Affinage

NPY2R

Neuropeptide Y receptor type 2 · UniProt P49146

Length
381 aa
Mass
42.7 kDa
Annotated
2026-06-10
22 papers in source corpus 8 papers cited in narrative 9 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

NPY2R is a Gi-coupled G-protein-coupled receptor for NPY/PYY ligands that inhibits adenylyl cyclase, suppressing cAMP production upon activation by PYY(3-36) and cross-inhibiting cAMP responses driven by co-expressed adenosine A2B receptors (PMID:29491394). The gene arose by duplication at chromosome 4q31 adjacent to NPY1R and is encoded across two exons with an intron interrupting the 5'-UTR (PMID:8975716). Beyond canonical Gi signaling, NPY2R engages distinct effector cascades in different tissues: in podocytes it activates PI3K, MAPK, and NFAT signaling, modulating RNA processing and inhibiting migration, with antagonism reducing albuminuria in glomerulosclerotic mice (PMID:32101625); in articular chondrocytes it drives hypertrophy and matrix degradation through mTORC1, whose effector S6K1 phosphorylates SMAD1/5/8 to promote SMAD4 nuclear translocation and Runx2 upregulation (PMID:32101625); and in sebaceous glands it forms a complex with NPY5R and NFATc1, where NFATc1 dephosphorylation and nuclear translocation (counteracted by DYRK1A phosphorylation) drives sebum-gene transcription (PMID:37501148). At the systems level, NPY2R mediates central and peripheral control of feeding—tectal NPY2R modulates prey-capture behavior and predator-induced food-intake suppression (PMID:31271760), and a long-acting NPY2R agonist reduces food intake and delays gastric emptying, synergizing with GLP-1R/GCGR co-agonism for body-weight reduction (PMID:40619099). NPY2R-expressing pulmonary vagal sensory neurons, activated via a purinergic ATP/P2rx2 axis, project to brainstem and midbrain nuclei to mediate analgesia (PMID:40874463). A functional promoter variant that increases NPY2R expression is associated with later Huntington disease onset, and NPY2R agonism protects against mutant huntingtin-induced cell death (PMID:24121255).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 1996 High

    Established the molecular identity of human NPY2R, defining it as a GPCR gene arising by duplication at a locus shared with NPY1R—the foundation for all subsequent receptor pharmacology.

    Evidence Gene cloning, genomic sequencing, Northern analysis, and chromosomal mapping

    PMID:8975716

    Open questions at the time
    • No ligand-binding or signaling characterization in this report
    • Tissue expression pattern not functionally interpreted
  2. 2014 Medium

    Connected NPY2R expression level to a neuroprotective phenotype, showing a promoter variant raises expression and that Y2-receptor agonism protects neuronal cells from mutant huntingtin toxicity.

    Evidence Luciferase promoter reporter assay, PC12 cell viability assay with mutant huntingtin, and HD-cohort genetic association

    PMID:24121255

    Open questions at the time
    • Downstream neuroprotective signaling pathway not defined
    • Association does not establish causal mechanism in vivo
    • PC12 model may not reflect neuronal context
  3. 2018 Medium

    Confirmed the core transduction mechanism—Gi-coupled cAMP inhibition—and demonstrated heterologous cross-talk with adenosine A2B receptor cAMP signaling.

    Evidence Real-time FRET-based cAMP assay in living cells with receptor-selective agonists/antagonists

    PMID:29491394

    Open questions at the time
    • Physiological relevance of A2B cross-talk untested
    • Single-lab cell-based system without in vivo validation
  4. 2019 Medium

    Located NPY2R within a central feeding circuit, showing tectal NPY acts through NPY2R to regulate prey-capture and predator-induced suppression of food intake.

    Evidence Bilateral tectal microinjection of NPY and antagonist BIIE0246 with behavioral phenotyping in Xenopus laevis

    PMID:31271760

    Open questions at the time
    • Non-mammalian model limits generalization
    • Downstream tectal circuitry not mapped
    • Cellular signaling mechanism not addressed
  5. 2020 High

    Revealed tissue-specific effector branching: NPY2R drives PI3K/MAPK/NFAT signaling in podocytes (with anti-albuminuric therapeutic potential) and mTORC1-S6K1-SMAD-Runx2 signaling in chondrocytes promoting cartilage degradation.

