Affinage

KISS1R

KiSS-1 receptor · UniProt Q969F8

Length
398 aa
Mass
42.6 kDa
Annotated
2026-06-10
100 papers in source corpus 30 papers cited in narrative 29 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

KISS1R (GPR54) is a Gαq/11-coupled G protein-coupled receptor activated by kisspeptins that serves as the central upstream switch for the hypothalamic-pituitary-gonadal axis and additionally couples kisspeptin signaling to cell migration, immunity, and metabolism (PMID:11387329, PMID:11414709, PMID:14573733). Ligand engagement triggers PLC-dependent IP3 generation, intracellular Ca2+ mobilization, and PKC activation, with sustained signaling requiring extracellular Ca2+ influx, alongside ERK1/2 and other MAPK outputs (PMID:14573733, PMID:23070548, PMID:15596153). Receptor signaling is shaped by GRK2-mediated desensitization and by β-arrestin 1/2, which can drive ERK1/2 activation independently of Gαq/11 — a branch that remains functional even in the disease-associated Gαq-uncoupled L148S mutant and is required for kisspeptin-dependent LH secretion in vivo (PMID:19846537, PMID:25147978). After agonist-induced internalization, the receptor is predominantly recycled back to the membrane while basally being turned over by the proteasome rather than the lysosome (PMID:21285314). The C-terminal cytoplasmic tail contains a proline/arginine-rich, SH3-motif segment that directly binds the PP2A catalytic subunit, and the receptor also associates with the scaffold IQGAP1 and transactivates EGFR (PMID:18977201, PMID:23525242, PMID:21738726). Loss-of-function mutations in KISS1R cause autosomal recessive idiopathic hypogonadotropic hypogonadism, and the receptor acts specifically in GnRH neurons to control puberty onset and fertility, as well as androgen-dependent sexual differentiation of the brain (PMID:14573733, PMID:24051579, PMID:17699664). Beyond reproduction, KISS1R signaling restrains antiviral innate immunity and inflammation via calcineurin/PP2A-mediated dephosphorylation of TBK1 and NF-κB/MAPK components, modulates breast cancer invasion through β-arrestin2/ERK1/2, EGFR, RhoA, and PKD1 pathways, and influences adipocyte and osteoblast differentiation (PMID:30101190, PMID:33609696, PMID:21738726, PMID:21852382, PMID:24894166, PMID:29593567, PMID:29391507).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 2001 High

    Establishing the cognate ligand for an orphan GPCR was the first requirement; pairing GPR54 with kisspeptins defined the receptor and its activation pharmacophore.

    Evidence Heterologous expression and functional agonist screening with substitution analysis in mammalian cells

    PMID:11387329 PMID:11414709

    Open questions at the time
    • Downstream physiological role not yet defined
    • Endogenous regulation of ligand-receptor system unknown
  2. 2003 High

    Whether KISS1R has an essential in vivo function was answered by human genetics and knockout mice, placing the receptor upstream of GnRH secretion and coupling it to the Gαq/11-PLC pathway.

    Evidence Homozygosity mapping/sequencing in HH patients, inositol phosphate assays of mutant receptors in COS-7, and Gpr54 knockout mouse phenotyping

    PMID:14573733 PMID:14652023

    Open questions at the time
    • Cell type responsible for the fertility phenotype not yet localized
    • Signaling branches beyond PLC not dissected
  3. 2007 High

    Beyond gonadotropin control, KISS1R was shown to be required for perinatal androgen-dependent masculinization of brain nuclei, extending its developmental role.

    Evidence Knockout mouse neuroanatomy (TH-IR neurons, Kiss1 mRNA, motoneuron counts) and behavior testing with hormone replacement

    PMID:17699664

    Open questions at the time
    • Direct neuronal site of action not pinpointed
    • Molecular signaling underlying masculinization unspecified
  4. 2008 High

    The intracellular signaling repertoire and a physical effector were defined, showing KISS1R engages multiple MAPK arms and directly binds PP2A-C through its C-terminal tail.

    Evidence Pathway synthesis across cell types, electrophysiology in hippocampal slices, and Y2H/GST pull-down/reconstitution with purified PP2A-C

    PMID:18765263 PMID:18775460 PMID:18977201

    Open questions at the time
    • Functional consequence of PP2A-C binding for receptor signaling not established at this stage
    • Cross-talk partners (CXCR4, GnRHR) mechanistically uncharacterized
  5. 2009 High

    How KISS1R activity is terminated and biased was addressed by identifying GRK2-mediated desensitization and β-arrestin-dependent ERK1/2 activation, and mapping the tail sequences governing membrane expression and internalization.

