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Showing NPY4R — PP1 is a alias.

NPY4R

Neuropeptide Y receptor type 4 · UniProt P50391

Length
375 aa
Mass
42.1 kDa
Annotated
2026-06-10
100 papers in source corpus 24 papers cited in narrative 24 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NPY4R (Y4/PPYR1) is a class A G-protein-coupled receptor that preferentially binds pancreatic polypeptide (PP) and serves as the principal receptor through which PP regulates appetite, endocrine secretion, and gut motility (PMID:7592911, PMID:20041129). The cloned human receptor binds PP with high affinity in a ligand hierarchy of PP > PYY > NPY and couples to pertussis toxin-sensitive Gi to inhibit cAMP while also mobilizing intracellular Ca2+ (PMID:7592911, PMID:10640301); in smooth muscle it additionally engages Gq to drive PLC/IP3-dependent Ca2+ release and contraction, and it activates ERK1/2 partly through PKC (PMID:15308651, PMID:11853873). PP recognition is mediated by the receptor N-terminus and a transmembrane pocket formed by the TM2 top and TM6-TM7 region, where electrostatic and hydrogen-bonding contacts with PP residues govern activation, and an allosteric site beneath the orthosteric pocket can be targeted by selective small-molecule antagonists (PMID:18767100, PMID:24375409, PMID:33595306). The receptor forms agonist-dissociable homodimers and, in rodent orthologs, undergoes rapid clathrin-mediated internalization to recycling endosomes, whereas human Y4R is notably resistant to agonist-promoted desensitization and internalization (PMID:14551289, PMID:11179953, PMID:10640301, PMID:16807358). In vivo, central Y4R signaling acts upstream of arcuate POMC/α-MSH/MC4R to suppress food intake and modulates LHA orexin and VMH BDNF neuron activity, indirectly inhibits the GnRH/gonadotropic axis, synergizes with Y2R to control bone mass and adiposity, mediates PP-driven colonic contractility and antisecretory responses, and suppresses glucagon release via PPYR1 expressed on pancreatic alpha-cells (PMID:20041129, PMID:17272395, PMID:12861009, PMID:19818748, PMID:25445712). Human genetic loss of NPY4R is causally linked to obesity through CNV loss and loss-of-function coding variants (PMID:26921218).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1995 High

    Establishing the identity and signaling output of the human Y4 receptor answered whether a distinct high-affinity PP receptor exists and how it transduces signal.

    Evidence Homology cloning with radioligand binding, cAMP RIA and Ca2+ assays in transfected cells

    PMID:7592911

    Open questions at the time
    • Endogenous tissue distribution not defined in the cloning study
    • Structural basis of PP selectivity unresolved
  2. 1997 Medium

    Comparison of rat, guinea pig, and chicken orthologs resolved how species-specific sequence divergence reshapes ligand selectivity, distinguishing PP-selective mammalian receptors from the broadly tuned avian receptor.

    Evidence Cross-species cloning with radioligand binding and cAMP assays in transfected cells

    PMID:12063188 PMID:9210181 PMID:9802391

    Open questions at the time
    • Residues responsible for divergent selectivity mapped only later
    • Physiological consequence of selectivity differences not addressed
  3. 2000 High

    Biochemical and trafficking characterization defined human Y4R as a glycosylated Gi-coupled receptor uniquely resistant to desensitization, while rodent Y4R internalizes rapidly, establishing a divergent regulatory behavior.

    Evidence Stable CHO transfectants with cross-linking, pertussis toxin, immunofluorescence, and clathrin-pathway inhibitor dissection

    PMID:10640301 PMID:11179953 PMID:16807358

    Open questions at the time
    • Molecular basis for human/rodent desensitization difference unknown
    • Phosphorylation/arrestin determinants not identified
  4. 1998 High

    Pharmacological probes (GR231118/1229U91) demonstrated that the NPY C-terminus suffices to activate Y4R, providing tools to dissect Y4 versus Y1 signaling.

    Evidence Radioligand binding and cAMP inhibition assays across cloned Y1, Y2, Y4, Y5 receptors

    PMID:9669502

    Open questions at the time
    • Partial-agonist behavior at hY4R clarified only later
    • Binding-pocket contacts not defined by this study
  5. 2002 High

    Defining receptor coupling and dimerization showed Y4R signals through both Gi and Gq, activates ERK via Gi/PKC, and forms agonist-dissociable homodimers that do not heterodimerize with other Y subtypes.

    Evidence Contraction/IP3/Ca2+ assays in smooth muscle, ERK phosphorylation with inhibitors, BRET2 and Western blot dimerization assays

    PMID:11853873 PMID:14551289 PMID:15308651

    Open questions at the time
    • Functional consequence of dimer dissociation not established
    • Stoichiometry and structural interface of dimer unknown
  6. 2002 High

    Genetic epistasis placed central Y4R as an inhibitor of the gonadotropic axis, explaining how elevated NPY tone suppresses fertility.

