Ontogeny and mechanisms of action for the stimulatory effect of kisspeptin on gonadotropin-releasing hormone system of the rat.
TL;DR: The present data document the ontogeny, sensitivity and intracellular signals for the stimulatory action of kisspeptin on the GnRH/LH axis in the rat and stress the essential role ofkisspeptin in normal, and eventually pathological, timing of puberty.
About: This article is published in Molecular and Cellular Endocrinology.The article was published on 2006-09-26. It has received 173 citations till now. The article focuses on the topics: Kisspeptin & Gonadotropin-releasing hormone.
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TL;DR: Kisspeptin signaling in the brain has been implicated in mediating the negative feedback action of sex steroids on gonadotropin secretion, generating the preovulatory GnRH/LH surge, triggering and guiding the tempo of sexual maturation at puberty, controlling seasonal reproduction, and restraining reproductive activity during lactation.
Abstract: Kisspeptin (a product of the Kiss1 gene) and its receptor (GPR54 or Kiss1r) have emerged as key players in the regulation of reproduction. Mutations in humans or genetically targeted deletions in mice of either Kiss1 or Kiss1r cause profound hypogonadotropic hypogonadism. Neurons that express Kiss1/kisspeptin are found in discrete nuclei in the hypothalamus, as well as other brain regions in many vertebrates, and their distribution, regulation, and function varies widely across species. Kisspeptin neurons directly innervate and stimulate GnRH neurons, which are the final common pathway through which the brain regulates reproduction. Kisspeptin neurons are sexually differentiated with respect to cell number and transcriptional activity in certain brain nuclei, and some kisspeptin neurons express other cotransmitters, including dynorphin and neurokinin B (whose physiological significance is unknown). Kisspeptin neurons express the estrogen receptor and the androgen receptor, and these cells are direct targets for the action of gonadal steroids in both male and female animals. Kisspeptin signaling in the brain has been implicated in mediating the negative feedback action of sex steroids on gonadotropin secretion, generating the preovulatory GnRH/LH surge, triggering and guiding the tempo of sexual maturation at puberty, controlling seasonal reproduction, and restraining reproductive activity during lactation. Kisspeptin signaling may also serve diverse functions outside of the classical realm of reproductive neuroendocrinology, including the regulation of metastasis in certain cancers, vascular dynamics, placental physiology, and perhaps even higher-order brain function.
761 citations
Cites background from "Ontogeny and mechanisms of action f..."
...Additionally, Kiss1r has been shown to stimulate arachidonic acid release and ERK1/2 and p38 activation, as well as Rho activation, which causes stress fiber formation (2, 20)....
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TL;DR: This review aims to provide a comprehensive account of the state-of-the-art in the field of kisspeptin physiology by covering in-depth the consensus knowledge on the major molecular features, biological effects, and mechanisms of action ofkisspeptins in mammals and, to a lesser extent, in nonmammalian vertebrates.
Abstract: Procreation is essential for survival of species. Not surprisingly, complex neuronal networks have evolved to mediate the diverse internal and external environmental inputs that regulate reproduction in vertebrates. Ultimately, these regulatory factors impinge, directly or indirectly, on a final common pathway, the neurons producing the gonadotropin-releasing hormone (GnRH), which stimulates pituitary gonadotropin secretion and thereby gonadal function. Compelling evidence, accumulated in the last few years, has revealed that kisspeptins, a family of neuropeptides encoded by the Kiss1 gene and produced mainly by neuronal clusters at discrete hypothalamic nuclei, are pivotal upstream regulators of GnRH neurons. As such, kisspeptins have emerged as important gatekeepers of key aspects of reproductive maturation and function, from sexual differentiation of the brain and puberty onset to adult regulation of gonadotropin secretion and the metabolic control of fertility. This review aims to provide a comprehensive account of the state-of-the-art in the field of kisspeptin physiology by covering in-depth the consensus knowledge on the major molecular features, biological effects, and mechanisms of action of kisspeptins in mammals and, to a lesser extent, in nonmammalian vertebrates. This review will also address unsolved and contentious issues to set the scene for future research challenges in the area. By doing so, we aim to endow the reader with a critical and updated view of the physiological roles and potential translational relevance of kisspeptins in the integral control of reproductive function.
614 citations
Cites background from "Ontogeny and mechanisms of action f..."
...As a whole, the pharmacological studies conducted so far strongly suggest that kisspeptins are able to elicit LH and FSH secretion both in males and females (101, 102, 299, 300), an effect that is already detected at early stages of postnatal development, including the infantile and/or juvenile periods in the rat, mouse, and monkey, although in the latter, only the juvenile phase has been tested (57, 161, 349)....
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...In good agreement, the sensitivity to the stimulatory effects of kisspeptin, in terms of LH responses in vivo, augments significantly during pubertal maturation, in both rats and mice (57, 161)....
