Affinage

KISS1R

KiSS-1 receptor · UniProt Q969F8

Length
398 aa
Mass
42.6 kDa
Annotated
2026-04-28
100 papers in source corpus 29 papers cited in narrative 28 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

KISS1R (GPR54) is a Gαq/11-coupled G protein-coupled receptor that serves as the essential gatekeeper of the hypothalamic-pituitary-gonadal axis by transducing kisspeptin signals in GnRH neurons to control puberty onset and reproductive competence. Ligand binding activates PLC–IP3–Ca²⁺–PKC and ERK1/2 cascades through Gαq/11, while a parallel β-arrestin-1/2-dependent pathway sustains ERK1/2 activation and contributes independently to GnRH/LH secretion, as demonstrated by the partial reproductive phenotype of GnRH neuron-specific Gαq/11 knockouts versus complete infertility in Kiss1r-null mice (PMID:14573733, PMID:26377475, PMID:25147978). Loss-of-function mutations in KISS1R cause autosomal recessive idiopathic hypogonadotropic hypogonadism, whereas a gain-of-function Arg386Pro mutation that increases receptor recycling to the plasma membrane is associated with central precocious puberty (PMID:14573733, PMID:21285314). Beyond the reproductive axis, KISS1R transactivates EGFR through β-arrestin-2 to promote breast cancer cell invasion, physically associates with PP2A-C to suppress NF-κB/MAPK inflammatory signaling, and drives ERK5–NR4A1-mediated T cell exhaustion in the tumor microenvironment (PMID:21738726, PMID:33609696, PMID:35224894).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2001 High

    Deorphanization of GPR54 as the kisspeptin receptor and its coupling to Gαq established the ligand-receptor pair and primary signaling mode, resolving the identity of the endogenous agonist for this orphan GPCR.

    Evidence Heterologous expression, radioligand binding, and Gαq activation assays in mammalian cells

    PMID:11387329 PMID:11414709

    Open questions at the time
    • Physiological function in vivo unknown at this stage
    • Downstream effectors beyond Gαq not yet mapped
    • Endogenous tissue-level expression pattern incompletely characterized
  2. 2003 High

    Human loss-of-function mutations and knockout mice proved KISS1R is indispensable for puberty and reproduction, placing it upstream of GnRH release and establishing it as a cause of idiopathic hypogonadotropic hypogonadism.

    Evidence Human genetic sequencing of IHH families, in vitro inositol phosphate assays for L148S, Gpr54 KO mouse phenotyping with GnRH/gonadotropin challenge

    PMID:14573733 PMID:14652023

    Open questions at the time
    • Cell-type specificity of Kiss1r requirement not yet determined
    • G-protein-independent signaling contributions unknown
    • Mechanism of receptor regulation (desensitization, trafficking) unexplored
  3. 2005 Medium

    Identification of PLC/PKC as obligatory and ERK as a partially contributing effector downstream of KISS1R resolved the intracellular signaling architecture, demonstrating pathway-selective gene regulation distinct from other Gαq-coupled receptors.

    Evidence cDNA microarray with PLC, PKC, and ERK inhibitors in MDA-MB-435S cells

    PMID:15596153

    Open questions at the time
    • Signaling dissection performed only in cancer cell line, not in GnRH neurons
    • β-arrestin-dependent arm not yet investigated
    • In vivo relevance of anti-metastatic signaling unclear
  4. 2008 Medium

    Discovery that the KISS1R C-terminal tail directly binds PP2A-C and that KISS1R modulates excitatory synaptic transmission in hippocampal neurons expanded its functional repertoire beyond reproduction and identified a non-canonical effector interaction.

    Evidence Yeast two-hybrid, GST pulldown, in vitro binding with purified PP2A-C; acute brain slice electrophysiology with pharmacological inhibitors

    PMID:18765263 PMID:18977201

    Open questions at the time
    • Physiological significance of PP2A-C binding not demonstrated in vivo
    • Whether PP2A modulates KISS1R-dependent GnRH signaling unknown
    • Hippocampal function of KISS1R not confirmed by genetic approaches
  5. 2009 High

    Characterization of GRK2-mediated phosphorylation, β-arrestin-1/2 recruitment via the second intracellular loop and C-tail, and β-arrestin-2-dependent ERK1/2 activation established the desensitization and G-protein-independent signaling framework for KISS1R.

    Evidence Co-immunoprecipitation, dominant-negative constructs, β-arrestin knockdown, confocal imaging in MDA-MB-231 and HEK293 cells

    PMID:19846537

    Open questions at the time
    • In vivo contribution of β-arrestin pathway to GnRH secretion not yet tested
    • Structural basis of GRK2 phosphorylation sites unknown
    • Relative contribution of β-arrestin-1 vs -2 in GnRH neurons not resolved
  6. 2011 High

    Multiple advances established receptor trafficking rules (proteasomal rather than lysosomal degradation, recycling to the plasma membrane), linked Arg386Pro gain-of-function to central precocious puberty via enhanced recycling, demonstrated EGFR transactivation through β-arrestin-2 for breast cancer invasion, and showed Gαq–p63RhoGEF–RhoA signaling promotes tumor growth.

