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: Recent advances in understanding the roles of KiSS1 and GPR54 in cancer development and metastasis are examined.
Abstract: KiSS1 and its cognate G-protein-coupled receptor, GPR54, have diverse functions. While KiSS1 and GPR54 have been intensively studied in physiology, their role in cancer is still unclear. In cancer, KiSS1 and GPR54 have been known to suppress metastasis by inhibiting cancer cell motility. However, recent studies suggest that KiSS1 and GPR54 have varied roles even in cancer development and metastasis. Here, we examine recent advances in understanding the roles of KiSS1 and GPR54 in cancer development and metastasis.
33 citations
TL;DR: Genotype–phenotype correlations in IHH due to GnRHR and GPR54 mutations indicate that similar mutations may lead to a variable phenotype and suggest that the pituitary might have its own pubertal maturation independent from GnRH, which result in a more quantitative than qualitative defect of the gonadotropic axis activation.
30 citations
TL;DR: It is reported that Gpr54 deletion leads to kidney branching morphogenesis and glomerular development retardation in embryonic kidneys in vivo and in explanted kidneys in vitro and that NFAT2 cooperates with Sp1 to promote Bmp7 transcription activation.
25 citations
TL;DR: The clinical findings and molecular analysis of GnRHR and KAL1 genes in 26 Brazilian males with IHH with and without hyposmia/anosmia are characterized.
Abstract: Summary
Objective The pathogenesis of idiopathic hypogonadotrophic hypogonadism (IHH) is mostly unclear. We characterized the clinical findings and molecular analysis of GnRHR and KAL1 genes in 26 Brazilian males with IHH with and without hyposmia/anosmia.
Design Clinical assessment was performed for endocrine status, olfactory structure and function, renal lesion, and mirror movement. The diagnosis of Kallmann syndrome (KS) included HH and the clinical complaint of hyposmia/anosmia or decreased olfactory acuity obtained by the Smell Identification Test™ (SIT). We analysed GnRHR and KAL1 genes using the polymerase chain reaction (PCR) direct sequencing method.
Results A variable degree of HH was observed, including various clinical abnormalities, such as cryptorchidism, hearing loss, strabismus, cleft lip/palate, high-arched palate, dental agenesis, psychiatric disorders, learning dysfunction, and bimanual synkinesia. Twenty-two out of 26 patients with IHH (85%) were classified as KS. Abnormalities of olfactory bulbs/sulci were observed in 79% of KS patients. One-third of KS patients had renal defects and 45·5% had a positive family history. GnRHR gene sequence analysis showed no mutations. KAL1 sequence analysis identified two novel missense mutations: c.1061A to G in exon 7 (N304S) and c.1583C to A in exon 10 (S478X). We also observed a 14-bp deletion within exon 11 that caused a premature termination. According to the National Center for Biotechnology Information (NCBI)-Single Nucleotide Polymorphism (SNP) database, two previously described polymorphisms (rs808119 and rs809446) were detected.
Conclusion KAL1 mutations accounted for 12% of KS patients. This low prevalence of KAL1 mutations indicates that other genes, such as the fibroblast growth factor receptor 1 (FGFR1) gene or other as yet undiscovered genes, epigenetic events and/or environmental factors might be involved in the aetiology and phenotypic variability of KS.
25 citations
TL;DR: The presence of a functional kisspeptin/kisspeptin receptor (Kiss-Kissr) system, which is involved in the regulation of reproduction in amphioxus, is demonstrated and insights are provided into the functional roles and evolutionary history of the Kiss-KISSr system.
Abstract: Amphioxus belongs to the Cephalochordata, which is the most basal subphylum of the chordates. Despite many studies on the endocrine system of amphioxus, key information about its regulation remains ambiguous. Here we clearly demonstrate the presence of a functional kisspeptin/kisspeptin receptor (Kiss-Kissr) system, which is involved in the regulation of reproduction in amphioxus. Evolutionary analyses revealed large expansion of Kiss and Kissr (gpr54) genes in amphioxus, and they might represent the ancestral type of the Kiss/gpr54 genes in chordates. Amphioxus Kiss was obviously expression at the cerebral vesicle and the Hatschek pit, whereas amphioxus gpr54 messenger RNA (mRNA) was abundantly present in nerve cord, ovary, and testes. Amphioxus GPR54-Like1 (GPR54L-1) was shown to be located on the cell membrane. The synthetic amphioxus Kiss-like (KissL) peptides were capable of activating the amphioxus GPR54L-1 with different potencies, hinting the interaction between Kiss and GPR54. Moreover, the expression of amphioxus gpr54 mRNA was significantly decreased during low or high temperature extremes. Importantly, the injection of amphioxus KissL could cause an elevation of zebrafish blood luteinizing hormone level and induce the expression of amphioxus gpb5, a gene encoding the ancestral type of vertebrate pituitary glycoprotein hormones. Also, the expression levels of BjkissL-2 or Bjgpr54L-1 were downregulated after spermiation or spawning. Collectively, the amphioxus Kiss-Kissr system has a correlation with the regulation of reproduction. Our studies provide insights into the functional roles and evolutionary history of the Kiss-Kissr system, as well as the origin of the vertebrate neuroendocrine axis for controlling reproduction.
20 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