    Evidence Co-IP, confocal imaging, internalization and ERK1/2 assays in HEK293 and β-arrestin-2-deficient MDA-MB-231 cells

    PMID:19846537

    Open questions at the time
    • Relative contribution of arrestin vs G protein signaling in vivo not yet resolved
    • Constitutive activity significance unclear
  6. 2011 High

    Receptor fate after activation and a non-reproductive role in cancer were resolved: KISS1R is proteasomally turned over but recycled after agonist, and it drives breast cancer invasion via EGFR transactivation and Gαq-p63RhoGEF-RhoA.

    Evidence Proteasome/lysosome inhibitor and recycling assays with a gain-of-function mutant; FRET, β-arrestin2 knockdown, invasion assays, and Kiss1r-haploinsufficient MMTV-PyMT mice

    PMID:21285314 PMID:21738726 PMID:21852382

    Open questions at the time
    • Link between trafficking route and signaling duration only partly defined
    • Context determining pro- vs anti-tumor outputs not yet clear
  7. 2012 High

    The Ca2+ source requirement for sustained signaling was defined, showing store Ca2+ suffices for acute PKC activation but extracellular Ca2+ influx is required for prolonged signaling across neuronal and non-neuronal cells.

    Evidence Single-cell Ca2+ imaging and PKC assays with Ca2+ chelation/channel blockade in HEK293, GT1-7, and CHO cells

    PMID:23070548

    Open questions at the time
    • Identity of the relevant Ca2+ channels not established
    • Physiological relevance to GnRH neuron firing not directly tested
  8. 2013 High

    The cellular site responsible for fertility was definitively localized to the GnRH neuron via complementary conditional knockout and cell-specific rescue.

    Evidence GnRH neuron-specific Gpr54 deletion and BAC transgenic rescue in global knockouts with reproductive and kisspeptin-responsiveness readouts

    PMID:24051579

    Open questions at the time
    • Roles of non-GnRH Kiss1r-expressing neurons not addressed
    • Molecular signaling in GnRH neurons not dissected here
  9. 2013 Medium

    Additional structural determinants and a cytoskeletal scaffold were defined: a 7TM residue (Tyr313) is required for MAPK/Ca2+ signaling, and IQGAP1 binding mediates EGFR transactivation.

    Evidence In vitro functional characterization of patient mutations, clinical GnRH challenge, Co-IP of KISS1R-IQGAP1, and IQGAP1 knockdown

    PMID:23349759 PMID:23525242

    Open questions at the time
    • IQGAP1 interaction shown by Co-IP without reciprocal/structural validation
    • Direct vs indirect EGFR association not fully distinguished
  10. 2014 High

    A G protein-independent signaling axis for the physiological reproductive output was established, showing β-arrestins are required for kisspeptin-driven LH secretion and that the Gαq-uncoupled L148S mutant still signals to ERK1/2.

    Evidence β-arrestin-1/-2 knockout mice LH assays and L148S mutant analysis in HEK293 and β-arrestin-deficient MEFs

    PMID:25147978

    Open questions at the time
    • Mechanism coupling ERK1/2 to LH release not defined
    • Relative weighting of G protein vs arrestin signaling in normal physiology unclear
  11. 2014 Medium

    Anti-tumor signaling branches and an ovarian role were defined: kisspeptin/GPR54 suppresses migration/EMT via PKC-PKD1-Slug/E-cadherin, and oocyte KISS1R is required for gonadotropin-induced NTRK2.FL upregulation.

    Evidence siRNA knockdown of GPR54/PKD1 with migration and EMT marker readouts; oocyte-specific conditional knockouts and BDNF/kisspeptin co-stimulation

    PMID:24877631 PMID:24894166

    Open questions at the time
    • Reconciliation of pro- and anti-invasive outputs in different breast cancer contexts unresolved
    • Direct KISS1R-NTRK2 coupling mechanism inferred by epistasis only
  12. 2015 High

    A small molecule (RF9) was shown to be a direct KISS1R agonist rather than an allosteric modulator, and an invadopodia-forming program was mapped to β-arrestin2/ERK1/2.

    Evidence Radioligand binding, IP/Ca2+/ERK assays in KISS1R-CHO cells, Kiss1r/Npffr1 knockout and GnRH-neuron rescue mice; KISS1R/β-arrestin2 knockdown and invadopodia assays

    PMID:26418326 PMID:26721186

    Open questions at the time
    • RF9 binding site relative to kisspeptin not defined
    • Src-independence of invadopodia program mechanism not fully explained
  13. 2018 Medium

    Non-reproductive roles in immunity, inflammation, and metabolism were established, mechanistically tying KISS1R to phosphatase recruitment (calcineurin and PP2A-C) and to differentiation programs.

    Evidence Gpr54 knockout cells/mice with calcineurin/TBK1 and IFN-I assays; macrophage PP2A-C binding and CIA model; 3T3-L1/MSC adipocyte and C3H10T1/2 osteoblast differentiation assays in knockout cells/mice

    PMID:29391507 PMID:29593567 PMID:30101190 PMID:33609696

    Open questions at the time
    • How a single receptor selectively recruits calcineurin vs PP2A-C in different cells not resolved
    • Tissue-specific expression driving metabolic phenotypes not mapped
  14. 2022 Medium

    A T cell-intrinsic role linking kisspeptin/GPR54 to tumor immune evasion was defined via ERK5-NR4A1-driven T cell dysfunction.