    Evidence Confocal trafficking with proteasome/lysosome inhibitors; FRET and co-IP for KISS1R-EGFR; Kiss1r heterozygous MMTV-PyMT mice; RhoA activation assays

    PMID:21285314 PMID:21738726 PMID:21852382

    Open questions at the time
    • Trafficking studies largely in HEK293, not in GnRH neurons
    • Whether EGFR transactivation occurs in reproductive tissues unknown
    • Role of RhoA pathway in normal reproductive physiology not tested
  7. 2013 High

    GnRH neuron-specific conditional knockout and BAC transgenic rescue definitively identified GnRH neurons as the essential cellular site of Kiss1r action for puberty and fertility, resolving a long-standing question about the critical target cell population.

    Evidence GnRH-Cre-driven Gpr54 deletion and BAC rescue with electrophysiology and reproductive phenotyping

    PMID:24051579

    Open questions at the time
    • Whether KISS1R functions cell-autonomously in other hypothalamic neuron types remains unresolved
    • Mechanism of kisspeptin-induced GnRH neuron firing not fully dissected
    • Whether KISS1R in GnRH neurons signals through the same β-arrestin arm as in cell lines not confirmed
  8. 2014 High

    β-arrestin knockout mice and the G-protein-uncoupled L148S mutant proved that β-arrestin-dependent signaling independently sustains kisspeptin-driven LH secretion in vivo, explaining partial phenotypes in patients with Gαq/11-uncoupled KISS1R mutations.

    Evidence β-arrestin-1 and -2 KO mice with LH measurements; L148S mutant retaining β-arrestin-dependent ERK in MEFs lacking both β-arrestins

    PMID:25147978

    Open questions at the time
    • Relative quantitative contributions of Gαq/11 vs β-arrestin arms to pulsatile GnRH secretion not determined
    • Biased agonist pharmacology not systematically explored
    • Structural basis for L148S uncoupling from Gαq but not β-arrestin unknown
  9. 2015 High

    Conditional Gαq/11 ablation in GnRH neurons caused only partial reproductive impairment while Kiss1r-null mice were completely infertile, providing in vivo genetic proof that KISS1R operates through Gαq/11-independent pathways to support GnRH secretion.

    Evidence GnRH neuron-specific Gnaq/Gna11 conditional KO with kisspeptin challenge and comparison to Kiss1r-null phenotype

    PMID:26377475

    Open questions at the time
    • Identity of the compensatory G-protein or adaptor remains unconfirmed in vivo
    • Whether β-arrestin rescue is sufficient alone or additional pathways contribute not tested genetically
    • Long-term reproductive consequences at advanced ages not characterized
  10. 2021 Medium

    Extension of KISS1R biology to inflammation and neuronal injury showed that PP2A-C binding suppresses NF-κB/MAPK inflammatory signaling in macrophages and that β-arrestin-2/AKT/GSK3β signaling is neuroprotective after subarachnoid hemorrhage, broadening the receptor's physiological relevance beyond reproduction.

    Evidence Gpr54-/- mice with collagen-induced arthritis; rat SAH model with kisspeptin-234 antagonist and ARRB2 siRNA

    PMID:33609696 PMID:33989759

    Open questions at the time
    • PP2A-C interaction not mapped to specific residues; stoichiometry unknown
    • Neuroprotective pathway not validated in genetic mouse models of SAH
    • Whether anti-inflammatory and neuroprotective roles operate under normal physiology or only in disease states
  11. 2022 Medium

    Discovery that KISS1R drives T cell exhaustion via ERK5–NR4A1 and that its CRISPR-mediated deletion enhances CAR T cell antitumor activity revealed an immunoregulatory function and potential therapeutic target in cancer immunotherapy.

    Evidence T cell-conditional Gpr54 KO, adoptive OT-1 transfer, CRISPR/Cas9 in CAR T cells, ERK5 inhibitor XMD8-92

    PMID:35224894

    Open questions at the time
    • Ligand source for KISS1R activation on T cells in the tumor microenvironment not identified
    • Whether ERK5 is a direct KISS1R effector or requires intermediate kinases not determined
    • Clinical translation of GPR54-deleted CAR T cells not yet evaluated

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of biased agonism at KISS1R, the identity of non-Gαq/11 G-proteins engaged in GnRH neurons, the physiological relevance of KISS1R in non-reproductive tissues under homeostatic conditions, and whether KISS1R-targeted therapies can selectively modulate reproductive versus immune/cancer pathways.
  • No high-resolution structure of KISS1R in active or inactive state
  • Biased agonist pharmacology not systematically characterized
  • In vivo role of KISS1R in osteoblasts, hippocampal neurons, and oocytes not confirmed by tissue-specific genetics

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3 GO:0098772 molecular function regulator activity 2
Localization
GO:0005886 plasma membrane 3
Pathway
R-HSA-162582 Signal Transduction 7 R-HSA-1266738 Developmental Biology 4 R-HSA-1474165 Reproduction 3 R-HSA-168256 Immune System 2 R-HSA-112316 Neuronal System 1
Partners
ARRB1ARRB2EGFRGNA11GNAQGRK2IQGAP1PPP2CA

