{"gene":"NPY2R","run_date":"2026-04-29T11:37:57","timeline":{"discoveries":[{"year":2018,"finding":"NPY2R mediates inhibition of cAMP production in response to PYY(3-36), and co-expressed with adenosine A2B receptors, NPY2R activation suppresses adenosine-stimulated cAMP production. A chimeric dual agonist peptide EP45 recapitulates these NPY2R-mediated effects while also activating GLP-1R.","method":"FRET-based real-time cAMP assay in living cells; dual-agonist pharmacological validation","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 — functional cell-based assay with defined receptor selectivity and cAMP readout; single lab","pmids":["29491394"],"is_preprint":false},{"year":1996,"finding":"The human NPY2R gene encodes a 381-amino-acid G-protein-coupled receptor, is organized on two exons spanning ~9 kb with the 5'-UTR interrupted by an intron (~4.5 kb), lacks an intron in the coding region (unlike NPY1R), and maps to chromosome 4q31 near the NPY1R locus, suggesting gene duplication.","method":"Gene cloning, Northern analysis, chromosomal mapping","journal":"Genomics","confidence":"High","confidence_rationale":"Tier 1 — direct cloning and structural characterization of the gene; foundational paper","pmids":["8975716"],"is_preprint":false},{"year":2020,"finding":"In articular chondrocytes, NPY signals via NPY2R (not NPY1R) to activate the mTORC1 pathway; mTORC1 downstream kinase S6K1 interacts with and phosphorylates SMAD1/5/8 and promotes SMAD4 nuclear translocation, upregulating Runx2 to drive chondrocyte hypertrophy and cartilage matrix degradation.","method":"Intra-articular NPY administration in vivo; specific NPY2R antagonist; rapamycin (mTORC1 inhibitor) in vitro; kinase-substrate interaction and phosphorylation assays; nuclear translocation and transcription factor readouts","journal":"Journal of bone and mineral research","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal in vivo and in vitro methods with receptor-specific antagonist and downstream pathway dissection","pmids":["32101625"],"is_preprint":false},{"year":2020,"finding":"In podocytes, NPY signals through NPY2R to stimulate PI3K, MAPK, and NFAT activation; NPY2R signaling modulates RNA processing and inhibits cell migration. Pharmacological inhibition of NPY2R in vivo reduces albuminuria in glomerulosclerotic mice.","method":"In vitro podocyte signaling assays (PI3K, MAPK, NFAT activation); unbiased proteomic analysis; NPY-knockout mice; NPY2R pharmacological inhibition in vivo (adriamycin model)","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (KO mice, pharmacological inhibition, proteomic, signaling assays) across in vitro and in vivo models","pmids":["32561647"],"is_preprint":false},{"year":2014,"finding":"A NPY2R promoter SNP (rs2234759) is functionally associated with Huntington disease age of onset; luciferase assays showed the high-expression NPY2R genotype correlates with later disease onset. Treatment of PC12 cells expressing mutant huntingtin with the NPY2R agonist NPY(3-36) protects against mutant htt-induced cell death.","method":"Luciferase reporter assays for promoter activity; cell death assay in PC12 cells with mutant huntingtin and NPY2R agonist","journal":"Journal of molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2/3 — functional promoter assay and cell-based neuroprotection assay; single lab","pmids":["24121255"],"is_preprint":false},{"year":2023,"finding":"NPY2R forms a protein complex with NPY5R and NFATc1 in sebaceous glands. NFATc1, when dephosphorylated and activated (regulated by DYRK1A-mediated phosphorylation), translocates to the nucleus and binds enhancer regions to drive transcription of sebum-related genes, placing NPY2R upstream of the DYRK1A/NFATc1 axis in sebaceous gland differentiation.","method":"Co-immunoprecipitation, mass spectrometry, gel filtration (complex identification); ChIP-seq (NFATc1 genomic occupancy); immunofluorescence (nuclear localization); western blot","journal":"Cellular & molecular biology letters","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal Co-IP/MS for complex, ChIP-seq for downstream target identification; single lab","pmids":["37501148"],"is_preprint":false},{"year":2025,"finding":"MSC-derived extracellular ATP, released via pannexin1, activates NPY2R-expressing vagal sensory neurons in the lung through purinergic receptor P2X2 (P2rx2). These Npy2r-expressing pulmonary vagal neurons project to the nucleus tractus solitarius and ventral lateral periaqueductal gray area, mediating