    Evidence In vitro pathway dissection, proteomics, co-IP of S6K1/SMAD1/5/8, in vivo selective antagonist treatment and knockout mouse studies

    PMID:32101625

    Open questions at the time
    • How a single Gi-coupled receptor selects between PI3K/MAPK/NFAT and mTORC1 effectors is unexplained
    • Direct receptor-to-PI3K/mTORC1 coupling step not resolved
  6. 2023 Medium

    Defined a transcriptional output of NPY2R signaling, placing it in a physical complex with NPY5R and NFATc1 that, opposed by DYRK1A, controls sebum-gene transcription.

    Evidence Reciprocal Co-IP, mass spectrometry, gel filtration, ChIP-seq, immunofluorescence, and RNA-seq in sebaceous gland tissue

    PMID:37501148

    Open questions at the time
    • Stoichiometry and direct vs. indirect nature of the NPY2R-NFATc1 association unclear
    • Single-lab finding without independent replication
    • Link from receptor activation to NFATc1 dephosphorylation not mechanistically traced
  7. 2025 Medium

    Identified NPY2R+ pulmonary vagal sensory neurons as the relay of a lung-to-brain analgesic circuit driven by a purinergic ATP/P2rx2 input.

    Evidence Murine pain models, chemogenetic DREADD activation, neural tracing, and P2rx2 agonist inhalation

    PMID:40874463

    Open questions at the time
    • Role of NPY2R signaling itself (vs. its use as a neuronal marker) in analgesia not isolated
    • Endogenous ligand engaging these neurons not defined
  8. 2025 Medium

    Translated NPY2R pharmacology into a metabolic therapeutic strategy, showing agonism reduces food intake and gastric emptying and synergizes with GLP-1R/GCGR co-agonism for weight loss.

    Evidence In vivo dose-response with selective NPY2R agonist BI 1820237 and combination interaction analysis in lean and diet-induced obese mice

    PMID:40619099

    Open questions at the time
    • Neuronal site and circuit mediating the anorectic effect not localized
    • Mechanism of synergy with incretin co-agonism unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How NPY2R selects among its divergent tissue-specific effector pathways (cAMP inhibition, PI3K/MAPK/NFAT, mTORC1/SMAD, NFATc1 transcription) from a single Gi-coupled receptor remains unresolved.
  • No structural model linking receptor conformations to effector choice
  • Determinants of tissue-specific signaling bias unknown
  • No unified receptor-proximal signaling map across tissues

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0001618 virus receptor activity 1 GO:0060089 molecular transducer activity 1
Localization
GO:0005886 plasma membrane 1
Pathway
R-HSA-162582 Signal Transduction 3
Partners
NFATC1NPY5R
Complex memberships
NPY2R/NPY5R/NFATc1 complex