    Evidence Y4 knockout crossed onto ob/ob background with hormone, morphometric, and GnRH mRNA readouts

    PMID:12000791 PMID:17272395

    Open questions at the time
    • Y4R not detected on GnRH neurons, so the intermediate circuit is undefined
    • Cell type mediating indirect regulation unidentified
  7. 2003 High

    Hypothalamic and brainstem mapping with selective agonists positioned Y4R upstream of orexin, BDNF, and POMC neuron populations controlling feeding.

    Evidence Y4-KO mice, c-Fos mapping, in situ hybridization, and intra-LHA/i.p. ligand injection

    PMID:12598637 PMID:20041129 PMID:20116098

    Open questions at the time
    • Direct versus indirect activation of each neuron population not fully resolved
    • Apparent bidirectional feeding effects across studies not reconciled
  8. 2003 High

    Double-knockout genetics revealed Y4R synergy with Y2R in regulating bone volume and adiposity, showing Y4R alone is insufficient for bone phenotypes.

    Evidence Y2/Y4 double-knockout mice with DXA, bone histomorphometry, and hormone measurements

    PMID:12861009

    Open questions at the time
    • Molecular basis of Y2/Y4 synergy unknown
    • Cell type and signaling node mediating bone effects undefined
  9. 2006 High

    Loss-of-function tissue studies established Y4R as the mediator of PP effects in the colon, including antisecretory and contractile responses, and defined recycling-endosome trafficking.

    Evidence Y4-KO colonic mucosa in Ussing chambers, contractility assays, GTPγS binding, and transferrin co-trafficking in HEK293

    PMID:16807358 PMID:19818748

    Open questions at the time
    • Effector mechanism downstream of Y4R in epithelium not detailed
    • Non-cholinergic contraction pathway only partially dissected
  10. 2008 Medium

    Structural and mutagenesis studies defined the molecular determinants of PP recognition, identifying an N-terminal helix and TM2/TM6-TM7 pocket residues that contact PP, and later an allosteric antagonist site.

    Evidence Solution NMR and SPR of N-Y4 domain, double-cycle mutagenesis with homology modeling, and SAR/docking for (S)-VU0637120

    PMID:18767100 PMID:24375409 PMID:33595306

    Open questions at the time
    • No experimental full-length receptor structure
    • Allosteric site location inferred computationally without crystallographic validation
  11. 2014 High

    Cell-type-resolved expression and functional assays placed PPYR1 on pancreatic alpha-cells where it mediates PP suppression of glucagon, extending Y4R function to islet endocrine control.

    Evidence Immunoblotting, qRT-PCR on FACS-sorted alpha-cells, immunohistochemistry, and isolated islet glucagon secretion assays in mouse and human

    PMID:25445712

    Open questions at the time
    • Intracellular signaling coupling glucagon suppression not detailed
    • In vivo contribution to glucose homeostasis not quantified
  12. 2016 Medium

    Human genetic analysis linked NPY4R loss-of-function to obesity, connecting the receptor's anorexigenic role to disease.

    Evidence Genome-wide CNV analysis and coding-variant screening with functional receptor assays

    PMID:26921218

    Open questions at the time
    • Penetrance and population-level effect size not established
    • Mechanistic link between variant dysfunction and adiposity not demonstrated in vivo

Open questions

Synthesis pass · forward-looking unresolved questions
  • How human Y4R achieves desensitization resistance and how its central circuits coordinate the opposing orexigenic and anorexigenic feeding outputs remain unresolved.
  • No experimental structure of the active receptor-G protein complex
  • Identity of intermediate neurons linking Y4R to GnRH and orexin circuits unknown
  • Regulatory determinants distinguishing human from rodent trafficking undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3 GO:0048018 receptor ligand activity 2
Localization
GO:0005768 endosome 2 GO:0005886 plasma membrane 2
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-9609507 Protein localization 2
Partners
NPY2R

