormones to castrate levels and elevated levels of serum gonadotropins. Rather than degenerating, the reproductive neuroendocrine axis in postmenopausal women is intact and responds robustly to the removal of ovarian hormones. Studies in both human and non-human primates provide evidence that the gonadotropin hypersecretion in postmenopausal women is secondary to increased gonadotropin-releasing hormone (GnRH) secretion from the hypothalamus. In addition, menopause is accompanied by hypertrophy of neurons in the infundibular (arcuate) nucleus expressing KiSS-1, neurokinin B (NKB), substance P, dynorphin and estrogen receptor α (ERα) mRNA. Ovariectomy in experimental animals induces nearly identical findings, providing evidence that these changes are a compensatory response to ovarian failure. The anatomical site of the hypertrophied neurons, as well as the extensive data implicating kisspeptin, NKB and dynorphin in the regulation of GnRH secretion, provide compelling evidence that these neurons are part of the neural network responsible for the increased levels of serum gonadotropins in postmenopausal women. We propose that neurons expressing KiSS-1, NKB, substance P, dynorphin and ERα mRNA in the infundibular nucleus play an important role in sex-steroid feedback on gonadotropin secretion in the human.
Keywords: Steroid feedback; GnRH; Estrogen; Progesterone; Aging; Reproduction; Pituitary; Ovary;

KiSS-1 and GPR54 at the pituitary level: Overview and recent insights by Nicolas Richard; Sophie Corvaisier; Elise Camacho; Marie-Laure Kottler (123-129).
Since the stimulatory effect of kisspeptin on gonadotropin secretion is blocked by a GnRH antagonist, it has been suggested that the effect of kisspeptin is manifest exclusively at the level of hypothalamic GnRH secretion. However, kisspeptins are present in ovine hypophysial portal blood suggesting that the pituitary gland may be a target of kisspeptin. Dual fluorescence labeling with a specific mouse monoclonal antibody against LHβ demonstrates that KiSS-1 and GPR54 are expressed by the gonadotrophs. Different paradigms were designed in animals and in humans in vivo to elucidate its role. However, in vitro studies assessing the direct stimulatory effects of kisspeptins on gonadotropin secretion in the pituitary have given conflicting results, depending on the hormonal (GnRH and/or estradiol) environment of the cells. Kisspeptins alone seem unable to induce the LH surge. It is therefore likely that kisspeptin has a synergic effect with GnRH and estradiol, at both hypothalamic and pituitary levels. However, kisspeptin may also play another role, distinct from that restricted to the reproductive axis. In this paper, we shall also review data on the potential role of kisspeptin in the control of other pituitary functions, e.g. somatotroph and lactotroph. Finally, kisspeptins could act as endocrine/autocrine/paracrine signals in modulating hormonal secretions of the anterior pituitary.
Keywords: KiSS-1; Kisspeptins; GPR54; Estradiol; GnRH; Gonadotroph; Pituitary;

Regulation of KiSS1 gene expression by Dali Li; Weishi Yu; Mingyao Liu (130-138).
Kisspeptins are the protein products encoded by KiSS1 gene, an important tumor metastatic suppressor and pivotal master hormone of puberty. Although KiSS1 gene is expressed in both central and peripheral tissues, the molecular mechanisms that determine the temporal and spatial expression of KiSS1 gene are not well understood. This review provides an update on the latest studies and ideas about the expression of KiSS1 gene as a puberty gatekeeper and a metastasis suppressor, with special emphasis on the molecular mechanisms for the transcriptional regulation of KiSS1 gene expression.
Keywords: KiSS1; GPR54; Expression; Transcriptional regulation;

KiSS-1/kisspeptins and the metabolic control of reproduction: Physiologic roles and putative physiopathological implications by J.M. Castellano; J. Roa; R.M. Luque; C. Dieguez; E. Aguilar; L. Pinilla; M. Tena-Sempere (139-145).
It is well established that reproductive function is gated by the state of energy reserves of the organism; conditions of metabolic stress and energy insufficiency being frequently coupled to disturbed reproductive maturation and/or infertility. In addition, obesity is also commonly linked to altered puberty onset and reproductive impairment. Such an impact of energy status on the reproductive axis is conveyed through a number of neuropeptide hormones and metabolic cues, whose nature and mechanisms of action have begun to be deciphered only in recent years. In this context, the emergence of kisspeptins, encoded by the KiSS-1 gene, and their receptor, GPR54, as indispensable signals for normal pubertal maturation and gonadal function, has raised the possibility that the KiSS-1/GRP54 system might also participate in coupling body energy status and reproduction. We revise herein the experimental evidence, gathered in rodent models, supporting the contention that the hypothalamic KiSS-1 system operates as a central conduit for conveying metabolic information onto the centers governing reproductive function, through a putative leptin–kisspeptin–GnRH pathway. Admittedly, key aspects of this ‘metabolic’ network involving the KiSS-1 system, such as its different peripheral regulators and central effectors, have not been fully elucidated. Nonetheless, the proposed hypothalamic circuitry, responsible for transmitting metabolic information onto the reproductive axis through KiSS-1 neurons, might explain, at least in part, the mechanisms for the well-known alterations of fertility linked to conditions of disturbed energy balance in humans, from anorexia nervosa to morbid obesity.
Keywords: Kisspeptins; KiSS-1; GPR54; GnRH; gonadotropins; LH; FSH; Energy balance; Body weight; Leptin; Mouse; Rat;

