{"gene":"NPY2R","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":1996,"finding":"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.","method":"Gene cloning, genomic sequencing, Northern analysis, chromosomal mapping","journal":"Genomics","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct molecular cloning with genomic sequencing, Northern blot, and chromosomal localization; primary characterization paper","pmids":["8975716"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Real-time FRET-based cAMP assay in living cells; pharmacological receptor-selective agonist/antagonist experiments","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional cAMP assay with receptor selectivity controls, single lab","pmids":["29491394"],"is_preprint":false},{"year":2014,"finding":"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.","method":"Luciferase promoter reporter assay; cell viability assay in PC12 cells with mutant huntingtin; genetic association in HD cohort","journal":"Journal of molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase functional assay plus cell-based neuroprotection experiment, single lab, two orthogonal methods","pmids":["24121255"],"is_preprint":false},{"year":2020,"finding":"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.","method":"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","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (proteomics, in vitro signaling, in vivo pharmacology, knockout mouse), single lab","pmids":["32101625"],"is_preprint":false},{"year":2020,"finding":"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.","method":"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":"Journal of bone and mineral research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (in vivo pharmacology, in vitro pathway dissection, protein interaction assay, nuclear translocation), multiple mechanistic nodes established","pmids":["32101625"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Immunoprecipitation, mass spectrometry, gel filtration (protein complex); ChIP-seq (genome-wide NFATc1 occupancy); western blot; immunofluorescence; RNA sequencing","journal":"Cellular & molecular biology letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus mass spec for complex, ChIP-seq for transcriptional mechanism, multiple orthogonal methods, single lab","pmids":["37501148"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Bilateral tectal microinjection of NPY and NPY2R antagonist BIIE0246; behavioral assays (food intake, prey-capture, predator avoidance) in Xenopus laevis","journal":"General and comparative endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological loss-of-function with specific antagonist plus behavioral phenotyping, single lab, non-mammalian model","pmids":["31271760"],"is_preprint":false},{"year":2025,"finding":"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.","method":"Murine pain models; chemogenetic (DREADD) activation of Npy2r neurons; neural tracing; pharmacological P2rx2 agonist inhalation; mechanistic dissection of MSC-pannexin1-ATP-P2rx2-Npy2r axis","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — chemogenetics plus circuit tracing plus pharmacological rescue, multiple orthogonal methods, single lab","pmids":["40874463"],"is_preprint":false},{"year":2025,"finding":"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.","method":"In vivo pharmacology in lean and diet-induced obese mice; dose-response and combination interaction analysis","journal":"Molecular metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo dose-response with selective NPY2R agonist and combination interaction analysis, single lab","pmids":["40619099"],"is_preprint":false}],"current_model":"NPY2R is a Gi-coupled GPCR that inhibits cAMP production upon activation by NPY/PYY ligands; in different tissues it signals through PI3K/MAPK/NFAT (podocytes), mTORC1/S6K1/SMAD (chondrocytes), and NFATc1/DYRK1A (sebaceous glands) pathways, forms a complex with NPY5R and NFATc1, modulates food intake and gastric emptying via central and peripheral circuits including Npy2r+ vagal sensory neurons that drive analgesia through a lung-to-brain axis, and its promoter activity is regulated by genetic variants that functionally alter expression and downstream neuroprotective signaling."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":1996,"claim":"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","pmids":["8975716"],"confidence":"High","gaps":["No ligand-binding or signaling characterization in this report","Tissue expression pattern not functionally interpreted"]},{"year":2014,"claim":"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","pmids":["24121255"],"confidence":"Medium","gaps":["Downstream neuroprotective signaling pathway not defined","Association does not establish causal mechanism in vivo","PC12 model may not reflect neuronal context"]},{"year":2018,"claim":"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","pmids":["29491394"],"confidence":"Medium","gaps":["Physiological relevance of A2B cross-talk untested","Single-lab cell-based system without in vivo validation"]},{"year":2019,"claim":"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","pmids":["31271760"],"confidence":"Medium","gaps":["Non-mammalian model limits generalization","Downstream tectal circuitry not mapped","Cellular signaling mechanism not