Evidence

Reading pass · 24 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 The human Y4 receptor (NPY4R/PPYR1) was cloned from a human placental genomic library and encodes a 375-amino acid GPCR. When transiently expressed, it binds 125I-PYY with high affinity (pKd=9.89) and shows ligand selectivity: PP > PYY > NPY. Human PP activation decreases cAMP and increases intracellular Ca2+ in Y4-transfected cells, establishing Gi-coupled and Ca2+-mobilizing signaling. Homology cloning, radioligand binding (125I-PYY), cAMP radioimmunoassay, intracellular Ca2+ measurement in transfected LMTK- cells The Journal of biological chemistry High 7592911
1997 The rat Y4 receptor was cloned and expressed; its pharmacological profile shows high selectivity for rat PP over NPY or PYY. The rat and human Y4 receptors share 75% amino acid identity but differ substantially in ligand selectivity and dependence on N-terminal PP residues, indicating species-specific ligand–receptor interactions. Cloning, 125I-PP radioligand binding, cAMP radioimmunoassay in transfected cells Peptides High 9210181
1998 GR231118 (1229U91) acts as a potent Y1 receptor antagonist (pA2=10.5 at human Y1) and simultaneously as a potent Y4 receptor agonist (pEC50=8.6 at human Y4), demonstrating that the C-terminus of NPY is sufficient for Y4 receptor activation but not Y1 activation. Activity confirmed in inhibition of forskolin-stimulated cAMP formation. Radioligand binding assays, functional cAMP inhibition assay across cloned Y1, Y2, Y4, Y5 receptors European journal of pharmacology High 9669502
1998 The guinea pig Y4 receptor was cloned; it is 84% identical to human Y4 (vs 74-75% for rat Y4) and its pharmacological profile (PP > NPY ≈ PYY > NPY2-36) is closer to human than rat Y4, establishing that accelerated sequence divergence in rodent Y4 receptors alters ligand selectivity. Cloning, 125I-hPP saturation and competition binding in expressed guinea pig Y4 receptor Regulatory peptides Medium 9802391
2000 Stable CHO cells expressing human Y4 receptor demonstrate: (1) a single binding site for 125I-hPP (Kd=0.26 nM), (2) a glycosylated receptor protein of Mr 60,000 identified by cross-linking, (3) hPP inhibits cAMP via pertussis toxin-sensitive Gi protein (EC50=0.56 nM), and (4) 24-hour exposure to 10 nM hPP produces no receptor desensitization, no reduction in binding capacity, and no internalization — establishing resistance to agonist-promoted desensitization as a defining functional property of human Y4R. Radioligand binding, cross-linking/SDS-PAGE, cAMP RIA, pertussis toxin treatment, immunofluorescence in stable CHO transfectants The Journal of pharmacology and experimental therapeutics High 10640301
2001 Cloned rat pancreatic polypeptide Y4 receptor expressed in CHO cells undergoes rapid, temperature-dependent, agonist-driven internalization via clathrin-mediated endocytosis (blocked by sucrose and phenylarsine oxide), in contrast to the Y2 receptor which shows minimal internalization. Internalized Y4 receptors traffic to endosome-like particulates, and receptor recovery is blocked by cycloheximide and monensin, indicating requirement for new protein synthesis and intact vesicular transport. Ligand internalization assays in CHO cells, pharmacological inhibitors (sucrose, phenylarsine oxide, cycloheximide, monensin), sucrose density gradient fractionation European journal of biochemistry Medium 11179953
2002 The chicken Y4 receptor was cloned and characterized; it binds PYYa, chicken PP, and NPY with similarly high affinities (Kd 68-160 pM), contrasting with mammalian Y4R which strongly prefers PP. RT-PCR and in situ hybridization showed expression in the dorsal motor nucleus of the vagus in the brainstem, suggesting conserved anatomical targeting. Cloning, 125I-pPYY saturation and competition binding in COS-7 cells, RT-PCR, in situ hybridization Journal of molecular endocrinology Medium 12063188
2002 Y2 and Y4 receptors are co-expressed on smooth muscle cells and both couple to Gq in addition to Gi2, enabling IP3-dependent Ca2+ release and muscle contraction. Y4 receptor activation by pancreatic polypeptide induces contraction insensitive to extracellular Ca2+ removal or L-type Ca2+ channel blockers but abolished by thapsigargin or PLC inhibitor U73122, establishing Y4R-Gq-IP3-Ca2+ release pathway for contraction. RT-PCR, radioligand binding with selective receptor protection, functional contraction assays, IP3 measurement, Ca2+ imaging, pertussis toxin treatment, pharmacological inhibitors in isolated smooth muscle cells The Journal of pharmacology and experimental therapeutics High 15308651