    Evidence T cell-specific Gpr54 knockout, ERK5 inhibitor, and CRISPR knockout of GPR54/ERK5 in CAR-T cells with in vivo tumor and T cell functional assays

    PMID:35224894

    Open questions at the time
    • Source of kisspeptin acting on tumor-infiltrating T cells not defined
    • Generality across tumor types not established
  15. 2017 Medium

    Direct kisspeptin targets beyond GnRH neurons were identified by neurochemical mapping of Kiss1r-expressing arcuate neurons.

    Evidence In situ hybridization combined with immunofluorescence in female rat hypothalamus

    PMID:27981646

    Open questions at the time
    • Functional consequences in POMC/TIDA neurons not tested
    • Species/sex generalizability unaddressed
  16. 2023 Low

    Expression and subcellular localization of GPR54 in human pancreatic islets was visualized using fluorogenic kisspeptin probes, hinting at a peripheral endocrine site.

    Evidence Fluorescence imaging with Trp-BODIPY PLUS kisspeptin probes in human cells and mouse islets

    PMID:36917014

    Open questions at the time
    • Low-confidence localization tool study; functional consequence in islets not established
    • Cell-type identity within islets not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single receptor selects among Gαq, β-arrestin, EGFR, PP2A, and calcineurin effector branches to produce its divergent reproductive, immune, metabolic, and oncogenic outputs in a cell-type-specific manner remains unresolved.
  • No structural model of effector selection
  • Determinants of biased agonism across tissues not defined
  • Endogenous regulators of receptor surface expression and turnover incompletely characterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3 GO:0048018 receptor ligand activity 2 GO:0060090 molecular adaptor activity 2
Localization
GO:0005886 plasma membrane 3 GO:0005829 cytosol 2
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1474165 Reproduction 3 R-HSA-1643685 Disease 3 R-HSA-168256 Immune System 3
Partners
ARRB1ARRB2EGFRGRK2IQGAP1KISS1PPP2CA