analgesia via a lung-to-brain axis. Chemogenetic activation of Npy2r sensory neurons reduces mechanical allodynia and thermal hyperalgesia.","method":"Murine pain models; chemogenetic (DREADD) activation of Npy2r neurons; mechanistic dissection of pannexin1/ATP/P2rx2 upstream signaling; circuit tracing to NTS and vlPAG","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 — chemogenetic manipulation with defined circuit and upstream mechanism; single lab but multiple orthogonal approaches","pmids":["40874463"],"is_preprint":false},{"year":2024,"finding":"In ventral hippocampal CA1, NPY2R-expressing neuronal sub-ensembles are distinct from NPY1R-expressing ensembles and mediate distinct stages of fear memory extinction. CRISPR/Cas9 knockout of NPY2R in mice reveals NPY2R governs late slow stages of extinction, with NPY release from GABAergic interneurons acting on NPY2R+ sub-ensembles to gate memory stability.","method":"Activity-dependent single-cell transcriptomics; genetically encoded NPY sensors; CRISPR/Cas9 knockout; bidirectional chemogenetic/optogenetic manipulation; calcium imaging; fear conditioning and extinction behavioral paradigms","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — CRISPR KO with defined behavioral phenotype, calcium imaging, and peptide sensors; preprint not yet peer-reviewed","pmids":["bio_10.1101_2024.05.09.593455"],"is_preprint":true},{"year":2019,"finding":"Tectal NPY2R activation in Xenopus laevis modulates prey-capture behavior; NPY microinjected into the optic tectum alters latency to contact food and time in contact with food, effects blocked by NPY2R antagonist BIIE0246. NPY2R antagonist alone increases baseline food intake and reverses predator-induced suppression of food intake, placing tectal NPY2R as a mediator of predator avoidance/prey capture tradeoffs.","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 — pharmacological receptor-specific antagonism with defined behavioral readouts in vivo; non-mammalian model but consistent receptor function","pmids":["31271760"],"is_preprint":false},{"year":2025,"finding":"The long-acting NPY2R agonist BI 1820237 dose-dependently reduces food intake and gastric emptying in lean mice, and in combination with the GCGR/GLP-1R dual agonist survodutide produces synergistic body weight reduction in diet-induced obese mice greater than either agent alone.","method":"In vivo pharmacological studies in lean and diet-induced obese mice; food intake and gastric emptying measurement; dose-response regression analysis","journal":"Molecular metabolism","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo agonist pharmacology with defined physiological readouts; demonstrates NPY2R-mediated anorexigenic and gastric emptying effects","pmids":["40619099"],"is_preprint":false}],"current_model":"NPY2R is a G-protein-coupled receptor that, upon activation by NPY/PYY, inhibits cAMP production and engages downstream signaling cascades including PI3K, MAPK, NFAT, and mTORC1/S6K1 in a tissue-specific manner; in the hypothalamus/hippocampus it gates feeding behavior and memory extinction through peptidergic inhibition of distinct neuronal sub-ensembles, in cartilage it drives chondrocyte hypertrophy via mTORC1-S6K1-SMAD-Runx2, in podocytes it promotes albuminuria via PI3K/MAPK/NFAT, in pulmonary vagal sensory neurons it mediates analgesia via a lung-to-brain circuit, and in sebaceous glands it forms a complex with NPY5R/NFATc1 to regulate sebum gene transcription through the DYRK1A/NFATc1 axis."},"narrative":{"teleology":[{"year":1996,"claim":"Cloning of the human NPY2R gene established it as a GPCR encoded by two exons on chromosome 4q31, resolving its genomic organization and evolutionary relationship to NPY1R via likely gene duplication.","evidence":"Gene cloning, Northern analysis, and chromosomal mapping of the human NPY2R locus","pmids":["8975716"],"confidence":"High","gaps":["No signal transduction pathway defined at this stage","Tissue-specific expression patterns only partially characterized by Northern blot","Ligand selectivity profile not fully delineated"]},{"year":2014,"claim":"A functional NPY2R promoter variant was linked to Huntington disease age of onset, and NPY2R agonism was shown to protect against mutant huntingtin-induced cell death, establishing a neuroprotective role for NPY2R signaling.","evidence":"Luciferase promoter reporter assays and cell death assays in PC12 cells expressing mutant huntingtin treated with NPY2R agonist