2002 Genetic deletion of Y4 receptor in ob/ob mice restores testosterone levels, testis and seminal vesicle size, and fertility in males (100% offspring production), and is associated with increased GnRH expression. This epistatic rescue establishes that central Y4 receptor signaling specifically inhibits the gonadotropic axis under conditions of elevated NPY tone. Genetic epistasis: Y4 knockout crossed onto ob/ob background; hormone ELISA, organ morphometry, GnRH mRNA analysis Genes & development High 12000791
2003 The rhesus Y4 receptor forms homodimers at the cell surface as demonstrated by BRET2 and Western blot analysis. Agonist stimulation with PP or 1229U91 dissociates these homodimers in a concentration-dependent manner. Y4 receptor does not heterodimerize with Y1, Y2, Y5, delta opioid, or mu opioid receptors. BRET2 (bioluminescence resonance energy transfer), Western blot analysis, C-terminal fusion with Renilla luciferase and GFP in transfected cells The Journal of pharmacology and experimental therapeutics Medium 14551289
2003 Y4 receptors are functionally expressed on orexin neurons in the lateral hypothalamic area; intra-LHA injection of the Y4-selective agonist rat PP (but not NPY) specifically activates c-Fos in orexin neurons and stimulates food and water intake, placing Y4R signaling upstream of orexin neuron activation in feeding regulation. Immunocytochemistry (co-localization of Y4 and orexin), in situ hybridization, stereotaxic intra-LHA injection of rPP and NPY, c-Fos immunohistochemistry The Journal of neuroscience High 12598637
2003 Double knockout of Y2 and Y4 receptors produces synergistic effects greater than either single knockout: a markedly lean phenotype despite hyperphagia, and a ~3-fold increase in bone volume with enhanced osteoblastic activity. Bone mass is not altered in Y4 single-knockout mice, suggesting Y4 pathway alone is insufficient but synergizes with Y2 pathway to regulate bone volume and adiposity. Double-knockout mouse genetics, dual-energy X-ray absorptiometry, bone histomorphometry, plasma hormone measurements Molecular and cellular biology High 12861009
2002 ERK1/2 phosphorylation by Y1, Y2, Y4, and Y5 receptors is blocked by pertussis toxin, indicating all four receptors couple to Gi/o to activate ERK. Y4 receptor-mediated ERK phosphorylation is reduced (but not eliminated) by the PKC inhibitor GF109203X, while Y5-mediated ERK activation is completely blocked by both PKC and PI3K inhibitors, revealing distinct downstream signaling divergence. ERK phosphorylation assays with pertussis toxin and selective kinase inhibitors in CHO cells expressing human Y1, Y2, Y4, or Y5 receptors Regulatory peptides Medium 11853873
2006 NPY4R agonist selectivity analysis in human and mouse colon: rPP responses are abolished in Y4-knockout mucosal preparations, establishing that Y4 receptors mediate antisecretory effects of PP at colonic epithelial cells. GR231118 acted as partial agonist at hY4 receptor; hPP internalization of Y4R traffics to recycling (transferrin-positive) endosomal pathways in HEK293 cells. Ussing chamber electrophysiology in Y4-knockout mouse tissue, radioligand displacement in Y4-transfected HEK293 cells, GTPγS binding, receptor internalization assay The Journal of pharmacology and experimental therapeutics High 16807358
2007 Y4 receptor knockout mice show reduced Y4 receptor-dependent c-Fos activation specifically in NTS/area postrema and arcuate nucleus POMC neurons after i.p. PP injection. Hypothalamus-specific conditional Y4 knockout abolishes PP-induced arcuate c-Fos activation and POMC mRNA upregulation. The hypophagic effect of PP is completely absent in melanocortin-4 receptor (MC4R) knockout mice, placing Y4R upstream of POMC/α-MSH/MC4R in the anorexigenic pathway. Global and conditional (hypothalamus-specific) Y4-knockout mice, c-Fos immunohistochemistry, in situ hybridization for POMC mRNA, MC4R-knockout epistasis, food intake measurement PloS one High 20041129
2007 Fasting-induced reduction of GnRH mRNA expression in the medial preoptic area and testis testosterone content are abolished in Y4-knockout mice but not Y2-knockout mice, while fasting-induced GHRH inhibition requires Y2 (not Y4) receptors. No Y4 receptors were detected on GnRH neurons, indicating that Y4 receptors indirectly regulate the gonadotropic axis. Y2 and Y4 receptor single and double knockout mice, hypothalamic conditional Y2 knockout, in situ hybridization, plasma hormone ELISA, immunohistochemistry Endocrinology High 17272395