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 AXOR12/GPR54 (KISS1R) is a G protein-coupled receptor that is activated by peptides derived from the KiSS-1 gene (kisspeptins), including surrogate agonist peptides with a common C-terminal amidated motif; heterologous expression in mammalian cells confirmed ligand-receptor pairing. GPR54 was also shown to be activated by invertebrate FMRFamide-related neuropeptides (RFamide/RWamide family) via the Gαq pathway, with the C-terminal optimal sequence Gly-Leu-Arg-Trp-NH2. Heterologous expression in mammalian cells, functional agonist screening, substitution analysis, Northern analysis The Journal of biological chemistry / Biochemical and biophysical research communications High 11387329 11414709
2003 Loss-of-function mutations in GPR54 (L148S homozygous; compound heterozygous R331X/X399R) cause autosomal recessive idiopathic hypogonadotropic hypogonadism in humans. In vitro transfection of COS-7 cells with mutant constructs demonstrated significantly decreased inositol phosphate accumulation, establishing that GPR54 signals via Gαq/11-coupled phospholipase C pathway. Gpr54-deficient mice recapitulated isolated hypogonadotropic hypogonadism with normal hypothalamic GnRH levels, placing GPR54 upstream of GnRH secretion (not GnRH synthesis). Human genetics (homozygosity mapping, sequencing), in vitro transfection/inositol phosphate assay (COS-7 cells), Gpr54 knockout mouse phenotyping The New England journal of medicine High 14573733
2003 Targeted disruption of GPR54 in mice results in developmental abnormalities of male and female genitalia and loss of sexually dimorphic tissue features, confirming that the GPR54/KiSS-1 system is essential for normal reproductive system development. Gpr54 knockout mouse generation and phenotypic analysis (histopathology, organ morphology) Biochemical and biophysical research communications High 14652023
2005 Activation of GPR54 by kisspeptin-10 in MDA-MB-435S cells promotes cell cycle arrest and apoptosis through a specific transcriptional program; this program requires PLC and PKC activation (upstream), and a subset of genes also requires p42/44 MAPK. The program is distinct from that activated by the bradykinin B2 receptor despite shared Gq/11 coupling, indicating GPR54-specific downstream gene regulation. cDNA microarray time-course, pharmacological inhibitors of PLC, PKC, and p42/44 MAPK, apoptosis assays, comparison with B2 receptor Biochemical and biophysical research communications Medium 15596153
2008 GPR54 signaling activates multiple intracellular pathways: Gαq/11-coupled PLC activation leading to IP3 accumulation, intracellular Ca2+ mobilization, and PKC activation; additionally ERK1/2 and p38 MAPK activation, PI3K/Akt, and effects on MMP9 expression via NFκB and calcineurin expression. GPR54 can also cross-talk with CXCR4 and GnRH receptor. Review synthesizing published functional assays across multiple cell types Peptides Medium 18775460
2008 In hippocampal dentate granule cells, GPR54 activation by kisspeptin-10 causes rapid, large increases in excitatory synaptic (AMPA receptor-mediated) response amplitude without changing membrane properties. This effect is postsynaptic, requires G-protein signaling (GDP-β-S-sensitive), intracellular Ca2+ (BAPTA-sensitive), and is abolished by inhibitors of ERK1/2, tyrosine kinase, and CaMKII. Electrophysiology (field recordings, mEPSC analysis), pharmacological inhibitors, RT-PCR, hippocampal slice cultures Peptides Medium 18765263
2008 The C-terminal cytoplasmic domain of GPR54, containing a proline- and arginine-rich segment with four overlapping SH3-binding motifs, physically associates with the catalytic subunit of protein phosphatase 2A (PP2A-C). GST pull-down experiments confirmed binding to PP2A-C in cell lysates, the complexes retained phosphatase activity, and direct binding to purified recombinant PP2A-C was demonstrated. The proline-arginine rich segment is necessary for this interaction. Yeast two-hybrid, GST fusion protein pull-down, phosphatase activity assay, binding to purified recombinant PP2A-C Biochemical and biophysical research communications High 18977201
2009 GPR54 signaling is regulated by GRK2 and β-arrestins 1 and 2. GPR54 is expressed at the plasma membrane and intracellularly, with membrane expression regulated by cytoplasmic tail sequences. GPR54 exhibits constitutive activity, undergoes agonist-induced internalization, and associates with GRK2 and β-arrestins through sequences in the second intracellular loop and cytoplasmic tail. GRK2 stimulates GPR54 desensitization; β-arrestin-2 mediates GPR54 activation of ERK1/2. Transfection of HEK293 cells and MDA-MB-231 cells (β-arrestin-2-deficient), co-immunoprecipitation, confocal imaging, ERK1/2 phosphorylation assays, receptor internalization assays Molecular endocrinology High 19846537
2011 Kisspeptin-10 (Kp-10) via GPR54 stimulates invasion of ERα-negative breast cancer cells (MDA-MB-231, Hs578T) and induces invasive stellate structures in 3D. Kp-10 increases MMP-9 activity. GPR54 directly associates (FRET-confirmed) with EGFR; Kp-10 stimulates EGFR transactivation, and this is increased upon Kp-10 treatment. β-arrestin 2 knockdown inhibits both EGFR transactivation and Kp-10-induced invasion. Matrigel invasion assays, 3D invasion assays, MMP-9 activity assay, β-arrestin-2 knockdown, FRET analysis, EGFR phosphorylation assays PloS one High 21738726