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 KISS1R (AXOR12/GPR54) was identified as the cognate receptor for kisspeptin peptides derived from the KiSS-1 gene; heterologous expression in mammalian cells showed high-potency agonism with KiSS-1-derived peptides, and the receptor was localized to neurons in cerebellum, cerebral cortex, and brainstem by polyclonal antibody staining. Heterologous expression in mammalian cells, radioligand binding, quantitative RT-PCR, immunohistochemistry The Journal of biological chemistry High 11387329
2001 GPR54 couples to the Gαq pathway; RFamide/RWamide invertebrate neuropeptides activate GPR54 at micromolar concentrations through this pathway, and C-terminal Gly-Leu-Arg-Trp-NH2 is the minimal active motif. Cell-based Gαq activation assay, substitution analysis in transfected cells Biochemical and biophysical research communications Medium 11414709
2003 Loss-of-function mutations in GPR54 (L148S, R331X, X399R) cause autosomal recessive idiopathic hypogonadotropic hypogonadism; L148S significantly decreased inositol phosphate accumulation in transfected COS-7 cells, demonstrating impaired Gαq/11 signaling. Gpr54-knockout mice showed isolated hypogonadotropic hypogonadism with normal GnRH levels in hypothalamus and retained responsiveness to exogenous GnRH and gonadotropins, placing GPR54 upstream of GnRH release. Human genetics (sequencing), in vitro transfection/inositol phosphate assay, Gpr54 knockout mouse phenotyping, exogenous GnRH/gonadotropin challenge The New England journal of medicine High 14573733
2003 Targeted disruption of GPR54 in mice causes developmental abnormalities of male and female genitalia and histopathological changes in sexually dimorphic tissues, establishing GPR54 as essential for normal sexual development. Gpr54 knockout mouse generation and phenotyping Biochemical and biophysical research communications High 14652023
2005 GPR54 activation by kisspeptin-10 in MDA-MB-435S cells induced a distinct transcriptional program (compared to bradykinin B2 receptor despite shared Gq coupling) involving pro-apoptotic genes, promoted cell cycle arrest and apoptosis; PLC and PKC inhibitors abolished all gene regulation, while p42/44 (ERK) inhibitor affected only a subset of genes. cDNA microarray time-course, pathway inhibitor experiments, cell viability/apoptosis assays Biochemical and biophysical research communications Medium 15596153
2007 GPR54 signaling is required for male-like sexual differentiation of the brain; GPR54 knockout males displayed female-like numbers of tyrosine hydroxylase-immunoreactive and Kiss1 mRNA-containing neurons in AVPV and fewer motoneurons in spino-bulbocavernosus nucleus, indicating GPR54 regulates perinatal androgen secretion critical for sexual differentiation. GPR54 knockout mouse phenotyping, immunohistochemistry, in situ hybridization, hormone replacement experiments The Journal of neuroscience High 17699664
2008 Activation of GPR54 in hippocampal dentate granule cells by kisspeptin-10 causes rapid, large increase in excitatory synaptic response amplitude (without changing membrane properties or event frequency) through a postsynaptic mechanism requiring G-protein signaling (GDP-β-S sensitive), intracellular Ca2+ (BAPTA-sensitive), and signaling cascades involving ERK1/2, tyrosine kinase, and CaMKII. Acute brain slice electrophysiology, miniature EPSC analysis, pharmacological inhibitors, RT-PCR Peptides Medium 18765263
2008 GPR54 C-terminal cytoplasmic domain physically associates with the catalytic subunit of protein phosphatase 2A (PP2A-C); the proline-arginine-rich segment containing SH3-binding motifs is required; pulldown with GST-GPR54-C-terminal confirmed binding to PP2A-C in cell lysates with phosphatase activity, and direct binding to purified recombinant PP2A-C was demonstrated. Yeast two-hybrid, GST pulldown, in vitro binding with purified recombinant protein Biochemical and biophysical research communications Medium 18977201
2008 GPR54 intracellular signaling via kisspeptin activates multiple pathways: Gαq/11-coupled PLC activation, IP3 accumulation, intracellular Ca2+ mobilization, PKC activation, as well as MAPK pathways (ERK1/2, p38) and PI3K/Akt; additionally, GPR54 can interact with CXCR4 and GnRH receptors and affects MMP-9 expression via NF-κB. Review synthesizing in vitro assays from multiple studies Peptides Medium 18775460
2009 GRK2 phosphorylates and desensitizes GPR54; β-arrestins-1 and -2 associate with GPR54 through sequences in the second intracellular loop and cytoplasmic tail; GPR54 exhibits constitutive internalization; β-arrestin-2 mediates GPR54 activation of ERK1/2; plasma membrane expression is regulated by cytoplasmic tail sequences; and GRK2 stimulates desensitization of GPR54 signaling. Co-immunoprecipitation, dominant-negative constructs, β-arrestin knockdown in MDA-MB-231 cells, confocal imaging, HEK293 cell transfection assays Molecular endocrinology High 19846537