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 The human NPY2R gene was cloned and characterized: it spans 9 kb of genomic sequence, is encoded on two exons, has a ~4.5 kb intron interrupting the 5'-UTR (analogous to NPY1R but lacking a coding-region intron), encodes a 381-amino-acid GPCR, and maps to chromosome 4q31—the same locus as NPY1R—suggesting origin by gene duplication. Gene cloning, genomic sequencing, Northern analysis, chromosomal mapping Genomics High 8975716
2018 NPY2R functions as a Gi-coupled receptor that inhibits cAMP production in response to PYY(3-36); the chimeric peptide EP45 recapitulates this NPY2R-mediated cAMP inhibition in living cells, and in cells co-expressing NPY2R and adenosine A2B receptors, NPY2R activation suppresses A2B-stimulated cAMP production. Real-time FRET-based cAMP assay in living cells; pharmacological receptor-selective agonist/antagonist experiments Scientific reports Medium 29491394
2014 A promoter SNP in NPY2R (rs2234759) functionally increases NPY2R expression (shown by luciferase reporter assay), and higher NPY2R expression is associated with later age of onset in Huntington disease. Treatment of PC12 cells expressing mutant huntingtin exon 1 with NPY or the NPY2R-selective agonist NPY(3-36) protected against mutant huntingtin-induced cell death, indicating NPY acts through Y2 receptors to confer neuroprotection. Luciferase promoter reporter assay; cell viability assay in PC12 cells with mutant huntingtin; genetic association in HD cohort Journal of molecular medicine Medium 24121255
2020 In podocytes, NPY signals via NPY2R to activate PI3K, MAPK, and NFAT signaling pathways; unbiased proteomic analysis showed that NPY-NPY2R signaling predicts nephrotoxicity, modulates RNA processing, and inhibits cell migration. Pharmacological inhibition of NPY2R in vivo significantly reduced albuminuria in adriamycin-treated glomerulosclerotic mice. In vitro podocyte signaling assays (PI3K, MAPK, NFAT pathway readouts); unbiased proteomic analysis; in vivo NPY2R antagonist treatment in mouse model; NPY-knockout mouse studies Proceedings of the National Academy of Sciences of the United States of America Medium 32101625
2020 NPY promotes chondrocyte hypertrophy and cartilage matrix degradation through NPY2R (not NPY1R), activating the mTORC1 pathway in articular chondrocytes; downstream, mTORC1 effector S6K1 interacts with and phosphorylates SMAD1/5/8, promoting SMAD4 nuclear translocation and upregulation of Runx2. Selective NPY2R antagonist treatment in vivo ameliorated NPY-mediated cartilage degradation, and the mTORC1 inhibitor rapamycin abrogated NPY-mediated effects in vitro. Intra-articular NPY administration in mice; selective NPY1R and NPY2R antagonists; in vitro pathway inhibition with rapamycin; co-immunoprecipitation/interaction assay for S6K1 and SMAD1/5/8; nuclear localization of SMAD4; Runx2 expression analysis Journal of bone and mineral research High 32101625
2023 NPY2R forms a protein complex with NPY5R and NFATc1 in sebaceous gland tissue; NFATc1 is dephosphorylated (activated) and translocates to the nucleus where it acts as a transcription factor binding enhancer regions to facilitate transcription of sebum-related genes. DYRK1A phosphorylates NFATc1 to keep it inactive, and DYRK1A inactivation permits NFATc1 nuclear localization, defining a NPY2R/NFATc1/DYRK1A regulatory axis in sebaceous glands. Immunoprecipitation, mass spectrometry, gel filtration (protein complex); ChIP-seq (genome-wide NFATc1 occupancy); western blot; immunofluorescence; RNA sequencing Cellular & molecular biology letters Medium 37501148
2019 Tectal NPY2R activation in Xenopus laevis modulates prey-capture behavior: bilateral tectal microinjection of a NPY2R antagonist (BIIE0246) increased baseline food intake, altered prey-capture kinematics, and reversed predator-induced suppression of food intake; effects of NPY on prey-capture latency and contact time were blocked by BIIE0246, establishing NPY2R as the mediator of tectal NPY effects on feeding behavior. Bilateral tectal microinjection of NPY and NPY2R antagonist BIIE0246; behavioral assays (food intake, prey-capture, predator avoidance) in Xenopus laevis General and comparative endocrinology Medium 31271760
2025 MSC-derived extracellular ATP, released via pannexin1, activates pulmonary Npy2r-expressing vagal sensory neurons through the purinergic receptor P2rx2; these Npy2r+ neurons project to the nucleus tractus solitarius and ventral lateral periaqueductal gray area to mediate analgesia via a vagal lung-to-brain pathway. Chemogenetic activation of Npy2r sensory neurons recapitulated analgesia in spared nerve injury mice. Murine pain models; chemogenetic (DREADD) activation of Npy2r neurons; neural tracing; pharmacological P2rx2 agonist inhalation; mechanistic dissection of MSC-pannexin1-ATP-P2rx2-Npy2r axis Advanced science Medium 40874463
2025 The long-acting NPY2R agonist BI 1820237 dose-dependently reduces food intake and delays gastric emptying in lean mice via NPY2R activation; combination with the GCGR/GLP-1R dual agonist survodutide produced synergistic body-weight reduction (~22%) in diet-induced obese mice, significantly greater than survodutide alone (~17%), demonstrating that NPY2R engagement enhances efficacy of GLP-1R/GCGR co-agonism. In vivo pharmacology in lean and diet-induced obese mice; dose-response and combination interaction analysis Molecular metabolism Medium 40619099