2011 KISS1R intracellular trafficking: WT KISS1R is degraded by proteasomes rather than lysosomes (proteasome inhibitor increased protein 24-fold; lysosome inhibitor had no effect). Upon kisspeptin stimulation, both WT and Arg386Pro KISS1R are internalized and recycled back to the membrane rather than degraded. The Arg386Pro gain-of-function mutation does not affect trafficking rate but decreases receptor degradation, resulting in net accumulation of recycled receptor at the plasma membrane, prolonging kisspeptin responsiveness. Confocal imaging with membrane and lysosome markers, proteasome and lysosome inhibitors, receptor internalization and recycling assays in transfected cells Endocrinology High 21285314
2011 Kiss1r haploinsufficiency in MMTV-PyMT mice attenuates breast cancer initiation, growth, latency, multiplicity, and lung metastasis. Kisspeptin-10 stimulation of Kiss1r activates RhoA through the Gαq-p63RhoGEF signaling pathway, and anchorage-independent growth is dose-dependently regulated by RhoA downstream of Kiss1r. siRNA knockdown of KISS1R or RhoA inactivation reduces Ras-induced anchorage-independent growth. Kiss1r heterozygous knockout in MMTV-PyMT mouse model, primary tumor cell isolation, in vitro tumorigenic assays, in vivo tumor growth in immunocompromised mice, RhoA activation assays, siRNA knockdown Cancer research High 21852382
2012 Sustained KISS1R signaling requires extracellular Ca2+. In single-cell analyses, chronic Kp-10 stimulation triggers prolonged activation of PLC, PKC, and Ca2+ mobilization in HEK293, GT1-7 GnRH neuronal, and CHO cells. Intracellular Ca2+ from stores is sufficient for acute PKC activation but insufficient for sustained signaling; extracellular Ca2+ influx is absolutely required for prolonged KISS1R signaling. Single-cell Ca2+ imaging, PKC activity assays, pharmacological Ca2+ chelation/channel blockade in multiple cell lines Endocrinology High 23070548
2013 The key cellular site of kisspeptin-Gpr54 signaling for fertility is the GnRH neuron. GnRH neuron-specific deletion of Gpr54 causes infertility, failure of puberty, reduced gonadal size, reduced FSH, and GnRH neurons unresponsive to kisspeptin. BAC transgenic rescue of Gpr54 expression specifically in GnRH neurons of global Gpr54-/- mice restores normal puberty, estrous cyclicity, fecundity, and kisspeptin responsiveness of GnRH neurons. Conditional knockout (GnRH neuron-specific Gpr54 deletion), BAC transgenesis for cell-specific knockin rescue, in vivo kisspeptin responsiveness testing, reproductive phenotyping Nature communications High 24051579
2013 KISS1R induces invasiveness in ERα-negative breast cancer cells via EGFR transactivation. ERα expression negatively regulates KISS1R-dependent migration, invasion, and EGFR transactivation by downregulating KISS1R expression. IQGAP1, an actin cytoskeletal scaffolding protein, was identified as a novel binding partner of KISS1R by co-immunoprecipitation, and KISS1R regulates EGFR transactivation in a KISS1R-IQGAP1-dependent manner. Co-immunoprecipitation (KISS1R-IQGAP1 interaction), invasion assays, EGFR transactivation assays, ERα re-expression experiments, IQGAP1 knockdown Endocrinology Medium 23525242
2014 KISS1R signals independently of Gαq/11 via β-arrestin to trigger LH (GnRH) secretion. In mice lacking β-arrestin-1 or β-arrestin-2, kisspeptin-dependent LH secretion was significantly diminished. The disease-associated Gαq/11-uncoupled L148S mutant retained the ability to trigger Kp-dependent ERK1/2 phosphorylation via a β-arrestin-dependent mechanism (demonstrated using MEFs lacking both β-arrestins). β-arrestin-1 and -2 knockout mice (LH secretion assay), HEK293 cell transfection with L148S mutant, MEF cells lacking β-arrestins, ERK1/2 phosphorylation assays Endocrinology High 25147978
2014 KiSS1/GPR54 signaling inhibits breast cancer cell migration and EMT through protein kinase D1 (PKD1). Kisspeptin stimulation elevates phosphorylated PKD1 in a PKC-dependent manner. GPR54 knockdown increases migration/invasion and blocks kisspeptin-induced PKD1 phosphorylation. PKD1 phosphorylation decreases expression of the EMT transcription factor Slug and increases E-cadherin expression. siRNA knockdown of GPR54 and PKD1, PKD1 phosphorylation assays, migration/invasion assays, colony formation assays, Slug and E-cadherin expression analysis Current molecular medicine Medium 24894166
2014 Loss of Kiss1r in oocytes causes impaired response to gonadotropins: oocytes lacking KISS1R fail to upregulate NTRK2 full-length receptor (NTRK2.FL) in response to the preovulatory LH surge. In a cell line co-expressing NTRK2.T1 and KISS1R, BDNF stimulation only activates NTRK2 expression if kisspeptin is present, and NTRK2.FL induction by gonadotropins fails in the absence of KISS1R in intact mice. Oocyte-specific Ntrk2 and Kiss1r conditional knockouts, in vitro BDNF/kisspeptin co-stimulation, Western blotting, RT-PCR, PI3K-AKT signaling assays Endocrinology Medium 24877631
2015 RF9 acts as a direct KISS1R agonist (not allosteric modulator). In CHO cells stably transfected with KISS1R, RF9 binds specifically to KISS1R (Kd ~1.6×10-5 M), stimulates intracellular Ca2+ increase and inositol phosphate accumulation (KISS1R-dependent), and stimulates ERK phosphorylation. In vivo, RF9-stimulated LH increase persists in Npffr1-/- mice but is markedly reduced in Kiss1r-/- mice and is rescued by GnRH neuron-specific Kiss1r re-expression. Radioligand binding assay, IP accumulation assay, Ca2+ assay, ERK phosphorylation, Npffr1-/-, Kiss1r-/-, and GnRH neuron-specific rescue mice Endocrinology High 26418326
2015 KISS1R signaling induces invadopodia formation in triple-negative breast cancer cells via a β-arrestin2- and ERK1/2-dependent mechanism, independent of Src. KISS1R activates cortactin, cofilin, and MT1-MMP (key invadopodia proteins). Depletion of KISS1R reduces mesenchymal phenotype and invasiveness. KISS1R knockdown/depletion, β-arrestin2 knockdown, invadopodia formation assays, cortactin/cofilin/MT1-MMP activity assays, ERK1/2 inhibition Cellular signalling Medium 26721186
