NCBI Summary:
The protein encoded by this gene is a galanin-like G protein-coupled receptor that binds metastin, a peptide encoded by the metastasis suppressor gene KISS1. The tissue distribution of the expressed gene suggests that it is involved in the regulation of endocrine function, and this is supported by the finding that this gene appears to play a role in the onset of puberty. Mutations in this gene have been associated with hypogonadotropic hypogonadism and central precocious puberty. [provided by RefSeq, Jul 2008]
General function
Receptor
Comment
Cellular localization
Plasma membrane
Comment
Ovarian function
Ovulation, Steroid metabolism, Luteinization
Comment
Kisspeptin-10 inhibits OHSS by suppressing VEGF secretion. Zhai J et al. (2017) The aim of the present study was to elucidate the effects of kisspeptin-10 (Kp-10) on ovarian hyperstimulation syndrome (OHSS) and its related mechanism in OHSS rat models, human umbilical vein endothelial cells (HUVECs) and human luteinized granulosa cells. OHSS is a systemic disorder with high vascular permeability (VP) and ovarian enlargement. KISS1R (KISS1 receptor) is the specific receptor of kisspeptin. The kisspeptin/KISS1R system inhibits the expression of vascular endothelial growth factor (VEGF), which is the main regulator of VP. In our study, decreased expression of Kiss1r was observed both in ovaries and lung tissue of OHSS rats. Injection of exogenous Kp-10 inhibited the increase of VP and VEGF while promoting the expression of Kiss1r in both the ovarian and lung tissue of OHSS rats. Using HUVECs, we revealed that a high level of 17-β estradiol (E2), a feature of OHSS, suppressed the expression of KISS1R and increased VEGF and nitric oxide (NO) through estrogen receptors (ERB). Furthermore, KISS1R mRNA also decreased in the luteinized human granulosa cells of high risk OHSS patients, and was consistent with the results in rat models and HUVECs. In conclusion, Kp-10 prevents the increased VP of OHSS by the activation of KISS1R and the inhibition of VEGF.//////////////////
Loss of Ntrk2/Kiss1r signaling in oocytes causes premature ovarian failure. Dorfman MD 2014 et al.
Neurotrophins (NTs), once believed to be neural-specific trophic factors, are now known to also provide developmental cues to non-neural cells. In the ovary, NTs contribute to both the formation and development of follicles. Here we show that oocyte-specific deletion of the Ntrk2 gene, which encodes the NTRK2 receptor (NTRK2) for neurotrophin-4/5 and brain-derived neurotrophic factor (BDNF), results in post-pubertal oocyte death, loss of follicular organization, and early adulthood infertility. Oocytes lacking NTRK2 do not respond to gonadotropins with activation of phosphatidylinositol 3-kinase (PI3K)-AKT-mediated signaling. Before puberty, oocytes only express a truncated NTRK2 form (NTRK2.T1), but at puberty full-length (NTRK2.FL) receptors are rapidly induced by the preovulatory gonadotropin surge. A cell line expressing both NTRK2.T1 and the kisspeptin receptor (KISS1R) responds to BDNF stimulation with activation of Ntrk2 expression only if kisspeptin is present. This suggests that BDNF and kisspeptin, which are produced by granulosa cells (GCs) of periovulatory follicles, act in concert to mediate the effect of gonadotropins on Ntrk2 expression in oocytes. In keeping with this finding, the oocytes of NTRK2-intact mice fail to respond to gonadotropins with increased Ntrk2 expression in the absence of KISS1R. Our results demonstrate that the preovulatory gonadotropin surge promotes oocyte survival at the onset of reproductive cyclicity by inducing oocyte expression of NTRK2.FL receptors, which set in motion an AKT-mediated survival pathway. They also suggest that gonadotropins activate NTRK2.FL expression via a dual communication pathway involving BDNF and kisspeptin produced in GCs and their respective receptors NTRK2.T1 and KISS1R expressed in oocytes.
/////////////////////////
Kisspeptin stimulates progesterone secretion via the Erk1/2 mitogen-activated protein kinase signaling pathway in rat luteal cells. Peng J et al. OBJECTIVE: To observe the effect of kisspeptin on the endocrine function of rat luteal cells. DESIGN: Experimental animal study. SETTING: Research institute laboratory. ANIMAL(S): Immature Sprague-Dawley rats. INTERVENTION(S): The expression of kisspeptin and its receptor, GPR54, in immature rat ovaries treated with gonadotropin was observed via immunohistochemistry and real-time polymerase chain reaction. Then recombinant kisspeptin was used to examine the effect on the endocrine function of rat luteal cells. MAIN OUTCOME MEASURE(S): Expression and localization of kisspeptin, localization of GPR54, P and E(2) secretion, expression of steroidogenic enzymes, and phosphorylation of Erk1/2. RESULT(S): Real-time polymerase chain reaction indicated that ovarian KiSS-1 mRNA levels increased significantly, showing a peak at the luteal period in gonadotropin-primed immature rats. Immunostaining analysis showed that after gonadotropin treatment, kisspeptin was strongly localized in theca cells, the interstitial compartment, and the corpus luteum and that GPR54 protein was clearly detected in the corpus luteum of rat ovaries. In cultured luteal cells, kisspeptin treatment augmented basal and hCG-induced P levels but not E(2) production, with concomitant increases detected in the transcript levels of key steroidogenic enzymes (StAR, CYP11A, and 3?HSD). Furthermore, treatment with kisspeptin increased the phosphorylation of Erk1/2 mitogen-activated protein kinase in cultured luteal cells. CONCLUSION(S): The kisspeptin/GPR54 signaling system could stimulate P secretion in rat luteal cells via the Erk1/2 mitogen-activated protein kinase signaling pathway, suggesting an important role for the function of the corpus luteum.