Source papers

Stage 0 corpus · 22 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2018 Chimeric peptide EP45 as a dual agonist at GLP-1 and NPY2R receptors. Scientific reports 40 29491394
2007 Association studies of BMI and type 2 diabetes in the neuropeptide Y pathway: a possible role for NPY2R as a candidate gene for type 2 diabetes in men. Diabetes 40 17325259
1996 Characterization of the human type 2 neuropeptide Y receptor gene (NPY2R) and localization to the chromosome 4q region containing the type 1 neuropeptide Y receptor gene. Genomics 40 8975716
2011 Polymorphisms in the NPY2R gene show significant associations with BMI that are additive to FTO, MC4R, and NPFFR2 gene effects. Obesity (Silver Spring, Md.) 34 21818152
2020 Neuropeptide Y Acts Directly on Cartilage Homeostasis and Exacerbates Progression of Osteoarthritis Through NPY2R. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 31 32101625
2018 iTRAQ-based proteomics suggests LRP6, NPY and NPY2R perturbation in the hippocampus involved in CSDS may induce resilience and susceptibility. Life sciences 25 30201296
2007 Single nucleotide polymorphisms in the neuropeptide Y2 receptor (NPY2R) gene and association with severe obesity in French white subjects. Diabetologia 25 17235527
2014 Association of age at onset in Huntington disease with functional promoter variations in NPY and NPY2R. Journal of molecular medicine (Berlin, Germany) 23 24121255
2006 Variants in the 5' region of the neuropeptide Y receptor Y2 gene (NPY2R) are associated with obesity in 5,971 white subjects. Diabetologia 23 17019604
2012 Neuropeptide Y2 receptor (NPY2R) expression in saliva predicts feeding immaturity in the premature neonate. PloS one 21 22629465
2020 A role for NPY-NPY2R signaling in albuminuric kidney disease. Proceedings of the National Academy of Sciences of the United States of America 19 32561647
2017 Evaluation of a Role for NPY and NPY2R in the Pathogenesis of Obesity by Mutation and Copy Number Variation Analysis in Obese Children and Adolescents. Annals of human genetics 11 28857123
2023 The role of NPY2R/NFATc1/DYRK1A regulatory axis in sebaceous glands for sebum synthesis. Cellular & molecular biology letters 6 37501148
2023 Neuropeptide Y receptor Y2 (npy2r) deficiency reduces anxiety and increases food intake in Japanese medaka (Oryzias latipes). Frontiers in cell and developmental biology 6 38020893
2007 No association of sequence variants in the neuropeptide Y2 receptor (NPY2R) gene with early onset obesity in Germans. Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme 6 17992642
2019 Neuroendocrine modulation of predator avoidance/prey capture tradeoffs: Role of tectal NPY2R receptors. General and comparative endocrinology 5 31271760
2018 The Association of CEP135 rs4865047 and NPY2R rs1902491 Single Nucleotide Polymorphisms (SNPs) with Rapid Progression of Proliferative Diabetic Retinopathy in Patients with Type 1 Diabetes Mellitus. Medical science monitor : international medical journal of experimental and clinical research 5 30531682
2013 Lack of Association Between Variants within the AHSG , HCRT and NPY2R Genes and Anthropometrical Parameters in Czech Post-Monica Study. Balkan journal of medical genetics : BJMG 2 24265586
2025 Novel NPY2R agonist BI 1820237 provides synergistic anti-obesity efficacy when combined with the GCGR/GLP-1R dual agonist survodutide. Molecular metabolism 1 40619099
2025 Association of Alzheimer's Disease with Promoter Variations in NPY2R Gene. Reports of biochemistry & molecular biology 1 40842904
2025 Mesenchymal Stromal Cells Play an Analgesic Role Through a Npy2r Sensory Neuron-Mediated Lung-to-Brain Axis. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 1 40874463
2026 NPY2R Agonist-Induced Gastric Effects Leading to Intestinal Dysbiosis and Secondary Intestinal Pathology in CD1 Mice. Toxicologic pathology 0 41757733

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