2018 Kisspeptin/GPR54 signaling restricts antiviral innate immune responses by recruiting calcineurin and increasing its phosphatase activity to dephosphorylate and inactivate TBK1 in a Ca2+-dependent manner, thereby suppressing type I interferon production. Gpr54-deficient cells and mice showed enhanced IFN-I production and restricted viral replication. Gpr54 knockout cells and mice, calcineurin phosphatase activity assays, TBK1 dephosphorylation assays, IFN-I production measurement, viral replication assays Science advances High 30101190
2018 KP-10/GPR54 signaling in macrophages binds PP2A-C and suppresses LPS-induced NF-κB and MAPK signaling, reducing inflammatory cytokine production. In vivo, KP-10 ameliorated collagen-induced arthritis in mice, while Gpr54-/- increased CIA severity. The mechanism involves GPR54 recruiting PP2A catalytic subunit to dephosphorylate/inactivate NF-κB and MAPK pathway components. Western blotting, immunofluorescence, BMDM KO cells, CIA mouse model, in vitro LPS stimulation, cytokine measurement Pharmacological research Medium 33609696
2018 KP-10 via GPR54 stimulates osteoblast differentiation by upregulating BMP2 expression through NFATc4-mediated transcription, activating Smad1/5/9 phosphorylation. BMP2 protein secreted acts in an autocrine manner. This effect is GPR54-dependent: KP-10 did not induce BMP2 or Runx2 expression in GPR54-/- cells, though conditioned medium from KP-10-treated cells could rescue Dlx5/Runx2 in GPR54-/- cells. KP-10 treatment of C3H10T1/2 cells and GPR54-/- cells, BMP2-luciferase reporter, Smad1/5/9 phosphorylation, conditioned medium experiments, osteogenic gene expression Scientific reports Medium 29391507
2018 GPR54 promotes adipocyte differentiation and fat accumulation. In 3T3-L1 cells, Kp-10 accelerates adipocyte differentiation and promotes triglyceride synthesis. Primary MSCs from Gpr54-/- mice are less likely to differentiate into adipocytes. Gpr54-/- mice on high-fat diet show reduced adiposity, smaller adipocyte size, lower triglycerides, and reduced PPARγ expression. ERK phosphorylation is decreased in Gpr54-/- mice, suggesting GPR54 promotes lipid synthesis via MAP kinase pathway. Gpr54 knockout mice, 3T3-L1 differentiation assays, primary MSC differentiation, lipid staining, triglyceride measurement, ERK phosphorylation, gene expression analysis Frontiers in physiology Medium 29593567
2022 GPR54 in T cells mediates kisspeptin-induced T cell dysfunction during tumor immune evasion via ERK5-mediated NR4A1 activation. Kisspeptin-10 impairs T cell function; Gpr54 knockout in T cells inhibits lung tumor progression by suppressing T cell dysfunction/exhaustion. CRISPR/Cas9 depletion of GPR54 or ERK5 in CAR-T cells enhances antitumor responses and eliminates T cell exhaustion. T cell-specific Gpr54 knockout, kisspeptin-10 treatment, ERK5 inhibitor (XMD8-92), CRISPR/Cas9 knockout of GPR54/ERK5 in CAR-T cells, in vivo tumor models, T cell functional assays Advanced science Medium 35224894
2007 GPR54 signaling is required for proper male sexual differentiation of the brain. GPR54 KO males display female-like numbers of tyrosine hydroxylase-immunoreactive neurons and Kiss1 mRNA-containing neurons in the AVPV, and fewer motoneurons in the spino-bulbocavernosus nucleus, indicating that perinatal kisspeptin-GPR54 signaling regulates androgen-dependent brain masculinization during critical developmental windows. Copulatory behavior, however, is intact with appropriate adult hormone replacement. GPR54 knockout mouse phenotyping, immunohistochemistry for TH neurons, in situ hybridization for Kiss1 mRNA, motoneuron counting, sexual behavior testing with gonadal hormone replacement The Journal of neuroscience High 17699664
2010 A novel loss-of-function mutation (p.F272S) in GPR54 causes almost complete inhibition of kisspeptin-induced GPR54 signaling and dramatically decreases mutated receptor expression at the cell surface, establishing that proper cell surface expression of GPR54 is required for functional kisspeptin signaling. GPR54 sequencing, in vitro transfection and functional signaling assay, cell surface expression analysis The Journal of clinical endocrinology and metabolism Medium 21193544
2013 A novel KISS1R mutation (p.Tyr313His) in the seventh transmembrane domain impairs MAP kinase signaling and intracellular calcium release, establishing the functional importance of Tyr313 in KISS1R signal transduction. GnRH administration to a patient with KISS1R compound heterozygous mutations restored pulsatile LH secretion, confirming the defect is hypothalamic in origin. KISS1R gene sequencing, in vitro functional characterization (MAPK assay, intracellular Ca2+ measurement), pulsatile GnRH administration in patients PloS one Medium 23349759
2017 In the arcuate nucleus, approximately 63% of Kiss1r-expressing neurons are POMC neurons, and approximately 15% are tuberoinfundibular dopamine (TIDA) neurons. NPY and kisspeptin neurons in the ARN do not express Kiss1r. This neurochemical characterization establishes direct kisspeptin targets beyond GnRH neurons in the hypothalamus. In situ hybridization combined with immunofluorescence in female rat hypothalamus Journal of neuroendocrinology Medium 27981646
2023 GPR54 receptors are expressed and localized in human pancreatic islets, visualized using novel fluorogenic kisspeptin-based probes (Trp-BODIPY PLUS) that exhibit turn-on fluorescence upon target binding; confirming GPR54 receptor presence and subcellular localization in intact pancreatic tissue. Fluorescence imaging with novel BODIPY-based kisspeptin fluorogenic probes in human cells and whole mouse pancreatic islets Angewandte Chemie (International ed. in English) Low 36917014