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...For example, initial studies in CHO-K1 cells stably expressing GPR54 demonstrated sustained phosphorylation of ERK1 and ERK2, together with weaker stimulation of p38 MAPK phosphorylation following exposure to kisspeptin, whereas no activation was observed for stress- activated protein kinase/c-Jun-terminal kinase (JNK) (228)....
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...Notably, ontogenic analyses of GnRH and LH responses to exogenous Kp-10 in male and female rats conclusively demonstrated that, albeit with lower sensitivity, the gonadotropic system is fully capable to robustly respond to kisspeptin even at early (infantile) stages of postnatal maturation (57)....
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...In this context, analyses using hypothalamic explants suggested that the stimulatory effects of kisspeptins in this tissue are mediated via both ERK1/2 and p38 MAPK (57)....
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TL;DR: Novel aspects of kisspeptin/GPR54 physiology have emerged, including their involvement in the neuroendocrine control of ovulation and the metabolic gating of reproductive function.
321 citations
TL;DR: Electrophysiology and calcium imaging studies indicate that kisspeptin activates G protein-coupled receptor 54 (GPR54) to initiate a PLC-IP3R-calcium cascade that modulates both potassium and NSC channels to initiate depolarization in GnRH neurons.
Abstract: The present study used perforated-patch electrophysiology and calcium imaging in GnRH transgenic mouse lines to determine the mechanisms underlying the potent excitatory effects of kisspeptin upon GnRH neurons in the acute brain slice preparation. Kisspeptin (100 nm) depolarized (6 ± 1 mV) and/or evoked an 87 ± 4% increase in firing rate of 75% of adult GnRH neurons (n = 51). No sex differences were found. Analyses of input resistance and current-voltage curves indicated that a heterogeneous closure of potassium channels and opening of nonselective cation (NSC) channels was involved in kisspeptin’s depolarizing response. Pharmacological pretreatment with either barium, a potassium channel blocker, or flufenamic acid, an NSC channel antagonist, reduced the percentage of responding GnRH neurons from 75 to 40% (P < 0.05). Pretreatment with both barium and flufenamic acid reduced the response rate to 17% (P < 0.05). To examine the intracellular signaling cascade involved, GnRH neurons were treated with antago...
248 citations
TL;DR: It appears that kisspeptin depolarizes GnRH neurons through activating TRPC-like channels and, to a lesser extent, inhibition of Kir channels, which contribute to the pronounced excitation of Gn RH neurons that is critical for mammalian reproduction.
Abstract: Kisspeptin and its cognate receptor, GPR54, are critical for reproductive development and for the regulation of gonadotropin-releasing hormone (GnRH) secretion. Although kisspeptin has been found to depolarize GnRH neurons, the underlying ionic mechanism has not been elucidated. Presently, we found that kisspeptin depolarized GnRH neurons in a concentration-dependent manner with a maximum depolarization of 22.6 +/- 0.6 mV and EC(50) of 2.8 +/- 0.2 nM. Under voltage-clamp conditions, kisspeptin induced an inward current of 18.2 +/- 1.6 pA (V(hold) = -60 mV) that reversed near -115 mV in GnRH neurons. The more negative reversal potential than E(K)(+) (-90 mV) was caused by the concurrent inhibition of barium-sensitive, inwardly rectifying (Kir) potassium channels and activation of sodium-dependent, nonselective cationic channels (NSCCs). Indeed, reducing extracellular Na(+) (to 5 mM) essentially eliminated the kisspeptin-induced inward current. The current-voltage relationships of the kisspeptin-activated NSCC currents exhibited double rectification with negative slope conductance below -40 mV in the majority of the cells. Pharmacological examination showed that the kisspeptin-induced inward currents were blocked by TRPC (canonical transient receptor potential) channel blockers 2-APB (2-aminoethyl diphenylborinate), flufenamic acid, SKF96365 (1-[beta-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenethyl]-1H-imidazole hydrochloride), and Cd(2+), but not by lanthanum (100 microM). Furthermore, single-cell reverse transcription-PCR analysis revealed that TRPC1, TRPC3, TRPC4, TRPC5, TRPC6, and TRPC7 subunits were expressed in GnRH neurons. Therefore, it appears that kisspeptin depolarizes GnRH neurons through activating TRPC-like channels and, to a lesser extent, inhibition of Kir channels. These actions of kisspeptin contribute to the pronounced excitation of GnRH neurons that is critical for mammalian reproduction.
228 citations
Cites background from "Ontogeny and mechanisms of action f..."
...Moreover, these signaling pathways appear to be necessary for kisspeptin10-stimulated GnRH secretion in rat hypothalamic explants (Castellano et al., 2006)....