Kisspeptin and the seasonal control of reproduction in hamsters by Valérie Simonneaux; Laura Ansel; Florent G. Revel; Paul Klosen; Paul Pévet; Jens D. Mikkelsen (146-153).
Reproduction is a complex and energy demanding function. When internal and external conditions might impair reproductive success (negative energy balance, stress, harsh season) reproductive activity has to be repressed. Recent evidence suggests that these inhibitory mechanisms operate on Kiss1-expressing neurons, which were recently shown to be implicated in the regulation of GnRH release. Hamsters are seasonal rodents which are sexually active in long photoperiod and quiescent in short photoperiod. The photoperiodic information is transmitted to the reproductive system by melatonin, a pineal hormone whose secretion is adjusted to night length. The photoperiodic variation in circulating melatonin has been shown to synchronize reproductive activity with seasons, but the mechanisms involved in this effect of melatonin were so far unknown. Recently we have observed that Kiss1 mRNA level in the arcuate nucleus of the Syrian hamster is lower in short photoperiod, when animals are sexually quiescent. Notably, intracerebroventricular infusion of Kiss1 gene product, kisspeptin, in hamsters kept in short photoperiod is able to override the inhibitory photoperiod and to reactivate sexual activity. The inhibition of Kiss1 expression in short photoperiod is driven by melatonin because pinealectomy prevents decrease in Kiss1 mRNA level in short photoperiod and melatonin injection in long photoperiod down regulates Kiss1 expression. Whether melatonin acts directly on arcuate Kiss1 expressing neurons or mediates its action via interneurons is the subject of the current investigations.
Keywords: Seasonal reproduction; Photoperiod; Melatonin; Kisspeptin; RFRP;

Kisspeptin and seasonality in sheep by Iain J. Clarke; Jeremy T. Smith; Alain Caraty; Robert L. Goodman; Michael N. Lehman (154-163).
Sheep are seasonal breeders, experiencing a period of reproductive quiescence during spring and early summer. During the non-breeding period, kisspeptin expression in the arcuate nucleus is markedly reduced. This strongly suggests that the mechanisms that control seasonal changes in reproductive function involve kisspeptin neurons. Kisspeptin cells appear to regulate GnRH neurons and transmit sex-steroid feedback to the reproductive axis. Since the non-breeding season is characterized by increased negative feedback of estrogen on GnRH secretion, the kisspeptin neurons seem to be fundamentally involved in the determination of breeding state. The reduction in kisspeptin neuronal function during the non-breeding season can be corrected by infusion of kisspeptin, which causes ovulation in seasonally acyclic females.
Keywords: GnRH; Photoperiod; Estrogen;

The KiSS1/GPR54 system in fish by Abigail Elizur (164-170).
The KiSS1/GPR54 system has now been identified in non-mammalian vertebrates. Transcripts encoding for KiSS1 and its receptor, GPR54, have been isolated from a number of fish species. The expression of their genes was characterized in the context of temporal and spatial expression and in response to endocrine manipulations. GPR54 sequence is conserved between mammals and fish, with a second receptor sequence identified in zebrafish. The KiSS1 gene sequence is highly divergent between mammals and fish, yet the human kisspeptin is capable of activating the fish GPR54. As in mammals, the fish KiSS1/GPR54 system appears to be partially regulated by gonadal steroids. The data available for fish are fragmented, yet indicate that the KiSS1/GPR54 system is functionally conserved in non-mammalian vertebrates and supports the notion that it has a role in pubertal development and reproduction in piscine systems.
Keywords: Fish; KiSS1; GPR54;

Molecular cloning of the bullfrog kisspeptin receptor GPR54 with high sensitivity to Xenopus kisspeptin by Jung Sun Moon; Yeo Reum Lee; Da Young Oh; Jong Ik Hwang; Ju Yeon Lee; Jae Il Kim; Hubert Vaudry; Hyuk Bang Kwon; Jae Young Seong (171-179).
Kisspeptin and its receptor, GPR54, play important roles in mammalian reproduction and cancer development. However, little is known about their function in nonmammalian species. In the present study, we have isolated the cDNA encoding the kisspeptin receptor, GPR54, from the bullfrog, Rana catesbeiana. The bullfrog GPR54 (bfGPR54) cDNA encodes a 379-amino acid heptahelical G protein-coupled receptor. bfGPR54 exhibits 45–46% amino acid identity with mammalian GPR54s and 70–74% identity with fish GPR54s. RT-PCR analysis showed that bfGPR54 mRNA is highly expressed in the forebrain, hypothalamus and pituitary. Upon stimulation by synthetic human kisspeptin-10 with Phe-amide residue at the C-terminus (h-Kiss-10F), bfGPR54 induces SRE-luc activity, a PKC-specific reporter, evidencing the PKC-linked signaling pathway of bfGPR54. Using a blast search, we found a gene encoding a kisspeptin-like peptide in Xenopus. The C-terminal decapeptide of Xenopus kisspeptin shows higher amino acid sequence identity to fish Kiss-10s than mammalian Kiss-10s. A synthetic Xenopus kisspeptin peptide (x-Kiss-12Y) showed a higher potency than mammalian Kiss-10s in the activation of bfGPR54. This study expands our understanding of the physiological roles and molecular evolution of kisspeptins and their receptors.
Keywords: Bullfrog; GPR54; Xenopus; Kisspeptin; Ligand selectivity; Signaling pathway;