2008 NMR spectroscopy of the isolated N-terminal domain of Y4 receptor (N-Y4) shows it is unstructured in solution but forms a helical segment in DPC/SDS micelles. Surface plasmon resonance reveals ~50 μM affinity binding of N-Y4 to PP; NPY and PYY bind much more weakly. Mutagenesis identifies electrostatic interactions between acidic ligand residues and basic N-Y4 receptor residues as the dominant binding determinants. Solution NMR spectroscopy, surface plasmon resonance, site-directed mutagenesis of N-terminal domain Chembiochem Medium 18767100
2009 PP enhances colonic muscle contraction and increases fecal output in wild-type mice but these effects are completely absent in Y4-receptor-knockout mice. PP-induced increases in colonic muscle tone and spontaneous contraction frequency in isolated colon are absent in KO mice. Atropine does not affect PP-induced responses, indicating Y4R-mediated colonic contractility is not cholinergic. Y4-knockout mice, fecal output quantification, isolated colon contractility assay, pharmacological dissection with atropine European journal of pharmacology High 19818748
2010 Peripherally administered PP activates orexin neurons in LHA and BDNF-expressing neurons in VMH via Y4 receptor-dependent c-Fos induction (absent in Y4-KO mice). PP injection down-regulates orexin mRNA in LHA in a Y4 receptor-dependent manner and up-regulates BDNF mRNA in VMH, placing Y4R signaling upstream of both orexin and BDNF pathways in appetite regulation. Y4-knockout mice, immunofluorescence c-Fos mapping, in situ hybridization for orexin and BDNF mRNA, i.p. PP injection Neuropeptides High 20116098
2013 Double-cycle mutagenesis and homology modeling of the hY4R-hPP complex identify residues Tyr(2.64), Asp(2.68), Asn(6.55), Asn(7.32), and Phe(7.35) of Y4R as critical for receptor activation by hPP. TM2 top and TM6-TM7 top form the core peptide binding pocket; Asn(7.32) likely hydrogen-bonds Arg(33) of hPP, and Phe(7.35) contacts hPP positions 33 and 36. Site-directed mutagenesis, double-cycle mutagenesis analysis, homology modeling based on class A GPCR crystal structures, radioligand binding and functional assays The Journal of biological chemistry Medium 24375409
2014 PPYR1 (NPY4R) protein is expressed in alpha-cells of mouse and human pancreatic islets (confirmed by immunoblotting, quantitative RT-PCR on FACS-sorted alpha-cells, and immunohistochemistry), but not in other islet cell types or exocrine pancreas. Glucose stimulation increases PP secretion, and direct exposure of islets to PP inhibits glucagon release, establishing a PP→PPYR1→glucagon suppression pathway in alpha-cells. Immunoblotting, quantitative RT-PCR on FACS-sorted pancreatic islet cell fractions, immunohistochemistry, isolated islet glucagon secretion assay Biochimica et biophysica acta High 25445712
2021 A selective allosteric antagonist (S)-VU0637120 inhibits native Y4R function and binds in an allosteric site located below the endogenous PP binding pocket within the core of Y4R transmembrane domains, as determined by in vitro, ex vivo, and in silico studies. This represents the first nonpeptide Y4R-selective antagonist and identifies an allosteric regulatory site distinct from the orthosteric PP binding pocket. Radioligand binding, functional assays, Ussing chamber ex vivo epithelium assay, computational docking/modeling, medicinal chemistry SAR Journal of medicinal chemistry Medium 33595306
2016 CNV loss in the NPY4R-containing 10q11.22 region is significantly more frequent in obese children than controls, and two rare non-synonymous heterozygous NPY4R coding variants identified only in the obese patient population demonstrate receptor dysfunction in functional assays, establishing a causal link between NPY4R loss-of-function and obesity pathogenesis. Genome-wide CNV analysis, mutation screening of NPY4R coding region, functional receptor assays for rare variants Obesity (Silver Spring, Md.) Medium 26921218
2005 Endogenous NPY acting via Y2 and Y4 receptors suppresses afferent c-Fos signaling from gastric acid challenge to the nucleus tractus solitarii. Y4-knockout mice show a 31% higher c-Fos response to intragastric HCl, and BIIE0246 (Y2 antagonist not crossing the blood-brain barrier) does not block the effect, indicating the Y4R-mediated suppression occurs centrally. Y2 and Y4 receptor-knockout mice, intragastric HCl challenge, c-Fos immunohistochemistry in NTS, peripheral vs. central antagonist discrimination Neuroscience Medium 16216428