NPY(3-36)","pmids":["24121255"],"confidence":"Medium","gaps":["Neuroprotective downstream mechanism not identified","In vivo validation in Huntington disease models lacking","Whether the promoter SNP effect is cell-type specific is unknown"]},{"year":2018,"claim":"Direct demonstration that NPY2R activation by PYY(3-36) inhibits cAMP production and can suppress adenosine-stimulated cAMP, defining the canonical Gi-coupled signaling output of the receptor.","evidence":"FRET-based real-time cAMP assay in living cells co-expressing NPY2R and adenosine A2B receptor","pmids":["29491394"],"confidence":"Medium","gaps":["G-protein coupling specificity (Gi subtypes) not resolved","Downstream effectors beyond cAMP inhibition not addressed","Endogenous tissue context not tested"]},{"year":2019,"claim":"Pharmacological studies in Xenopus tectum showed that NPY2R mediates suppression of prey-capture and food intake, establishing an evolutionarily conserved role for NPY2R in feeding and predator-avoidance behavior.","evidence":"Bilateral tectal microinjection of NPY and NPY2R-specific antagonist BIIE0246 with behavioral assays in Xenopus laevis","pmids":["31271760"],"confidence":"Medium","gaps":["Non-mammalian system; direct applicability to mammalian hypothalamic circuits uncertain","Downstream intracellular signaling in tectal neurons not characterized","Cell-type identity of NPY2R-expressing tectal neurons unknown"]},{"year":2020,"claim":"Two studies concurrently revealed tissue-specific NPY2R downstream signaling: in chondrocytes, NPY2R activates mTORC1–S6K1 which phosphorylates SMAD1/5/8 and promotes Runx2-driven hypertrophy; in podocytes, NPY2R engages PI3K, MAPK, and NFAT to modulate migration and albuminuria, demonstrating that NPY2R couples to distinct effector pathways depending on cell type.","evidence":"NPY2R antagonist and rapamycin in chondrocytes with kinase-substrate interaction assays in vitro and intra-articular NPY in vivo [PMID:32101625]; PI3K/MAPK/NFAT signaling assays in podocytes, proteomics, NPY-KO mice, and NPY2R pharmacological inhibition in adriamycin nephropathy model [PMID:32561647]","pmids":["32101625","32561647"],"confidence":"High","gaps":["How NPY2R selectively engages mTORC1 versus PI3K/MAPK/NFAT in different cell types is unknown","Identity of the G-protein or adaptor mediating pathway divergence not defined","Whether NPY2R signals through beta-arrestin in these contexts is untested"]},{"year":2023,"claim":"Discovery that NPY2R forms a physical complex with NPY5R and NFATc1 in sebaceous glands placed NPY2R upstream of DYRK1A-regulated NFATc1 nuclear translocation and sebum gene transcription, revealing a non-canonical signaling mode involving receptor hetero-complexation.","evidence":"Co-immunoprecipitation, mass spectrometry, gel filtration for complex identification; ChIP-seq for NFATc1 genomic occupancy in sebocytes","pmids":["37501148"],"confidence":"Medium","gaps":["Stoichiometry and direct versus indirect interaction between NPY2R and NPY5R not resolved","Whether NPY2R–NPY5R complex signals differently from NPY2R alone is untested","Functional consequence of disrupting the complex on sebaceous differentiation in vivo not shown"]},{"year":2024,"claim":"Single-cell transcriptomics and CRISPR knockout in ventral hippocampal CA1 demonstrated that NPY2R-expressing neuronal sub-ensembles are functionally distinct from NPY1R ensembles and specifically govern late-phase fear memory extinction, establishing a circuit-level role for NPY2R in memory stability.","evidence":"Activity-dependent scRNA-seq, genetically encoded NPY sensors, CRISPR/Cas9 NPY2R knockout, chemogenetic/optogenetic manipulation, and calcium imaging during fear conditioning in mice (preprint)","pmids":["bio_10.1101_2024.05.09.593455"],"confidence":"Medium","gaps":["Preprint; not yet peer-reviewed","Intracellular signaling cascade downstream of NPY2R in hippocampal extinction neurons not characterized","Whether NPY2R modulates other forms of learning or only fear extinction is unknown"]},{"year":2025,"claim":"Two 2025 studies expanded NPY2R's physiological roles: a long-acting NPY2R agonist demonstrated dose-dependent anorexigenic and gastric emptying effects synergistic with GLP-1R/GCGR agonism in obesity, while a separate study identified Npy2r-expressing pulmonary vagal neurons as mediators of MSC-derived analgesic signaling via a lung-to-brain circuit through NTS and vlPAG.","evidence":"In vivo pharmacology with BI 1820237 in lean and diet-induced obese mice [PMID:40619099]; chemogenetic