addressed"]},{"year":2020,"claim":"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","pmids":["32101625"],"confidence":"High","gaps":["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"]},{"year":2023,"claim":"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","pmids":["37501148"],"confidence":"Medium","gaps":["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"]},{"year":2025,"claim":"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","pmids":["40874463"],"confidence":"Medium","gaps":["Role of NPY2R signaling itself (vs. its use as a neuronal marker) in analgesia not isolated","Endogenous ligand engaging these neurons not defined"]},{"year":2025,"claim":"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","pmids":["40619099"],"confidence":"Medium","gaps":["Neuronal site and circuit mediating the anorectic effect not localized","Mechanism of synergy with incretin co-agonism unresolved"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Medium","gaps":["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":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[1]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,3,4]}],"complexes":["NPY2R/NPY5R/NFATc1 complex"],"partners":["NPY5R","NFATC1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P49146","full_name":"Neuropeptide Y receptor type 2","aliases":["NPY-Y2 receptor","Y2 receptor"],"length_aa":381,"mass_kda":42.7,"function":"Receptor for neuropeptide Y and peptide YY. The rank order of affinity of this receptor for pancreatic polypeptides is PYY > NPY > PYY (3-36) > NPY (2-36) > [Ile-31, Gln-34] PP > [Leu-31, Pro-34] NPY > PP, [Pro-34] PYY and NPY free acid","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/P49146/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NPY2R","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/NPY2R","total_profiled":1310},"omim":[{"mim_id":"607122","title":"PROKINETICIN RECEPTOR 1; PROKR1","url":"https://www.omim.org/entry/607122"},{"mim_id":"604796","title":"TASTE RECEPTOR, TYPE 2, MEMBER 1; TAS2R1","url":"https://www.omim.org/entry/604796"},{"mim_id":"601790","title":"PANCREATIC POLYPEPTIDE RECEPTOR 1; PPYR1","url":"https://www.omim.org/entry/601790"},{"mim_id":"600781","title":"PEPTIDE YY; PYY","url":"https://www.omim.org/entry/600781"},{"mim_id":"162643","title":"CHEMOKINE, CXC MOTIF, RECEPTOR 4; CXCR4","url":"https://www.omim.org/entry/162643"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"brain","ntpm":1.8},{"tissue":"breast","ntpm":1.6}],"url":"https://www.proteinatlas.org/search/NPY2R"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"P49146","domains":[{"cath_id":"1.20.1070.10","chopping":"43-246_261-339","consensus_level":"high","plddt":92.6297,"start":43,"end":339}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P49146","model_url":"https://alphafold.ebi.ac.uk/files/AF-P49146-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P49146-F1-predicted_aligned_error_v6.png","plddt_mean":82.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NPY2R","jax_strain_url":"https://www.jax.org/strain/search?query=NPY2R"},"sequence":{"accession":"P49146","fasta_url":"https://rest.uniprot.org/uniprotkb/P49146.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P49146/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P49146"}},"corpus_meta":[{"pmid":"17325259","id":"PMC_17325259","title":"Association 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FTO, MC4R, and NPFFR2 gene effects.","date":"2011","source":"Obesity (Silver Spring, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/21818152","citation_count":34,"is_preprint":false},{"pmid":"32101625","id":"PMC_32101625","title":"Neuropeptide Y Acts Directly on Cartilage Homeostasis and Exacerbates Progression of Osteoarthritis Through NPY2R.","date":"2020","source":"Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research","url":"https://pubmed.ncbi.nlm.nih.gov/32101625","citation_count":31,"is_preprint":false},{"pmid":"17235527","id":"PMC_17235527","title":"Single nucleotide polymorphisms in the neuropeptide Y2 receptor (NPY2R) gene and association with severe obesity in French white subjects.","date":"2007","source":"Diabetologia","url":"https://pubmed.ncbi.nlm.nih.gov/17235527","citation_count":25,"is_preprint":false},{"pmid":"30201296","id":"PMC_30201296","title":"iTRAQ-based proteomics suggests LRP6, NPY and NPY2R perturbation in the hippocampus involved in CSDS may induce resilience and susceptibility.","date":"2018","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/30201296","citation_count":25,"is_preprint":false},{"pmid":"17019604","id":"PMC_17019604","title":"Variants in the 5' region of the neuropeptide Y receptor Y2 gene (NPY2R) are associated with obesity in 5,971 white subjects.","date":"2006","source":"Diabetologia","url":"https://pubmed.ncbi.nlm.nih.gov/17019604","citation_count":23,"is_preprint":false},{"pmid":"24121255","id":"PMC_24121255","title":"Association of age at onset in Huntington disease with functional promoter variations in NPY and NPY2R.","date":"2014","source":"Journal of molecular medicine (Berlin, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/24121255","citation_count":23,"is_preprint":false},{"pmid":"22629465","id":"PMC_22629465","title":"Neuropeptide Y2 receptor (NPY2R) expression in saliva predicts feeding immaturity in the premature neonate.