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1997 Establishment of an osteocyte-like cell line, MLO-Y4. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 430 9421234
1995 Cloning and functional expression of a human Y4 subtype receptor for pancreatic polypeptide, neuropeptide Y, and peptide YY. The Journal of biological chemistry 333 7592911
2007 Oscillating fluid flow activation of gap junction hemichannels induces ATP release from MLO-Y4 osteocytes. Journal of cellular physiology 244 17301958
2002 MLO-Y4 osteocyte-like cells support osteoclast formation and activation. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 229 12412815
2001 Expression of functional gap junctions and regulation by fluid flow in osteocyte-like MLO-Y4 cells. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 156 11204425
1998 Species differences in the expression and distribution of the neuropeptide Y Y1, Y2, Y4, and Y5 receptors in rodents, guinea pig, and primates brains. The Journal of comparative neurology 154 9853905
2015 Effects of high glucose and advanced glycation end products on the expressions of sclerostin and RANKL as well as apoptosis in osteocyte-like MLO-Y4-A2 cells. Biochemical and biophysical research communications 137 25721666
2002 Y4 receptor knockout rescues fertility in ob/ob mice. Genes & development 135 12000791
2010 Activation of β-catenin signaling in MLO-Y4 osteocytic cells versus 2T3 osteoblastic cells by fluid flow shear stress and PGE2: Implications for the study of mechanosensation in bone. Bone 119 20713195
1999 Establishment and characterization of an osteocyte-like cell line, MLO-Y4. Journal of bone and mineral metabolism 107 10084404
2006 Serotonin transporter and receptor expression in osteocytic MLO-Y4 cells. Bone 99 16884969
1998 GR231118 (1229U91) and other analogues of the C-terminus of neuropeptide Y are potent neuropeptide Y Y1 receptor antagonists and neuropeptide Y Y4 receptor agonists. European journal of pharmacology 96 9669502
2017 Crosstalk between MLO-Y4 osteocytes and C2C12 muscle cells is mediated by the Wnt/β-catenin pathway. JBMR plus 93 29104955
2003 Synergistic effects of Y2 and Y4 receptors on adiposity and bone mass revealed in double knockout mice. Molecular and cellular biology 86 12861009
1998 Identification and distribution of mRNA encoding the Y1, Y2, Y4, and Y5 receptors for peptides of the PP-fold family in the rat intestine and colon. Biochemical and biophysical research communications 83 9636652
2003 Orexin neurons express a functional pancreatic polypeptide Y4 receptor. The Journal of neuroscience : the official journal of the Society for Neuroscience 76 12598637
2003 CD40 ligand blocks apoptosis induced by tumor necrosis factor alpha, glucocorticoids, and etoposide in osteoblasts and the osteocyte-like cell line murine long bone osteocyte-Y4. Endocrinology 76 12697681
1989 Immunodominant antigen of Actinobacillus actinomycetemcomitans Y4 in high-responder patients. Infection and immunity 75 2496034
2011 Association of the α(2)δ(1) subunit with Ca(v)3.2 enhances membrane expression and regulates mechanically induced ATP release in MLO-Y4 osteocytes. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 69 21638318
2008 Reduced anxiety-like and depression-related behavior in neuropeptide Y Y4 receptor knockout mice. Genes, brain, and behavior 68 18221379
1998 The pharmacology of neuropeptide Y (NPY) receptor-mediated feeding in rats characterizes better Y5 than Y1, but not Y2 or Y4 subtypes. Regulatory peptides 66 9802430
2008 Increased novelty-induced motor activity and reduced depression-like behavior in neuropeptide Y (NPY)-Y4 receptor knockout mice. Neuroscience 64 19121371
2011 Expression of muscle anabolic and metabolic factors in mechanically loaded MLO-Y4 osteocytes. American journal of physiology. Endocrinology and metabolism 59 22114022
2001 Cloned neuropeptide Y (NPY) Y1 and pancreatic polypeptide Y4 receptors expressed in Chinese hamster ovary cells show considerable agonist-driven internalization, in contrast to the NPY Y2 receptor. European journal of biochemistry 58 11179953
2016 Circulating osteocyte-derived exosomes contain miRNAs which are enriched in exosomes from MLO-Y4 cells. Biomedical reports 56 28357077
1997 The neuropeptide Y (Y4) receptor is highly expressed in neurones of the rat dorsal vagal complex. Brain research. Molecular brain research 56 9379829
2009 Critical role of arcuate Y4 receptors and the melanocortin system in pancreatic polypeptide-induced reduction in food intake in mice. PloS one 55 20041129
2002 Neuropeptide Y, Y1, Y2 and Y4 receptors mediate Y agonist responses in isolated human colon mucosa. British journal of pharmacology 54 11906964
2006 Neuropeptide Y (NPY) Y4 receptor selective agonists based on NPY(32-36): development of an anorectic Y4 receptor selective agonist with picomolar affinity. Journal of medicinal chemistry 52 16610810
2021 Bisphenol A induces pyroptotic cell death via ROS/NLRP3/Caspase-1 pathway in osteocytes MLO-Y4. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association 50 34929351
2004 Coexpression of Y1, Y2, and Y4 receptors in smooth muscle coupled to distinct signaling pathways. The Journal of pharmacology and experimental therapeutics 50 15308651
2003 Neuropeptide Y Y4 receptor homodimers dissociate upon agonist stimulation. The Journal of pharmacology and experimental therapeutics 50 14551289
2006 Combined deletion of Y1, Y2, and Y4 receptors prevents hypothalamic neuropeptide Y overexpression-induced hyperinsulinemia despite persistence of hyperphagia and obesity. Endocrinology 47 16873543
2002 Activation of extracellular signal regulated protein kinase by neuropeptide Y and pancreatic polypeptide in CHO cells expressing the NPY Y(1), Y(2), Y(4) and Y(5) receptor subtypes. Regulatory peptides 46 11853873