2011 Wild-type KISS1R is degraded by proteasomes rather than lysosomes; upon kisspeptin stimulation, both WT and Arg386Pro mutant KISS1R are internalized and recycled back to the plasma membrane rather than degraded; the Arg386Pro gain-of-function mutation associated with central precocious puberty prolongs kisspeptin responsiveness by decreasing receptor degradation, leading to net increase in recycled receptor at the plasma membrane. Confocal imaging with membrane/lysosome markers, proteasome/lysosome inhibitor treatment, receptor trafficking assays, recycling blockade experiments Endocrinology High 21285314
2011 GPR54/KISS1R transactivates EGFR to promote breast cancer cell invasiveness; kisspeptin-10 stimulates MMP-9 activity and invasion; β-arrestin-2 knockdown inhibits EGFR transactivation and invasion; GPR54 and EGFR associate under basal conditions and FRET analysis demonstrated direct interaction; kisspeptin increases stability of the GPR54-EGFR receptor complex. Matrigel invasion assay, 3D invasion assay, MMP-9 zymography, β-arrestin-2 knockdown, co-immunoprecipitation, FRET analysis PloS one High 21738726
2011 Kiss1r knockout male mice have normal prenatal and neonatal testosterone levels similar to wild-type males, demonstrating that kisspeptin-Kiss1r signaling is not required for sexually dimorphic perinatal testosterone secretion; necessity of Kiss1r for testicular function first becomes apparent after postnatal day 5. Kiss1r KO mouse serum testosterone measurement at different developmental stages, hypothalamic Kiss1/NKB mRNA quantification, testicular weight comparison Endocrinology High 22202164
2012 KISS1R mediates sustained Gαq/11 signaling upon prolonged kisspeptin treatment by maintaining a dynamic active pool at the cell surface; sustained signaling requires extracellular Ca2+ influx (not just intracellular stores) for prolonged PKC activation, demonstrated in HEK293, GT1-7 GnRH neuronal, and CHO cell lines. Single-cell Ca2+ imaging, PKC activity assays, EGTA chelation of extracellular Ca2+, multiple cell lines Endocrinology High 23070548
2013 The GnRH neuron is the key cellular site of kisspeptin-Gpr54 signaling for fertility; GnRH neuron-specific Gpr54 deletion causes infertility, failure of puberty, reduced FSH, and GnRH neurons unresponsive to kisspeptin; BAC transgenic rescue of Gpr54 expression specifically in GnRH neurons restores normal puberty, estrous cyclicity, and fecundity. Conditional (GnRH neuron-specific) Gpr54 knockout, BAC transgenic rescue, electrophysiology of GnRH neurons, reproductive phenotyping Nature communications High 24051579
2013 KISS1R induces invasiveness of ERα-negative breast cancer cells via transactivation of EGFR in a manner dependent on IQGAP1 (identified as novel KISS1R binding partner); ERα negatively regulates KISS1R-dependent invasion and EGFR transactivation; exogenous ERα expression in MDA-MB-231 cells abolished KP-10-induced invasion by downregulating KISS1R. Co-immunoprecipitation, invasion assays, ERα overexpression, in vivo extravasation assay, KISS1R overexpression Endocrinology Medium 23525242
2013 KISS1R activation by kisspeptin potentiates extravillous trophoblast adhesion to type-I collagen in a PKC- and ERK1/2-dependent manner; kisspeptin transiently activates PKC and ERK1/2 in EVTs, and inhibition of both attenuates kisspeptin-dependent adhesion increase; kisspeptin also increases mouse blastocyst adhesion to collagen I. Adhesion assay, PKC/ERK inhibitor treatment, kinase activity assays, blastocyst adhesion assay Molecular reproduction and development Medium 24273038
2014 KISS1R signals via both Gαq/11- and β-arrestin-dependent pathways to regulate LH (GnRH) secretion; β-arrestin-1 or β-arrestin-2 knockout mice show significantly diminished KP-dependent LH secretion; the hypogonadism-associated L148S mutant, though Gαq/11-uncoupled, retains β-arrestin-dependent ERK1/2 phosphorylation, providing a mechanism for partial phenotypes in patients with Gαq/11-uncoupled KISS1R mutations. β-arrestin KO mice, LH measurement, HEK293 cell transfection, mouse embryonic fibroblasts lacking β-arrestin-1 and -2, ERK1/2 phosphorylation assays Endocrinology High 25147978
2014 RF9 acts as a direct KISS1R agonist rather than an NPFFR1 antagonist; RF9 binds KISS1R (Kd ~16 µM), stimulates intracellular calcium and inositol phosphate accumulation in a KISS1R-dependent manner, phosphorylates ERK1/2, and stimulates LH secretion in vivo in a Kiss1r-dependent manner; RF9's stimulatory action on GnRH neurons is entirely dependent on Kiss1r expression (no effect in Kiss1r-null mice). CHO-KISS1R stable cells (radioligand binding, IP/Ca2+ assays, ERK phosphorylation), Npffr1-/-, Kiss1r-/-, and GnRH neuron-specific Kiss1r rescue mice; electrophysiology of GnRH neurons Endocrinology High 25322463 26418326