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References
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Book•
15 Jan 1994
TL;DR: The gametes, fertilization and early embryogenesis the reproductive systems - the female, the male the pituitary and the hypothalmus, and the reproductive processes and their control.
Abstract: Volume 1: The gametes, fertilization and early embryogenesis the reproductive systems - the female, the male the pituitary and the hypothalmus. Volume 2: Reproductive behaviour and its control reproductive processes and their control.
7,667 citations
TL;DR: SP600125 blocked (bacterial) lipopolysaccharide-induced expression of tumor necrosis factor-α and inhibited anti-CD3-induced apoptosis of CD4+ CD8+ thymocytes and supports targeting JNK as an important strategy in inflammatory disease, apoptotic cell death, and cancer.
Abstract: Jun N-terminal kinase (JNK) is a stress-activated protein kinase that can be induced by inflammatory cytokines, bacterial endotoxin, osmotic shock, UV radiation, and hypoxia. We report the identification of an anthrapyrazolone series with significant inhibition of JNK1, -2, and -3 (Ki = 0.19 μM). SP600125 is a reversible ATP-competitive inhibitor with >20-fold selectivity vs. a range of kinases and enzymes tested. In cells, SP600125 dose dependently inhibited the phosphorylation of c-Jun, the expression of inflammatory genes COX-2, IL-2, IFN-γ, TNF-α, and prevented the activation and differentiation of primary human CD4 cell cultures. In animal studies, SP600125 blocked (bacterial) lipopolysaccharide-induced expression of tumor necrosis factor-α and inhibited anti-CD3-induced apoptosis of CD4+ CD8+ thymocytes. Our study supports targeting JNK as an important strategy in inflammatory disease, apoptotic cell death, and cancer.
2,460 citations
TL;DR: Puberty is initiated when gonadotropin-releasing hormone begins to be secreted by the hypothalamus, and complementary genetic approaches in humans and mice identified genetic factors that determine the onset of puberty.
Abstract: Background Puberty, a complex biologic process involving sexual development, accelerated linear growth, and adrenal maturation, is initiated when gonadotropin-releasing hormone begins to be secreted by the hypothalamus. We conducted studies in humans and mice to identify the genetic factors that determine the onset of puberty. Methods We used complementary genetic approaches in humans and in mice. A consanguineous family with members who lacked pubertal development (idiopathic hypogonadotropic hypogonadism) was examined for mutations in a candidate gene, GPR54, which encodes a G protein–coupled receptor. Functional differences between wild-type and mutant GPR54 were examined in vitro. In parallel, a Gpr54-deficient mouse model was created and phenotyped. Responsiveness to exogenous gonadotropin-releasing hormone was assessed in both the humans and the mice. Results Affected patients in the index pedigree were homozygous for an L148S mutation in GPR54, and an unrelated proband with idiopathic hypogonadotro...
2,253 citations
TL;DR: The present study shows that loss of function of GPR54 is a cause of IHH, and it identifies GPR 54 and possibly KiSS1 protein-derived peptide as playing a major and previously unsuspected role in the physiology of the gonadotropic axis.
Abstract: Hypogonadotropic hypogonadism is defined as a deficiency of the pituitary secretion of follicle-stimulating hormone and luteinizing hormone, which results in the impairment of pubertal maturation and of reproductive function. In the absence of pituitary or hypothalamic anatomical lesions and of anosmia (Kallmann syndrome), hypogonadotropic hypogonadism is referred to as isolated hypogonadotropic hypogonadism (IHH). A limited number of IHH cases are due to loss-of-function mutations of the gonadotropin-releasing hormone receptor. To identify additional gene defects leading to IHH, a large consanguineous family with five affected siblings and with a normal gonadotropin-releasing hormone receptor coding sequence was studied. Homozygosity whole-genome mapping allowed the localization of a new locus within the short arm of chromosome 19 (19p13). Sequencing of several genes localized within this region showed that all affected siblings of the family carried a homozygous deletion of 155 nucleotides in the GPR54 gene. This deletion encompassed the splicing acceptor site of intron 4-exon 5 junction and part of exon 5. The deletion was absent or present on only one allele in unaffected family members. GPR54 has been initially identified as an orphan G protein-coupled receptor with 40% homology to galanin receptors. Recently, a 54-aa peptide derived from the KiSS1 protein was identified as a ligand of GPR54. The present study shows that loss of function of GPR54 is a cause of IHH, and it identifies GPR54 and possibly KiSS1 protein-derived peptide as playing a major and previously unsuspected role in the physiology of the gonadotropic axis.
2,147 citations
TL;DR: It is established that MAPKAP kinase‐2 is a physiological RK substrate, and that HSP27 is phosphorylated by MAPK AP kinase-2 in vivo.
2,097 citations