DREADD activation of Npy2r vagal neurons, circuit tracing, and pain behavior assays in murine models [PMID:40874463]","pmids":["40619099","40874463"],"confidence":"Medium","gaps":["Whether NPY2R agonism has direct central versus peripheral anorexigenic effects is unresolved","The ligand activating NPY2R on pulmonary vagal neurons (NPY versus PYY versus other) is not identified","Human translational data for both anti-obesity and analgesic applications absent"]},{"year":null,"claim":"The mechanism by which NPY2R engages distinct downstream cascades (cAMP inhibition, mTORC1, PI3K/MAPK, NFAT) in a cell-type-specific manner — and whether this involves differential G-protein coupling, beta-arrestin recruitment, or receptor heteromerization — remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of NPY2R in complex with G-proteins or beta-arrestin","Cell-type-specific signaling bias not mechanistically explained","Role of NPY2R internalization and trafficking in signal diversification untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,2,3]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,5]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,2,3,5]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[6,7,8]}],"complexes":["NPY2R–NPY5R–NFATc1 complex"],"partners":["NPY5R","NFATC1","S6K1","P2RX2"],"other_free_text":[]},"mechanistic_narrative":"NPY2R is a Gi-coupled neuropeptide Y receptor that functions as a key integrator of peptidergic signaling across neural, renal, cartilaginous, and glandular tissues, primarily transducing NPY and PYY signals into inhibition of cAMP and activation of PI3K, MAPK, NFAT, and mTORC1 cascades. Encoded by a two-exon gene on chromosome 4q31 with an intronless coding region, NPY2R inhibits cAMP production upon ligand binding and, in a tissue-dependent manner, engages mTORC1–S6K1–SMAD–Runx2 signaling to drive chondrocyte hypertrophy in articular cartilage [PMID:32101625] or PI3K/MAPK/NFAT signaling in podocytes to regulate cell migration and albuminuria [PMID:32561647]. In the nervous system, NPY2R activation reduces food intake and gastric emptying [PMID:40619099], mediates late-phase fear memory extinction in hippocampal sub-ensembles, and defines a population of pulmonary vagal sensory neurons that project to brainstem and periaqueductal gray to produce analgesia [PMID:40874463]. NPY2R also forms a complex with NPY5R and NFATc1 in sebaceous glands, positioning it upstream of the DYRK1A/NFATc1 transcriptional axis that controls sebum gene expression [PMID:37501148]."},"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":"29491394","id":"PMC_29491394","title":"Chimeric peptide EP45 as a dual agonist at GLP-1 and NPY2R receptors.","date":"2018","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/29491394","citation_count":40,"is_preprint":false},{"pmid":"8975716","id":"PMC_8975716","title":"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.","date":"1996","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/8975716","citation_count":40,"is_preprint":false},{"pmid":"17325259","id":"PMC_17325259","title":"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.","date":"2007","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/17325259","citation_count":40,"is_preprint":false},{"pmid":"21818152","id":"PMC_21818152","title":"Polymorphisms in the NPY2R gene show significant associations with BMI that are additive to FTO, MC4R, and NPFFR2 gene effects.","date":"2011","source":"Obesity (Silver Spring, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/21818152","citation_count":33,"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":30,"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":"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":"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":22,"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":20,"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":18,"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":"37501148","id":"PMC_37501148","title":"The role of NPY2R/NFATc1/DYRK1A regulatory axis in sebaceous glands for sebum synthesis.","date":"2023","source":"Cellular & molecular biology 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Analgesic Role 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":"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":"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":"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},{"pmid":null,"id":"bio_10.1101_2024.05.09.593455","title":"Neuropeptide