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22629465","citation_count":21,"is_preprint":false},{"pmid":"32561647","id":"PMC_32561647","title":"A role for NPY-NPY2R signaling in albuminuric kidney disease.","date":"2020","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/32561647","citation_count":19,"is_preprint":false},{"pmid":"28857123","id":"PMC_28857123","title":"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.","date":"2017","source":"Annals of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/28857123","citation_count":11,"is_preprint":false},{"pmid":"38020893","id":"PMC_38020893","title":"Neuropeptide Y receptor Y2 (npy2r) deficiency reduces anxiety and increases food intake in Japanese medaka (Oryzias latipes).","date":"2023","source":"Frontiers in cell 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Through a Npy2r Sensory Neuron-Mediated Lung-to-Brain Axis.","date":"2025","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/40874463","citation_count":1,"is_preprint":false},{"pmid":"40619099","id":"PMC_40619099","title":"Novel NPY2R agonist BI 1820237 provides synergistic anti-obesity efficacy when combined with the GCGR/GLP-1R dual agonist survodutide.","date":"2025","source":"Molecular metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/40619099","citation_count":1,"is_preprint":false},{"pmid":"40842904","id":"PMC_40842904","title":"Association of Alzheimer's Disease with Promoter Variations in NPY2R Gene.","date":"2025","source":"Reports of biochemistry & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/40842904","citation_count":1,"is_preprint":false},{"pmid":"41757733","id":"PMC_41757733","title":"NPY2R Agonist-Induced Gastric Effects Leading to Intestinal Dysbiosis and Secondary Intestinal Pathology in CD1 Mice.","date":"2026","source":"Toxicologic pathology","url":"https://pubmed.ncbi.nlm.nih.gov/41757733","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":13291,"output_tokens":2675,"usd":0.039999,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9917,"output_tokens":3131,"usd":0.06393,"stage2_stop_reason":"end_turn"},"total_usd":0.103929,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1996,\n      \"finding\": \"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.\",\n      \"method\": \"Gene cloning, genomic sequencing, Northern analysis, chromosomal mapping\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct molecular cloning with genomic sequencing, Northern blot, and chromosomal localization; primary characterization paper\",\n      \"pmids\": [\"8975716\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Real-time FRET-based cAMP assay in living cells; pharmacological receptor-selective agonist/antagonist experiments\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional cAMP assay with receptor selectivity controls, single lab\",\n      \"pmids\": [\"29491394\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"Luciferase promoter reporter assay; cell viability assay in PC12 cells with mutant huntingtin; genetic association in HD cohort\",\n      \"journal\": \"Journal of molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase functional assay plus cell-based neuroprotection experiment, single lab, two orthogonal methods\",\n      \"pmids\": [\"24121255\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (proteomics, in vitro signaling, in vivo pharmacology, knockout mouse), single lab\",\n      \"pmids\": [\"32101625\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Journal of bone and mineral research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (in vivo pharmacology, in vitro pathway dissection, protein interaction assay, nuclear translocation), multiple mechanistic nodes established\",\n      \"pmids\": [\"32101625\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Immunoprecipitation, mass spectrometry, gel filtration (protein complex); ChIP-seq (genome-wide NFATc1 occupancy); western blot; immunofluorescence; RNA sequencing\",\n      \"journal\": \"Cellular & molecular biology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus mass spec for complex, ChIP-seq for transcriptional mechanism, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"37501148\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Bilateral tectal microinjection of NPY and NPY2R antagonist BIIE0246; behavioral assays (food intake, prey-capture, predator avoidance) in Xenopus laevis\",\n      \"journal\": \"General and comparative endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological loss-of-function with specific antagonist plus behavioral phenotyping, single lab, non-mammalian model\",\n      \"pmids\": [\"31271760\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"Murine pain models; chemogenetic (DREADD) activation of Npy2r neurons; neural tracing; pharmacological P2rx2 agonist inhalation; mechanistic dissection of MSC-pannexin1-ATP-P2rx2-Npy2r axis\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — chemogenetics plus circuit tracing plus pharmacological rescue, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"40874463\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"In vivo pharmacology in lean and diet-induced obese mice; dose-response and combination interaction analysis\",\n      \"journal\": \"Molecular metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo dose-response with selective NPY2R agonist and combination interaction analysis, single lab\",\n      \"pmids\": [\"40619099\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NPY2R is a Gi-coupled GPCR that inhibits cAMP production upon activation by NPY/PYY ligands; in different tissues it signals through PI3K/MAPK/NFAT (podocytes), mTORC1/S6K1/SMAD (chondrocytes), and NFATc1/DYRK1A (sebaceous glands) pathways, forms a complex with NPY5R and NFATc1, modulates food intake and gastric emptying via central and peripheral circuits including Npy2r+ vagal sensory neurons that drive analgesia through a lung-to-brain axis, and its promoter activity is regulated by genetic variants that functionally alter expression and downstream neuroprotective signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#1]. The gene arose by duplication at chromosome 4q31 adjacent to NPY1R and is encoded across two exons with an intron interrupting the 5'-UTR [#0]. 