2015 Ablation of Gαq/11 specifically in GnRH neurons results in only partial reproductive impairment (unlike complete infertility of Kiss1r-null mice), and kisspeptin stimulation still triggers significant LH/testosterone increases in Gnaq(d/d) mice, demonstrating that KISS1R signals through Gαq/11-independent (β-arrestin) pathways to support GnRH secretion. Conditional Gnaq KO in GnRH neurons (Gnaq(fl/fl);Gna11-/-;Gnrh-Cre), reproductive phenotyping, kisspeptin challenge tests, comparison to Kiss1r-null phenotype The Journal of neuroscience High 26377475
2015 KISS1R signaling induces invadopodia formation in triple-negative breast cancer cells via a β-arrestin-2 and ERK1/2-dependent mechanism (independent of Src), activating invadopodia proteins cortactin, cofilin, and MT1-MMP; KISS1R depletion reduced mesenchymal phenotype and invasiveness. KISS1R knockdown, invadopodia formation assay, Western blot for cortactin/cofilin/MT1-MMP, β-arrestin-2 knockdown, ERK inhibition Cellular signalling Medium 26721186
2011 Kiss1r heterozygosity in MMTV-PyMT breast cancer mice attenuated tumor initiation, growth, and lung metastasis; kisspeptin-10 activation of Kiss1r in tumor cells triggered RhoA activation and RhoA-dependent gene expression through a Gαq-p63RhoGEF signaling pathway, and anchorage-independent growth was dose-dependently regulated by Kiss1r via RhoA. Kiss1r heterozygous KO in MMTV-PyMT model, primary tumor cell assays, RhoA activation assay, siRNA knockdown of KISS1R and RhoA in MCF10A cells, in vivo NOD/SCID tumor growth Cancer research Medium 21852382
2021 KP54/GPR54 attenuates oxidative stress and neuronal apoptosis after subarachnoid hemorrhage through GPR54/ARRB2 (β-arrestin-2)/AKT/GSK3β signaling; GPR54 blockade or ARRB2 knockout abolished neuroprotective effects of KP54; siRNA knockdown of KISS1 aggravated injury. Rat SAH model, intranasal KP54, siRNA knockdown, selective GPR54 antagonist (kisspeptin-234), ARRB2 siRNA, Western blot, immunofluorescence, behavioral tests Free radical biology & medicine Medium 33989759
2021 KP-10/GPR54 binds PP2A-C to suppress LPS-induced NF-κB and MAPK signaling in bone marrow-derived macrophages; Gpr54 knockout increased inflammatory cytokines; KP-10 reduced inflammatory cytokines in vitro and ameliorated collagen-induced arthritis in vivo. Gpr54-/- mice, collagen-induced arthritis model, Western blot, immunofluorescence, PP2A-C binding assay Pharmacological research Medium 33609696
2022 Kisspeptin/GPR54 signaling promotes T cell dysfunction via ERK5-mediated NR4A1 activation; Gpr54 knockout in T cells inhibits lung tumor progression by suppressing T cell exhaustion; CRISPR/Cas9 depletion of GPR54 or ERK5 in CAR T cells intensifies antitumor responses while eliminating T cell exhaustion. Gpr54 T cell conditional KO, adoptive transfer OT-1 experiments, ERK5 inhibitor (XMD8-92), CRISPR/Cas9 in CAR T cells, restraint stress model Advanced science Medium 35224894
2011 Estrogen (E2) induces rhythmic/circadian expression of GPR54 in GT1-7 GnRH neurons; disruption of endogenous clock in GnRH neurons dampens E2-induced GPR54 rhythmicity; kisspeptin treatment of GT1-7 cells at positive feedback E2 levels increases GnRH secretion, suggesting clock-regulated GPR54 expression gates GnRH sensitivity to kisspeptin. GT1-7 cell culture, E2 treatment, mRNA and protein abundance time-course, clock disruption, GnRH secretion assay Journal of neuroendocrinology Medium 21756268
2018 KP-10 stimulates osteoblast differentiation through GPR54-mediated NFATc4-dependent BMP2 gene expression and activation of Smad1/5/9 phosphorylation; KP-10 did not induce BMP2 or Runx2 expression in GPR54-null cells; secreted BMP2 has an autocrine effect mediating downstream osteogenic gene expression. C3H10T1/2 cells, GPR54-/- cells, BMP2-luc reporter, Smad1/5/9 phosphorylation assay, conditioned medium experiments, osteogenic gene expression Scientific reports Medium 29391507
2014 Oocytes express KISS1R and respond to kisspeptin from granulosa cells; a cell line co-expressing NTRK2.T1 and KISS1R responds to BDNF with Ntrk2 expression only in the presence of kisspeptin, indicating BDNF and kisspeptin act in concert on oocytes; NTRK2-intact mice fail to respond to gonadotropins with increased Ntrk2 expression in the absence of KISS1R. Oocyte-specific Ntrk2 KO, cell line co-expression assays, gonadotropin challenge experiments, PI3K-AKT pathway analysis Endocrinology Medium 24877631

