New Gatekeepers of Reproduction: GPR54 and Its Cognate Ligand, KiSS-1
About: This article is published in Endocrinology.The article was published on 2005-04-01 and is currently open access. It has received 60 citations till now.
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TL;DR: The poorly understood role of KiSS1 in response to chemotherapeutic agents appears to be linked to stimulation of the intrinsic apoptotic pathway and inhibition of cell defense factors as well as autophagy modulation.
19 citations
TL;DR: P KiSS-1 gene is a strong candidate gene that affects litter size in goats and the SNPs loci were in Hardy–Weinberg disequilibrium in three goat breeds.
15 citations
TL;DR: It is concluded thatkisspeptin has no role in testicular regulation related to testosterone and inhibin release but kisspeptin may have other roles intesticular regulation.
Abstract: Summary
Kisspeptin expression has been found in gonads but a direct role of kisspeptin in reproduction is not known. The objective of this study was to find a dose and time related effect of kisspeptin on testicular hormones secretion of adult male rhesus monkey (n = 5). Kisspeptin (1, 10, 100, 1000 pm) was incubated to a culture of testes (100 mg fragments) of male rhesus monkey and medium for hormone (testosterone and inhibin) measurement was collected after 30, 60 and 120 min. 10 IU hCG (180 min) and 50 ng FSH (60 and 120 min) were incubated to the culture for checking testicular cells ability to secrete hormones in vitro. Kisspeptin did not significantly (P < 0.05) increase the testosterone and inhibin levels at any dose. However, one way anova at pooled doses showed an increase in testosterone levels and paired t-test at pooled doses showed inhibin decrease after 120 min of incubation suggesting an independent effect of time. hCG and FSH significantly (P < 0.05) increased hormone concentration compared to the basal groups. We concluded that kisspeptin has no role in testicular regulation related to testosterone and inhibin release but kisspeptin may have other roles in testicular regulation.
15 citations
Cites background from "New Gatekeepers of Reproduction: GP..."
...Thus, our data suggest that although Kiss1r is present in the testis of adult monkey but more probably involved in other kisspeptin actions which may not be directly related to testosterone and inhibin secretion....
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...Kisspeptin act through G protein-coupled receptor (Kiss1r) (Lee et al., 1999; Kotani et al., 2001; Muir et al., 2001; Ohtaki et al., 2001)....
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...These results of lack of effect of kisspeptin on testosterone release are in accordance with our expression analysis where we did not find any expression of Kiss1r in the Leydig cells....
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...Continuous peripheral administration of kisspeptins to monkeys and rodents desensitised the Kiss1r (Seminara & Kaiser, 2005; Thompson et al., 2006; Ramaswamy et al., 2008)....
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...Kiss1/Kiss1r system is not only involved in signalling cascades at central level but has also been evidenced to play role in peripheral organs (neocortex of foetal adrenals, pancreatic islet endocrine cells as well (Nakamura et al., 2007; Hauge-Evans et al., 2006)....
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TL;DR: The existence and distribution of kisspeptin-like peptides (Kiss-l) and their receptors in the central nervous system (CNS) of the giant freshwater prawn, Macrobrachium rosenbergii, and that these peptides could induce the oogonial proliferation, ovarian maturation, and spawning are demonstrated.
12 citations
References
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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: Stimulation of oxytocin secretion after kisspeptin administration to rats confirmed this hypothesis that human GPR54 was highly expressed in placenta, pituitary, pancreas, and spinal cord, suggesting a role in the regulation of endocrine function.
1,431 citations
TL;DR: It is shown that KiSS-1 encodes a carboxy-terminally amidated peptide with 54 amino-acid residues, which is isolated from human placenta as the endogenous ligand of an orphan G-protein-coupled receptor (hOT7T175) and named ‘metastin’.
Abstract: Metastasis is a major cause of death in cancer patients and involves a multistep process including detachment of cancer cells from a primary cancer, invasion of surrounding tissue, spread through circulation, re-invasion and proliferation in distant organs. KiSS-1 is a human metastasis suppressor gene1, that suppresses metastases of human melanomas2 and breast carcinomas3 without affecting tumorigenicity. However, its gene product and functional mechanisms have not been elucidated. Here we show that KiSS-1 (refs 1, 4) encodes a carboxy-terminally amidated peptide with 54 amino-acid residues, which we have isolated from human placenta as the endogenous ligand of an orphan G-protein-coupled receptor (hOT7T175) and have named ‘metastin’. Metastin inhibits chemotaxis and invasion of hOT7T175-transfected CHO cells in vitro and attenuates pulmonary metastasis of hOT7T175-transfected B16-BL6 melanomas in vivo. The results suggest possible mechanisms of action for KiSS-1 and a potential new therapeutic approach.
1,355 citations
TL;DR: Kisspeptins are products of the KiSS-1 gene, which bind to a G protein-coupled receptor known as GPR54, and it is concluded that kisspeptin-GPR54 signaling may be part of the hypothalamus circuitry that governs the hypothalamic secretion of GnRH.
Abstract: Kisspeptins are products of the KiSS-1 gene, which bind to a G protein-coupled receptor known as GPR54. Mutations or targeted disruptions in the GPR54 gene cause hypogonadotropic hypogonadism in humans and mice, suggesting that kisspeptin signaling may be important for the regulation of gonadotropin secretion. To examine the effects of kisspeptin-54 (metastin) and kisspeptin-10 (the biologically active C-terminal decapeptide) on gonadotropin secretion in the mouse, we administered the kisspeptins directly into the lateral cerebral ventricle of the brain and demonstrated that both peptides stimulate LH secretion. Further characterization of kisspeptin-54 demonstrated that it stimulated both LH and FSH secretion, at doses as low as 1 fmol; moreover, this effect was shown to be blocked by pretreatment with acyline, a potent GnRH antagonist. To learn more about the functional anatomy of kisspeptins, we mapped the distribution of KiSS-1 mRNA in the hypothalamus. We observed that KiSS-1 mRNA is expressed in areas of the hypothalamus implicated in the neuroendocrine regulation of gonadotropin secretion, including the anteroventral periventricular nucleus, the periventricular nucleus, and the arcuate nucleus. We conclude that kisspeptin-GPR54 signaling may be part of the hypothalamic circuitry that governs the hypothalamic secretion of GnRH.
1,090 citations