Effects of kisspeptin-10 on progesterone secretion in cultured chicken ovarian granulosa cells from preovulatory (F(1)-F(3)) follicles. Xiao Y et al. The effect of kisspeptin-10 (Kp-10) on the secretion of progesterone (P(4)) was investigated in cultured granulosa cells from F(1) to F(3) follicles of hens. The results showed that granulosa cells were stained with clear signals for kisspeptin using immunocytochemistry with the specific antibody against Kp-10. Among 10, 100 and 1000nM concentrations tested, 100nM Kp-10 treated for 24h significantly increased P(4) secretion in granulosa cells from F(1) to F(3) follicles. After 24h and 48h of treatment, 100nM Kp-10 showed a significant increase in P(4) secretion, while after 72h of treatment P(4) secretion was markedly decreased by Kp-10 compared to the control group (P<0.05). F(1) and F(2/3) cells treated with 100nM Kp-10 for 24h showed significantly increased viability (P<0.05) and which was in parallel to a marked increase in P(4) secretion (P<0.01). Real-time PCR results showed that the gene expression of the steroidogenic acute regulatory protein (StAR), cytochrome P450 side-chain cleavage (P450scc) and the enzyme 3?hydroxysteroid dehydrogenase (3?HSD) in F(1) and F(2/3) granulosa cells was significantly up-regulated by 24h-100nM Kp-10 treatment (P<0.05 versus P<0.01, respectively). However, there was no significant difference in StAR, P450scc and 3?HSD protein content between control and the Kp-10 treated group (P>0.05). These results indicate that Kp-10 stimulates P(4) secretion in cultured chicken granulosa cells, which was associated with an up-regulation in StAR, P450scc and 3?HSD gene transcription.
KiSS-1 in the Mammalian Ovary: Distribution of Kisspeptin in Human and Marmoset, and Alterations in KiSS-1 mRNA Levels in a Rat Model of Ovulatory Dysfunction. Gaytan F et al. Kisspeptins, the products of the KiSS-1 gene acting via GPR54, have recently emerged as pivotal signals in the hypothalamic network triggering the preovulatory surge of gonadotropins and, hence, ovulation. Additional actions of kisspeptins at other levels of the hypothalamic-pituitary-ovarian axis have been suggested, but remain to date scarcely studied. We report herein the pattern of expression of KiSS-1 and GPR54 in the human and non-human primate ovary, and evaluate changes in ovarian KiSS-1 expression in a rat model of ovulatory dysfunction. KiSS-1 and GPR54 mRNAs were detected in human ovarian tissue and cultured granulosa-lutein cells. In good agreement, kisspeptin immunoreactivity (IR) was observed in cyclic human and marmoset ovaries, with prominent signals in the theca layer of growing follicles, corpora lutea, interstitial gland and ovarian surface epithelium. GPR54-IR was also found in human theca and luteal cells. Administration of indomethacin to cyclic female rats disturbed ovulation and resulted in a dramatic drop in ovarian KiSS-1, but not GPR54, COX-2 or progesterone receptor, mRNA levels at the time of ovulation; an effect mimicked by the selective COX-2 inhibitor, NS398, and rescued by co-administration of PGE2. Likewise, the stimulatory effect of human choriogonadotropin on ovarian KiSS-1 expression was partially blunted by indomethacin. In contrast, KiSS-1 mRNA levels remained unaltered in another model of ovulatory failure; i.e., the RU486-trated rat. In sum, we document for the first time the expression of KiSS-1/kisspeptin and GPR54 in the human and non-human primate ovary. In addition, we provide evidence for the ability of inhibitors of COX-2, known to disturb follicular rupture and ovulation, to selectively alter the expression of KiSS-1 gene in rat ovary. Altogether, our results are suggestive of a conserved role of local KiSS-1 in the direct control of ovarian functions in mammals. Key words: Kisspeptin, GPR54, ovary, rodent, primate.
Phenotypes
Mutations
1 mutations
Species: mouse
Mutation name: type: null mutation fertility: fertile Comment: Crowding and Follicular Fate: Spatial Determinants of Follicular Reserve and Activation of Follicular Growth in the Mammalian Ovary. Gaytan F et al. (2015) Initiation of growth of resting ovarian follicles is a key phenomenon for providing an adequate number of mature oocytes in each ovulation, while preventing premature exhaustion of primordial follicle reserve during the reproductive lifespan. Resting follicle dynamics strongly suggest that primordial follicles are under constant inhibitory influences, by mechanisms and factors whose nature remains ill defined. In this work, we aimed to assess the influence of spatial determinants, with special attention to clustering patterns and crowding, on the fate of early follicles in the adult mouse and human ovary. To this end, detailed histological and morphometric analyses, targeting resting and early growing follicles, were conducted in ovaries from mice, either wild type (WT) or genetically modified to lack kisspeptin receptor expression (Kiss1r KO), and healthy adult women. Kiss1r KO mice were studied as model of persistent hypogonadotropism and anovulation. Different qualitative and quantitative indices of the patterns of spatial distribution of resting and early growing follicles in the mouse and human ovary, including the Morisita's index of clustering, were obtained. Our results show that resting primordial follicles display a clear-cut clustered pattern of spatial distribution in adult mouse and human ovaries, and that resting follicle aggrupation is inversely correlated with the proportion of follicles initiating growth and entering into the growing pool. As a whole, our data suggest that resting follicle crowding, defined by changes in density and clustered pattern of distribution, is a major determinant of follicular activation and the fate of ovarian reserve. Uneven follicle crowding would constitute the structural counterpart of the major humoral regulators of early follicular growth, with potential implications in ovarian ageing and pathophysiology.//////////////////