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 [#3]; 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 [#4]; 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 [#5]. At the systems level, NPY2R mediates central and peripheral control of feeding—tectal NPY2R modulates prey-capture behavior and predator-induced food-intake suppression [#6], and a long-acting NPY2R agonist reduces food intake and delays gastric emptying, synergizing with GLP-1R/GCGR co-agonism for body-weight reduction [#8]. NPY2R-expressing pulmonary vagal sensory neurons, activated via a purinergic ATP/P2rx2 axis, project to brainstem and midbrain nuclei to mediate analgesia [#7]. 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 [#2].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"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.\",\n      \"evidence\": \"Gene cloning, genomic sequencing, Northern analysis, and chromosomal mapping\",\n      \"pmids\": [\"8975716\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No ligand-binding or signaling characterization in this report\", \"Tissue expression pattern not functionally interpreted\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"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.\",\n      \"evidence\": \"Luciferase promoter reporter assay, PC12 cell viability assay with mutant huntingtin, and HD-cohort genetic association\",\n      \"pmids\": [\"24121255\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream neuroprotective signaling pathway not defined\", \"Association does not establish causal mechanism in vivo\", \"PC12 model may not reflect neuronal context\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Confirmed the core transduction mechanism—Gi-coupled cAMP inhibition—and demonstrated heterologous cross-talk with adenosine A2B receptor cAMP signaling.\",\n      \"evidence\": \"Real-time FRET-based cAMP assay in living cells with receptor-selective agonists/antagonists\",\n      \"pmids\": [\"29491394\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological relevance of A2B cross-talk untested\", \"Single-lab cell-based system without in vivo validation\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Located NPY2R within a central feeding circuit, showing tectal NPY acts through NPY2R to regulate prey-capture and predator-induced suppression of food intake.\",\n      \"evidence\": \"Bilateral tectal microinjection of NPY and antagonist BIIE0246 with behavioral phenotyping in Xenopus laevis\",\n      \"pmids\": [\"31271760\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Non-mammalian model limits generalization\", \"Downstream tectal circuitry not mapped\", \"Cellular signaling mechanism not addressed\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"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.\",\n      \"evidence\": \"In vitro pathway dissection, proteomics, co-IP of S6K1/SMAD1/5/8, in vivo selective antagonist treatment and knockout mouse studies\",\n      \"pmids\": [\"32101625\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"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.\",\n      \"evidence\": \"Reciprocal Co-IP, mass spectrometry, gel filtration, ChIP-seq, immunofluorescence, and RNA-seq in sebaceous gland tissue\",\n      \"pmids\": [\"37501148\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified NPY2R+ pulmonary vagal sensory neurons as the relay of a lung-to-brain analgesic circuit driven by a purinergic ATP/P2rx2 input.\",\n      \"evidence\": \"Murine pain models, chemogenetic DREADD activation, neural tracing, and P2rx2 agonist inhalation\",\n      \"pmids\": [\"40874463\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Role of NPY2R signaling itself (vs. its use as a neuronal marker) in analgesia not isolated\", \"Endogenous ligand engaging these neurons not defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"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.\",\n      \"evidence\": \"In vivo dose-response with selective NPY2R agonist BI 1820237 and combination interaction analysis in lean and diet-induced obese mice\",\n      \"pmids\": [\"40619099\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Neuronal site and circuit mediating the anorectic effect not localized\", \"Mechanism of synergy with incretin co-agonism unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model linking receptor conformations to effector choice\", \"Determinants of tissue-specific signaling bias unknown\", \"No unified receptor-proximal signaling map across tissues\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 3, 4]}\n    ],\n    \"complexes\": [\n      \"NPY2R/NPY5R/NFATc1 complex\"\n    ],\n    \"partners\": [\n      \"NPY5R\",\n      \"NFATc1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}