Y co-opts neuronal ensembles for memory lability and stability","date":"2024-05-10","source":"bioRxiv","url":"https://doi.org/10.1101/2024.05.09.593455","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":13112,"output_tokens":2746,"usd":0.040263},"stage2":{"model":"claude-opus-4-6","input_tokens":6053,"output_tokens":2687,"usd":0.14616},"total_usd":0.186423,"stage1_batch_id":"msgbatch_012ZiiCUBfB62NCTQd4Bk1Jo","stage2_batch_id":"msgbatch_01Xuqq9aUHoQouS7UVGZNStZ","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2018,\n      \"finding\": \"NPY2R mediates inhibition of cAMP production in response to PYY(3-36), and co-expressed with adenosine A2B receptors, NPY2R activation suppresses adenosine-stimulated cAMP production. A chimeric dual agonist peptide EP45 recapitulates these NPY2R-mediated effects while also activating GLP-1R.\",\n      \"method\": \"FRET-based real-time cAMP assay in living cells; dual-agonist pharmacological validation\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional cell-based assay with defined receptor selectivity and cAMP readout; single lab\",\n      \"pmids\": [\"29491394\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"The human NPY2R gene encodes a 381-amino-acid G-protein-coupled receptor, is organized on two exons spanning ~9 kb with the 5'-UTR interrupted by an intron (~4.5 kb), lacks an intron in the coding region (unlike NPY1R), and maps to chromosome 4q31 near the NPY1R locus, suggesting gene duplication.\",\n      \"method\": \"Gene cloning, Northern analysis, chromosomal mapping\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct cloning and structural characterization of the gene; foundational paper\",\n      \"pmids\": [\"8975716\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In articular chondrocytes, NPY signals via NPY2R (not NPY1R) to activate the mTORC1 pathway; mTORC1 downstream kinase S6K1 interacts with and phosphorylates SMAD1/5/8 and promotes SMAD4 nuclear translocation, upregulating Runx2 to drive chondrocyte hypertrophy and cartilage matrix degradation.\",\n      \"method\": \"Intra-articular NPY administration in vivo; specific NPY2R antagonist; rapamycin (mTORC1 inhibitor) in vitro; kinase-substrate interaction and phosphorylation assays; nuclear translocation and transcription factor readouts\",\n      \"journal\": \"Journal of bone and mineral research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal in vivo and in vitro methods with receptor-specific antagonist and downstream pathway dissection\",\n      \"pmids\": [\"32101625\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In podocytes, NPY signals through NPY2R to stimulate PI3K, MAPK, and NFAT activation; NPY2R signaling modulates RNA processing and inhibits cell migration. Pharmacological inhibition of NPY2R in vivo reduces albuminuria in glomerulosclerotic mice.\",\n      \"method\": \"In vitro podocyte signaling assays (PI3K, MAPK, NFAT activation); unbiased proteomic analysis; NPY-knockout mice; NPY2R pharmacological inhibition in vivo (adriamycin model)\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (KO mice, pharmacological inhibition, proteomic, signaling assays) across in vitro and in vivo models\",\n      \"pmids\": [\"32561647\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"A NPY2R promoter SNP (rs2234759) is functionally associated with Huntington disease age of onset; luciferase assays showed the high-expression NPY2R genotype correlates with later disease onset. Treatment of PC12 cells expressing mutant huntingtin with the NPY2R agonist NPY(3-36) protects against mutant htt-induced cell death.\",\n      \"method\": \"Luciferase reporter assays for promoter activity; cell death assay in PC12 cells with mutant huntingtin and NPY2R agonist\",\n      \"journal\": \"Journal of molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — functional promoter assay and cell-based neuroprotection assay; single lab\",\n      \"pmids\": [\"24121255\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"NPY2R forms a protein complex with NPY5R and NFATc1 in sebaceous glands. NFATc1, when dephosphorylated and activated (regulated by DYRK1A-mediated phosphorylation), translocates to the nucleus and binds enhancer regions to drive transcription of sebum-related genes, placing NPY2R upstream of the DYRK1A/NFATc1 axis in sebaceous gland differentiation.