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 1940 14573733
2001 AXOR12, a novel human G protein-coupled receptor, activated by the peptide KiSS-1. The Journal of biological chemistry 722 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 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 177 24051579
2008 The role of kisspeptins and GPR54 in the neuroendocrine regulation of reproduction. Annual review of physiology 173 17988212
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
2009 Down-regulation of hypothalamic kisspeptin and its receptor, Kiss1r, mRNA expression is associated with stress-induced suppression of luteinising hormone secretion in the female rat. Journal of neuroendocrinology 150 19094090
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 104 18775460
2009 Regulation of GPR54 signaling by GRK2 and {beta}-arrestin. Molecular endocrinology (Baltimore, Md.) 101 19846537
2012 Analysis of the expression of neurokinin B, kisspeptin, and their cognate receptors NK3R and KISS1R in the human female genital tract. Fertility and sterility 99 22424618
2001 FMRFamide-related neuropeptides are agonists of the orphan G-protein-coupled receptor GPR54. Biochemical and biophysical research communications 95 11414709
2006 Kisspepeptin-GPR54 signaling in the neuroendocrine reproductive axis. Molecular and cellular endocrinology 92 16762492
2009 Kisspeptin/Gpr54-independent gonadotrophin-releasing hormone activity in Kiss1 and Gpr54 mutant mice. Journal of neuroendocrinology 89 19840236
2018 Kisspeptin/GPR54 System: What Do We Know About Its Role in Human Reproduction? Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 84 30205368
2019 Reproductive functions of Kisspeptin/KISS1R Systems in the Periphery. Reproductive biology and endocrinology : RB&E 79 31399145
2011 GPR54 (KISS1R) transactivates EGFR to promote breast cancer cell invasiveness. PloS one 79 21738726
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 78 21193544
2008 The kisspeptin (KiSS-1)/GPR54 system in cancer biology. Cancer treatment reviews 77 18583061
2009 Neonatal lipopolysaccharide exposure delays puberty and alters hypothalamic Kiss1 and Kiss1r mRNA expression in the female rat. Journal of neuroendocrinology 76 19500221
2008 Transgenic mouse models to study Gpr54/kisspeptin physiology. Peptides 68 18571287
2014 Loss of Ntrk2/Kiss1r signaling in oocytes causes premature ovarian failure. Endocrinology 66 24877631
2011 Sexually dimorphic testosterone secretion in prenatal and neonatal mice is independent of kisspeptin-Kiss1r and GnRH signaling. Endocrinology 64 22202164
2011 Expression of Kisspeptin and its receptor GPR54 in the first trimester trophoblast of women with recurrent pregnancy loss. American journal of reproductive immunology (New York, N.Y. : 1989) 62 21996032
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
2005 Metastin and its G protein-coupled receptor, GPR54: critical pathway modulating GnRH secretion. Frontiers in neuroendocrinology 59 16309735
2007 Expression of metastin and a G-protein-coupled receptor (AXOR12) in epithelial ovarian cancer. European journal of cancer (Oxford, England : 1990) 57 17442564
2011 KISS1R intracellular trafficking and degradation: effect of the Arg386Pro disease-associated mutation. Endocrinology 53 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
2015 KISS1R signaling promotes invadopodia formation in human breast cancer cell via β-arrestin2/ERK. Cellular signalling 47 26721186
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
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
2006 GPR54 and KiSS-1: role in the regulation of puberty and reproduction. Reviews in endocrine & metabolic disorders 43 17206526
2013 KISS1R induces invasiveness of estrogen receptor-negative human mammary epithelial and breast cancer cells. Endocrinology 42 23525242
2009 Gene structure of the Kiss1 receptor-2 (Kiss1r-2) in the Atlantic halibut: insights into the evolution and regulation of Kiss1r genes. Molecular and cellular endocrinology 42 19931349
2005 KiSS-1 and GPR54 as new players in gonadotropin regulation and puberty. Endocrine 42 16034182
2017 Characterisation of Kiss1r (Gpr54)-Expressing Neurones in the Arcuate Nucleus of the Female Rat Hypothalamus. Journal of neuroendocrinology 40 27981646
2018 KISS1/KISS1R in Cancer: Friend or Foe? Frontiers in endocrinology 39 30123188
2013 Kisspeptin/KISS1R System in Breast Cancer. Journal of Cancer 39 24155777
2008 G protein-coupled receptors of the hypothalamic-pituitary-gonadal axis: a case for Gnrh, LH, FSH, and GPR54 receptor ligands. Medicinal research reviews 38 18561294