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 The GPR54 gene as a regulator of puberty. The New England journal of medicine 1932 14573733
2001 AXOR12, a novel human G protein-coupled receptor, activated by the peptide KiSS-1. The Journal of biological chemistry 721 11387329
2003 The KiSS-1 receptor GPR54 is essential for the development of the murine reproductive system. Biochemical and biophysical research communications 520 14652023
2007 Kiss1-/- mice exhibit more variable hypogonadism than Gpr54-/- mice. Endocrinology 411 17595229
2007 New frontiers in kisspeptin/GPR54 physiology as fundamental gatekeepers of reproductive function. Frontiers in neuroendocrinology 242 17870152
2006 Regulation of the neuroendocrine reproductive axis by kisspeptin-GPR54 signaling. Reproduction (Cambridge, England) 178 16595713
2013 Dependence of fertility on kisspeptin-Gpr54 signaling at the GnRH neuron. Nature communications 175 24051579
2008 The role of kisspeptins and GPR54 in the neuroendocrine regulation of reproduction. Annual review of physiology 173 17988212
2009 Molecular evolution of multiple forms of kisspeptins and GPR54 receptors in vertebrates. Endocrinology 171 19164475
2007 Emerging ideas about kisspeptin- GPR54 signaling in the neuroendocrine regulation of reproduction. Trends in neurosciences 157 17904653
2007 The kisspeptin receptor GPR54 is required for sexual differentiation of the brain and behavior. The Journal of neuroscience : the official journal of the Society for Neuroscience 156 17699664
2006 GPR54 and kisspeptin in reproduction. Human reproduction update 147 16731583
2009 Oestrogen, kisspeptin, GPR54 and the pre-ovulatory luteinising hormone surge. Journal of neuroendocrinology 124 19207812
2008 Intracellular signaling pathways activated by kisspeptins through GPR54: do multiple signals underlie function diversity? Peptides 102 18775460
2009 Regulation of GPR54 signaling by GRK2 and {beta}-arrestin. Molecular endocrinology (Baltimore, Md.) 98 19846537
2001 FMRFamide-related neuropeptides are agonists of the orphan G-protein-coupled receptor GPR54. Biochemical and biophysical research communications 95 11414709
2009 Kisspeptin/Gpr54-independent gonadotrophin-releasing hormone activity in Kiss1 and Gpr54 mutant mice. Journal of neuroendocrinology 89 19840236
2011 GPR54 (KISS1R) transactivates EGFR to promote breast cancer cell invasiveness. PloS one 79 21738726
2019 Reproductive functions of Kisspeptin/KISS1R Systems in the Periphery. Reproductive biology and endocrinology : RB&E 78 31399145
2010 A novel loss-of-function mutation in GPR54/KISS1R leads to hypogonadotropic hypogonadism in a highly consanguineous family. The Journal of clinical endocrinology and metabolism 77 21193544
2008 The kisspeptin (KiSS-1)/GPR54 system in cancer biology. Cancer treatment reviews 77 18583061
2008 Transgenic mouse models to study Gpr54/kisspeptin physiology. Peptides 68 18571287
2009 Differential ovarian expression of KiSS-1 and GPR-54 during the estrous cycle and photoperiod induced recrudescence in Siberian hamsters (Phodopus sungorus). Molecular reproduction and development 67 18937338
2014 Loss of Ntrk2/Kiss1r signaling in oocytes causes premature ovarian failure. Endocrinology 65 24877631
2011 Sexually dimorphic testosterone secretion in prenatal and neonatal mice is independent of kisspeptin-Kiss1r and GnRH signaling. Endocrinology 64 22202164
2009 Kisspeptin/GPR54 system as potential target for endocrine disruption of reproductive development and function. International journal of andrology 61 19906185
2008 Kisspeptin and GPR54: discovery of a novel pathway in reproduction. Journal of neuroendocrinology 60 18601695
2007 Expression of metastin and a G-protein-coupled receptor (AXOR12) in epithelial ovarian cancer. European journal of cancer (Oxford, England : 1990) 56 17442564
2008 Identification of two isoforms of the Kisspeptin-1 receptor (kiss1r) generated by alternative splicing in a modern teleost, the Senegalese sole (Solea senegalensis). Biology of reproduction 54 18815354
2011 KISS1R intracellular trafficking and degradation: effect of the Arg386Pro disease-associated mutation. Endocrinology 52 21285314
2004 GPR54 and puberty. Trends in endocrinology and metabolism: TEM 51 15519892
2008 GPR54 and kisspeptins. Results and problems in cell differentiation 50 18193176
2010 Physiological roles of the kisspeptin/GPR54 system in the neuroendocrine control of reproduction. Progress in brain research 49 20478433
2010 Decrease in hypothalamic Kiss1 and Kiss1r expression: a potential mechanism for fasting-induced suppression of the HPG axis in the adult male rhesus monkey (Macaca mulatta). Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme 48 21154197
2005 Activation of GPR54 promotes cell cycle arrest and apoptosis of human tumor cells through a specific transcriptional program not shared by other Gq-coupled receptors. Biochemical and biophysical research communications 48 15596153