1998 Involvement of prostaglandin E2 and interleukin-1 alpha in the differentiation and survival of osteoclasts induced by lipopolysaccharide from Actinobacillus actinomycetemcomitans Y4. Journal of periodontal research 46 9879525
2017 Estrogen deficiency attenuates fluid flow-induced [Ca2+]i oscillations and mechanoresponsiveness of MLO-Y4 osteocytes. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 45 28363954
2014 Pancreatic polypeptide regulates glucagon release through PPYR1 receptors expressed in mouse and human alpha-cells. Biochimica et biophysica acta 44 25445712
2012 Studying osteocyte function using the cell lines MLO-Y4 and MLO-A5. Methods in molecular biology (Clifton, N.J.) 43 22130923
2009 Evidence from knockout mice for distinct implications of neuropeptide-Y Y2 and Y4 receptors in the circadian control of locomotion, exploration, water and food intake. Neuropeptides 42 19781771
1995 Actinobacillus actinomycetemcomitans Y4 capsular-polysaccharide-like polysaccharide promotes osteoclast-like cell formation by interleukin-1 alpha production in mouse marrow cultures. Infection and immunity 40 7729899
2013 Interactions of zebrafish peptide YYb with the neuropeptide Y-family receptors Y4, Y7, Y8a, and Y8b. Frontiers in neuroscience 39 23508731
1994 The human Y4 small cytoplasmic RNA gene is controlled by upstream elements and resides on chromosome 7 with all other hY scRNA genes. Nucleic acids research 39 7520568
2017 miR-199a-3p is involved in estrogen-mediated autophagy through the IGF-1/mTOR pathway in osteocyte-like MLO-Y4 cells. Journal of cellular physiology 38 28708244
2013 Replacement of Thr32 and Gln34 in the C-terminal neuropeptide Y fragment 25-36 by cis-cyclobutane and cis-cyclopentane β-amino acids shifts selectivity toward the Y(4) receptor. Journal of medicinal chemistry 38 24090364
2006 Y(4) receptors mediate the inhibitory responses of pancreatic polypeptide in human and mouse colon mucosa. The Journal of pharmacology and experimental therapeutics 37 16807358
2021 Mechanical loading activates the YAP/TAZ pathway and chemokine expression in the MLO-Y4 osteocyte-like cell line. Laboratory investigation; a journal of technical methods and pathology 36 34521992
2010 Y4 receptors and pancreatic polypeptide regulate food intake via hypothalamic orexin and brain-derived neurotropic factor dependent pathways. Neuropeptides 36 20116098
2002 Chicken neuropeptide Y-family receptor Y4: a receptor with equal affinity for pancreatic polypeptide, neuropeptide Y and peptide YY. Journal of molecular endocrinology 36 12063188
2000 [(125)I]-GR231118: a high affinity radioligand to investigate neuropeptide Y Y(1) and Y(4) receptors. British journal of pharmacology 36 10694200
1998 The cloned guinea pig pancreatic polypeptide receptor Y4 resembles more the human Y4 than does the rat Y4. Regulatory peptides 36 9802391
2015 Activation of AMP-activated protein kinase protects against homocysteine-induced apoptosis of osteocytic MLO-Y4 cells by regulating the expressions of NADPH oxidase 1 (Nox1) and Nox2. Bone 35 25933943
2017 Advanced glycation end products induced IL-6 and VEGF-A production and apoptosis in osteocyte-like MLO-Y4 cells by activating RAGE and ERK1/2, P38 and STAT3 signalling pathways. International immunopharmacology 34 28910744
2012 17β estradiol regulation of connexin 43-based gap junction and mechanosensitivity through classical estrogen receptor pathway in osteocyte-like MLO-Y4 cells. Bone 34 23247057
2007 Determination of affinity and activity of ligands at the human neuropeptide Y Y4 receptor by flow cytometry and aequorin luminescence. Journal of receptor and signal transduction research 33 17885919
2017 Advanced Glycation End Product 3 (AGE3) Increases Apoptosis and the Expression of Sclerostin by Stimulating TGF-β Expression and Secretion in Osteocyte-Like MLO-Y4-A2 Cells. Calcified tissue international 32 28229177
2001 Hormonally-regulated expression of voltage-operated Ca(2+) channels in osteocytic (MLO-Y4) cells. Biochemical and biophysical research communications 32 11401493
2000 Functional and molecular properties of the human recombinant Y4 receptor: resistance to agonist-promoted desensitization. The Journal of pharmacology and experimental therapeutics 32 10640301
1997 A structure-activity analysis of the cloned rat and human Y4 receptors for pancreatic polypeptide. Peptides 30 9210181
2016 CNV analysis and mutation screening indicate an important role for the NPY4R gene in human obesity. Obesity (Silver Spring, Md.) 29 26921218
2016 Molecular characterization of neuropeptide Y (NPY) receptors (Y1, Y4 and Y6) and investigation of the tissue expression of their ligands (NPY, PYY and PP) in chickens. General and comparative endocrinology 29 27641685
2013 Pancreatic polypeptide is recognized by two hydrophobic domains of the human Y4 receptor binding pocket. The Journal of biological chemistry 28 24375409
2009 Evidence from knockout mice that neuropeptide-Y Y2 and Y4 receptor signalling prevents long-term depression-like behaviour caused by immune challenge. Journal of psychopharmacology (Oxford, England) 28 19939871
2020 HIF-1α induces hypoxic apoptosis of MLO-Y4 osteocytes via JNK/caspase-3 pathway and the apoptotic-osteocyte-mediated osteoclastogenesis in vitro. Tissue & cell 27 32835935
1999 Neuropeptide Y-induced contraction is mediated by neuropeptide Y Y2 and Y4 receptors in the rat colon. European journal of pharmacology 26 10422644
2016 High Affinity Agonists of the Neuropeptide Y (NPY) Y4 Receptor Derived from the C-Terminal Pentapeptide of Human Pancreatic Polypeptide (hPP): Synthesis, Stereochemical Discrimination, and Radiolabeling. Journal of medicinal chemistry 24 27223253