2013 Two families with normosmic congenital hypogonadotropic hypogonadism and biallelic mutations in KISS1R (KISS1 receptor): clinical evaluation and molecular characterization of a novel mutation. PloS one 36 23349759
2011 GPR54 is a target for suppression of metastasis in endometrial cancer. Molecular cancer therapeutics 35 21282360
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) 34 35224894
2014 Implication of metastasis suppressor gene, Kiss-1 and its receptor Kiss-1R in colorectal cancer. BMC cancer 34 25260785
2011 LIN28B, LIN28A, KISS1, and KISS1R in idiopathic central precocious puberty. BMC research notes 34 21939553
2008 Kisspeptin and KISS1R: a critical pathway in the reproductive system. Reproduction (Cambridge, England) 33 18515314
2018 Altered expression of the kisspeptin/KISS1R and neurokinin B/NK3R systems in mural granulosa and cumulus cells of patients with polycystic ovarian syndrome. Journal of assisted reproduction and genetics 32 30382469
2018 Kisspeptin/GPR54 signaling restricts antiviral innate immune response through regulating calcineurin phosphatase activity. Science advances 31 30101190
2021 KP-10/Gpr54 attenuates rheumatic arthritis through inactivating NF-κB and MAPK signaling in macrophages. Pharmacological research 30 33609696
2018 Metabolic Impact on the Hypothalamic Kisspeptin-Kiss1r Signaling Pathway. Frontiers in endocrinology 30 29643834
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
2012 KiSS1 and its G-protein-coupled receptor GPR54 in cancer development and metastasis. Cancer metastasis reviews 29 22692479
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
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
2013 Developmental profile and sexually dimorphic expression of kiss1 and kiss1r in the fetal mouse brain. Frontiers in endocrinology 27 24130552
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
2020 The KiSS-1/GPR54 system: Essential roles in physiological homeostasis and cancer biology. Genes & diseases 26 35005105
2018 Kisspeptin-10 (KP-10) stimulates osteoblast differentiation through GPR54-mediated regulation of BMP2 expression and activation. Scientific reports 26 29391507
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 25 23070548
2016 Role of the Kiss1/Kiss1r system in the regulation of pituitary cell function. Molecular and cellular endocrinology 24 27477782
2006 GnRH receptor and GPR54 inactivation in isolated gonadotropic deficiency. Best practice & research. Clinical endocrinology & metabolism 24 17161329
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
2013 Changes in methylation patterns of kiss1 and kiss1r gene promoters across puberty. Genetics & epigenetics 23 25512707
2020 MKRN3 and KISS1R mutations in precocious and early puberty. Italian journal of pediatrics 22 32228714
2013 Kiss1 and Kiss1r mRNA expression in the rat placenta: changes with gestational age and regulation by glucocorticoids. Placenta 22 23684378
2010 A high-throughput small-molecule ligand screen targeted to agonists and antagonists of the G-protein-coupled receptor GPR54. Journal of biomolecular screening 22 20460252
2008 Physical association of GPR54 C-terminal with protein phosphatase 2A. Biochemical and biophysical research communications 22 18977201
2019 Kp-10 promotes bovine mammary epithelial cell proliferation by activating GPR54 and its downstream signaling pathways. Journal of cellular physiology 21 31621904
2014 Menstrual cyclic change of metastin/GPR54 in endometrium. Medical molecular morphology 21 24908069
2014 KiSS1-induced GPR54 signaling inhibits breast cancer cell migration and epithelial-mesenchymal transition via protein kinase D1. Current molecular medicine 20 24894166
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
2005 [Expression and clinical significance of KISS-1 and GPR54 mRNA in endometrial carcinoma]. Zhonghua zhong liu za zhi [Chinese journal of oncology] 20 15949424
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
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 19 22619348
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
2020 Regulation of Pregnancy: Evidence for Major Roles by the Uterine and Placental Kisspeptin/KISS1R Signaling Systems. Seminars in reproductive medicine 18 31972863
2012 KISS1/KISS1R expression in eutopic and ectopic endometrium of women suffering from endometriosis. In vivo (Athens, Greece) 18 22210725
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
2018 Kisspeptin Receptor GPR54 Promotes Adipocyte Differentiation and Fat Accumulation in Mice. Frontiers in physiology 17 29593567
2018 The role of neuropeptides and neurotransmitters on kisspeptin/kiss1r-signaling in female reproduction. Journal of chemical neuroanatomy 17 30008384

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