2010 A novel homozygous splice acceptor site mutation of KISS1R in two siblings with normosmic isolated hypogonadotropic hypogonadism. European journal of endocrinology 47 20371656
2016 Metabolism and Energy Expenditure, But Not Feeding or Glucose Tolerance, Are Impaired in Young Kiss1r KO Female Mice. Endocrinology 46 27649089
2015 KISS1R signaling promotes invadopodia formation in human breast cancer cell via β-arrestin2/ERK. Cellular signalling 46 26721186
2008 The role of kisspeptin and GPR54 in the hippocampus. Peptides 46 18765263
2008 The KiSS1/GPR54 system in fish. Peptides 44 18817822
2011 Haploinsufficiency in the prometastasis Kiss1 receptor Gpr54 delays breast tumor initiation, progression, and lung metastasis. Cancer research 43 21852382
2013 KISS1R induces invasiveness of estrogen receptor-negative human mammary epithelial and breast cancer cells. Endocrinology 42 23525242
2006 GPR54 and KiSS-1: role in the regulation of puberty and reproduction. Reviews in endocrine & metabolic disorders 42 17206526
2005 KiSS-1 and GPR54 as new players in gonadotropin regulation and puberty. Endocrine 42 16034182
2008 Molecular cloning of the bullfrog kisspeptin receptor GPR54 with high sensitivity to Xenopus kisspeptin. Peptides 41 18550222
2017 Characterisation of Kiss1r (Gpr54)-Expressing Neurones in the Arcuate Nucleus of the Female Rat Hypothalamus. Journal of neuroendocrinology 40 27981646
2013 Design, synthesis, and biological evaluation of novel investigational nonapeptide KISS1R agonists with testosterone-suppressive activity. Journal of medicinal chemistry 40 24047141
2011 Oestrogen induces rhythmic expression of the Kisspeptin-1 receptor GPR54 in hypothalamic gonadotrophin-releasing hormone-secreting GT1-7 cells. Journal of neuroendocrinology 40 21756268
2013 Kisspeptin receptor, GPR54, as a candidate for the regulation of testicular activity in the frog Rana esculenta. Biology of reproduction 39 23365413
2018 KISS1/KISS1R in Cancer: Friend or Foe? Frontiers in endocrinology 37 30123188
2013 Kisspeptin/KISS1R signaling potentiates extravillous trophoblast adhesion to type-I collagen in a PKC- and ERK1/2-dependent manner. Molecular reproduction and development 36 24273038
2012 Negative fetal FSH/LH regulation in late pregnancy is associated with declined kisspeptin/KISS1R expression in the tuberal hypothalamus. The Journal of clinical endocrinology and metabolism 36 23015653
2021 Kisspeptin-54 attenuates oxidative stress and neuronal apoptosis in early brain injury after subarachnoid hemorrhage in rats via GPR54/ARRB2/AKT/GSK3β signaling pathway. Free radical biology & medicine 35 33989759
2011 LIN28B, LIN28A, KISS1, and KISS1R in idiopathic central precocious puberty. BMC research notes 34 21939553
2014 Implication of metastasis suppressor gene, Kiss-1 and its receptor Kiss-1R in colorectal cancer. BMC cancer 33 25260785
2008 Kisspeptin and KISS1R: a critical pathway in the reproductive system. Reproduction (Cambridge, England) 33 18515314
2014 RF9 excitation of GnRH neurons is dependent upon Kiss1r in the adult male and female mouse. Endocrinology 31 25322463
2022 Neuroendocrine Regulation of Stress-Induced T Cell Dysfunction during Lung Cancer Immunosurveillance via the Kisspeptin/GPR54 Signaling Pathway. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 30 35224894
2021 KP-10/Gpr54 attenuates rheumatic arthritis through inactivating NF-κB and MAPK signaling in macrophages. Pharmacological research 30 33609696
2015 RF9 Acts as a KISS1R Agonist In Vivo and In Vitro. Endocrinology 30 26418326
2018 Downregulation of leptin receptor and kisspeptin/GPR54 in the murine hypothalamus contributes to male hypogonadism caused by high-fat diet-induced obesity. Endocrine 29 29948931
2018 Metabolic Impact on the Hypothalamic Kisspeptin-Kiss1r Signaling Pathway. Frontiers in endocrinology 28 29643834
2017 Potent Vasoconstrictor Kisspeptin-10 Induces Atherosclerotic Plaque Progression and Instability: Reversal by its Receptor GPR54 Antagonist. Journal of the American Heart Association 28 28411243
2015 KISS1R: Hallmarks of an Effective Regulator of the Neuroendocrine Axis. Neuroendocrinology 28 25765628
2015 GnRH Neuron-Specific Ablation of Gαq/11 Results in Only Partial Inactivation of the Neuroendocrine-Reproductive Axis in Both Male and Female Mice: In Vivo Evidence for Kiss1r-Coupled Gαq/11-Independent GnRH Secretion. The Journal of neuroscience : the official journal of the Society for Neuroscience 28 26377475
2014 KISS1R signals independently of Gαq/11 and triggers LH secretion via the β-arrestin pathway in the male mouse. Endocrinology 28 25147978
2018 Presence and function of kisspeptin/KISS1R system in swine ovarian follicles. Theriogenology 27 29698886
2012 Serum stability of selected decapeptide agonists of KISS1R using pseudopeptides. Bioorganic & medicinal chemistry letters 27 22975302