2012 17β-estradiol rapidly activates calcium release from intracellular stores via the GPR30 pathway and MAPK phosphorylation in osteocyte-like MLO-Y4 cells. Calcified tissue international 24 22392527
2017 The potential role of spectrin network in the mechanotransduction of MLO-Y4 osteocytes. Scientific reports 23 28112189
2016 Advanced oxidation protein products induce apoptosis, and upregulate sclerostin and RANKL expression, in osteocytic MLO-Y4 cells via JNK/p38 MAPK activation. Molecular medicine reports 23 28000869
2010 Y2 and Y4 receptor signaling synergistically act on energy expenditure and physical activity. American journal of physiology. Regulatory, integrative and comparative physiology 23 20881101
2019 FOXO1 Mediates Advanced Glycation End Products Induced Mouse Osteocyte-Like MLO-Y4 Cell Apoptosis and Dysfunctions. Journal of diabetes research 22 31886284
2016 Beta-adrenergic signaling affect osteoclastogenesis via osteocytic MLO-Y4 cells' RANKL production. Biochemical and biophysical research communications 22 27823934
2007 Fasting inhibits the growth and reproductive axes via distinct Y2 and Y4 receptor-mediated pathways. Endocrinology 22 17272395
2005 BODIPY-conjugated neuropeptide Y ligands: new fluorescent tools to tag Y1, Y2, Y4 and Y5 receptor subtypes. British journal of pharmacology 22 16231000
2021 Bisphenol A induces apoptosis and autophagy in murine osteocytes MLO-Y4: Involvement of ROS-mediated mTOR/ULK1 pathway. Ecotoxicology and environmental safety 21 34954677
2018 Fluid shear stress improves morphology, cytoskeleton architecture, viability, and regulates cytokine expression in a time-dependent manner in MLO-Y4 cells. Cell biology international 21 30022568
2014 Acetylcholine affects osteocytic MLO-Y4 cells via acetylcholine receptors. Molecular and cellular endocrinology 21 24508663
2002 Vitamin E and the Y4 agonist BA-129 decrease prostate cancer growth and production of vascular endothelial growth factor. The Journal of surgical research 21 12069504
2002 Cardiac function in neuropeptide Y Y4 receptor-knockout mice. Regulatory peptides 21 12468109
2001 Three types of K(+) currents in murine osteocyte-like cells (MLO-Y4). Bone 21 11165940
1983 Lytic sensitivity of Actinobacillus actinomycetemcomitans Y4 to lysozyme. Infection and immunity 21 6404833
2022 Piezo1-mediated fluid shear stress promotes OPG and inhibits RANKL via NOTCH3 in MLO-Y4 osteocytes. Channels (Austin, Tex.) 20 35754337
2014 Concomitant activation of the PI3K/Akt and ERK1/2 signalling is involved in cyclic compressive force-induced IL-6 secretion in MLO-Y4 cells. Cell biology international 20 24375569
2008 Studies of the structure of the N-terminal domain from the Y4 receptor - a G protein-coupled receptor - and its interaction with hormones from the NPY family. Chembiochem : a European journal of chemical biology 20 18767100
2003 Ligand internalization by cloned neuropeptide Y Y5 receptors excludes Y2 and Y4 receptor-selective peptides. European journal of pharmacology 20 12909193
2015 Activation of AMP-activated protein kinase decreases receptor activator of NF-κB ligand expression and increases sclerostin expression by inhibiting the mevalonate pathway in osteocytic MLO-Y4 cells. Biochemical and biophysical research communications 19 26713363
2010 Regulatory effects of Y4 receptor agonist (BVD-74D) on food intake. Peptides 19 20600429
2009 Pancreatic polypeptide enhances colonic muscle contraction and fecal output through neuropeptide Y Y4 receptor in mice. European journal of pharmacology 19 19818748
2007 Neuropeptide Y (NPY) Y2 receptor-selective agonist inhibits food intake and promotes fat metabolism in mice: combined anorectic effects of Y2 and Y4 receptor-selective agonists. Peptides 19 17204349
2001 Studies of the human, rat, and guinea pig Y4 receptors using neuropeptide Y analogues and two distinct radioligands. Peptides 19 11287089
2021 Highly Selective Y4 Receptor Antagonist Binds in an Allosteric Binding Pocket. Journal of medicinal chemistry 18 33595306
2020 High Glucose Downregulates Connexin 43 Expression and Its Gap Junction and Hemichannel Function in Osteocyte-like MLO-Y4 Cells Through Activation of the p38MAPK/ERK Signal Pathway. Diabetes, metabolic syndrome and obesity : targets and therapy 18 32161481
2017 Glucose uptake inhibition decreases expressions of receptor activator of nuclear factor-kappa B ligand (RANKL) and osteocalcin in osteocytic MLO-Y4-A2 cells. American journal of physiology. Endocrinology and metabolism 18 29018002
2023 ROS-mediated mitophagy and necroptosis regulate osteocytes death caused by TCP particles in MLO-Y4 cells. Toxicology 17 37678662
2022 Enhancing the Activity of Carboxymethyl Cellulase Enzyme Using Highly Stable Selenium Nanoparticles Biosynthesized by Bacillus paralicheniformis Y4. Molecules (Basel, Switzerland) 17 35889450
2018 Copy number of pancreatic polypeptide receptor gene NPY4R correlates with body mass index and waist circumference. PloS one 17 29621259
2005 Endogenous neuropeptide Y depresses the afferent signaling of gastric acid challenge to the mouse brainstem via neuropeptide Y type Y2 and Y4 receptors. Neuroscience 17 16216428
2010 Low-intensity pulsed ultrasound modulates shear stress induced PGHS-2 expression and PGE2 synthesis in MLO-Y4 osteocyte-like cells. Annals of biomedical engineering 16 20820919
2007 NPY Y2 and Y4 receptors selective ligands: promising anti-obesity drugs? Current topics in medicinal chemistry 16 17979782
2005 Internalization of cloned pancreatic polypeptide receptors is accelerated by all types of Y4 agonists. Regulatory peptides 16 16213038
2001 Constitutive neuropeptide Y Y(4) receptor expression in human colonic adenocarcinoma cell lines. British journal of pharmacology 16 11156595

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