2012 Trypsin resistance of a decapeptide KISS1R agonist containing an Nω-methylarginine substitution. Bioorganic & medicinal chemistry letters 27 22995619
2010 Expression of functional KISS1 and KISS1R system is altered in human pituitary adenomas: evidence for apoptotic action of kisspeptin-10. European journal of endocrinology 27 21169415
2018 Kisspeptin-10 (KP-10) stimulates osteoblast differentiation through GPR54-mediated regulation of BMP2 expression and activation. Scientific reports 26 29391507
2020 The KiSS-1/GPR54 system: Essential roles in physiological homeostasis and cancer biology. Genes & diseases 25 35005105
2019 Cre/lox generation of a novel whole-body Kiss1r KO mouse line recapitulates a hypogonadal, obese, and metabolically-impaired phenotype. Molecular and cellular endocrinology 25 31442544
2012 Single-cell analyses reveal that KISS1R-expressing cells undergo sustained kisspeptin-induced signaling that is dependent upon an influx of extracellular Ca2+. Endocrinology 24 23070548
2006 GnRH receptor and GPR54 inactivation in isolated gonadotropic deficiency. Best practice & research. Clinical endocrinology & metabolism 24 17161329
2017 In vitro and in vivo effects of kisspeptin antagonists p234, p271, p354, and p356 on GPR54 activation. PloS one 23 28650956
2016 α-Bisabolol Inhibits Invasiveness and Motility in Pancreatic Cancer Through KISS1R Activation. Anticancer research 23 26851012
2016 Leptin/leptinR-kisspeptin/kiss1r-GnRH pathway reacting to regulate puberty onset during negative energy balance. Life sciences 23 27212704
2016 Role of the Kiss1/Kiss1r system in the regulation of pituitary cell function. Molecular and cellular endocrinology 23 27477782
2013 Changes in methylation patterns of kiss1 and kiss1r gene promoters across puberty. Genetics & epigenetics 23 25512707
2019 Maternal high-fat diet impairs follicular development of offspring through intraovarian kisspeptin/GPR54 system. Reproductive biology and endocrinology : RB&E 22 30670046
2015 The pregnant mouse uterus exhibits a functional kisspeptin/KISS1R signaling system on the day of embryo implantation. Reproductive biology and endocrinology : RB&E 22 26384646
2008 Structure-activity relationship study and NMR analysis of fluorobenzoyl pentapeptide GPR54 agonists. Biopolymers 22 18302161
2008 Physical association of GPR54 C-terminal with protein phosphatase 2A. Biochemical and biophysical research communications 22 18977201
2020 MKRN3 and KISS1R mutations in precocious and early puberty. Italian journal of pediatrics 21 32228714
2019 Kp-10 promotes bovine mammary epithelial cell proliferation by activating GPR54 and its downstream signaling pathways. Journal of cellular physiology 21 31621904
2014 Normosmic idiopathic hypogonadotropic hypogonadism due to a novel homozygous nonsense c.C969A (p.Y323X) mutation in the KISS1R gene in three unrelated families. Clinical endocrinology 20 25262569
2015 The role of KISS1/KISS1R system in tumor growth and invasion of differentiated thyroid cancer. Anticancer research 19 25667462
2015 Honokiol suppresses metastasis of renal cell carcinoma by targeting KISS1/KISS1R signaling. International journal of oncology 19 25846316
2015 Novel FGFR1 and KISS1R Mutations in Chinese Kallmann Syndrome Males with Cleft Lip/Palate. BioMed research international 19 26199944
2015 Effects of systematic N-terminus deletions and benzoylations of endogenous RF-amide peptides on NPFF1R, NPFF2R, GPR10, GPR54 and GPR103. Peptides 19 26211894
2010 Synthesis and structure-activity relationships of 2-acylamino-4,6-diphenylpyridine derivatives as novel antagonists of GPR54. Bioorganic & medicinal chemistry 19 20457527
2023 Acid-Resistant BODIPY Amino Acids for Peptide-Based Fluorescence Imaging of GPR54 Receptors in Pancreatic Islets. Angewandte Chemie (International ed. in English) 18 36917014
2021 The Traditional Chinese Medicine Fuyou Formula Alleviates Precocious Puberty by Inhibiting GPR54/GnRH in the Hypothalamus. Frontiers in pharmacology 18 33551803
2020 Association of Polymorphisms in the Kisspeptin/GPR54 Pathway Genes With Risk of Early Puberty in Chinese Girls. The Journal of clinical endocrinology and metabolism 18 32160304
2012 KISS1/KISS1R expression in eutopic and ectopic endometrium of women suffering from endometriosis. In vivo (Athens, Greece) 18 22210725
2012 A novel severe N-terminal splice site KISS1R gene mutation causes hypogonadotropic hypogonadism but enables a normal development of neonatal external genitalia. European journal of endocrinology 18 22619348
2011 Lack of KISS1R expression is associated with rapid progression of conventional renal cell carcinomas. The Journal of pathology 18 20922711
2010 Role of kisspeptin/GPR54 system in human reproductive axis. Frontiers of hormone research 18 20389082
2009 Association between sexual precocity and alleles of KISS-1 and GPR54 genes in goats. Animal biotechnology 18 19544215