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, gel filtration (complex identification); ChIP-seq (NFATc1 genomic occupancy); immunofluorescence (nuclear localization); western blot\",\n      \"journal\": \"Cellular & molecular biology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP/MS for complex, ChIP-seq for downstream target identification; single lab\",\n      \"pmids\": [\"37501148\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MSC-derived extracellular ATP, released via pannexin1, activates NPY2R-expressing vagal sensory neurons in the lung through purinergic receptor P2X2 (P2rx2). These Npy2r-expressing pulmonary vagal neurons project to the nucleus tractus solitarius and ventral lateral periaqueductal gray area, mediating analgesia via a lung-to-brain axis. Chemogenetic activation of Npy2r sensory neurons reduces mechanical allodynia and thermal hyperalgesia.\",\n      \"method\": \"Murine pain models; chemogenetic (DREADD) activation of Npy2r neurons; mechanistic dissection of pannexin1/ATP/P2rx2 upstream signaling; circuit tracing to NTS and vlPAG\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — chemogenetic manipulation with defined circuit and upstream mechanism; single lab but multiple orthogonal approaches\",\n      \"pmids\": [\"40874463\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In ventral hippocampal CA1, NPY2R-expressing neuronal sub-ensembles are distinct from NPY1R-expressing ensembles and mediate distinct stages of fear memory extinction. CRISPR/Cas9 knockout of NPY2R in mice reveals NPY2R governs late slow stages of extinction, with NPY release from GABAergic interneurons acting on NPY2R+ sub-ensembles to gate memory stability.\",\n      \"method\": \"Activity-dependent single-cell transcriptomics; genetically encoded NPY sensors; CRISPR/Cas9 knockout; bidirectional chemogenetic/optogenetic manipulation; calcium imaging; fear conditioning and extinction behavioral paradigms\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — CRISPR KO with defined behavioral phenotype, calcium imaging, and peptide sensors; preprint not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2024.05.09.593455\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Tectal NPY2R activation in Xenopus laevis modulates prey-capture behavior; NPY microinjected into the optic tectum alters latency to contact food and time in contact with food, effects blocked by NPY2R antagonist BIIE0246. NPY2R antagonist alone increases baseline food intake and reverses predator-induced suppression of food intake, placing tectal NPY2R as a mediator of predator avoidance/prey capture tradeoffs.\",\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 — pharmacological receptor-specific antagonism with defined behavioral readouts in vivo; non-mammalian model but consistent receptor function\",\n      \"pmids\": [\"31271760\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The long-acting NPY2R agonist BI 1820237 dose-dependently reduces food intake and gastric emptying in lean mice, and in combination with the GCGR/GLP-1R dual agonist survodutide produces synergistic body weight reduction in diet-induced obese mice greater than either agent alone.\",\n      \"method\": \"In vivo pharmacological studies in lean and diet-induced obese mice; food intake and gastric emptying measurement; dose-response regression analysis\",\n      \"journal\": \"Molecular metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo agonist pharmacology with defined physiological readouts; demonstrates NPY2R-mediated anorexigenic and gastric emptying effects\",\n      \"pmids\": [\"40619099\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NPY2R is a G-protein-coupled receptor that, upon activation by NPY/PYY, inhibits cAMP production and engages downstream signaling cascades including PI3K, MAPK, NFAT, and mTORC1/S6K1 in a tissue-specific manner; in the hypothalamus/hippocampus it gates feeding behavior and memory extinction through peptidergic inhibition of distinct neuronal sub-ensembles, in cartilage it drives chondrocyte hypertrophy via mTORC1-S6K1-SMAD-Runx2, in podocytes it promotes albuminuria via PI3K/MAPK/NFAT, in pulmonary vagal sensory neurons it mediates analgesia via a lung-to-brain circuit, and in sebaceous glands it forms a complex with NPY5R/NFATc1 to regulate sebum gene transcription through the DYRK1A/NFATc1 axis.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"NPY2R is a Gi-coupled neuropeptide Y receptor that functions as a key integrator of peptidergic signaling across neural, renal, cartilaginous, and glandular tissues, primarily transducing NPY and PYY signals into inhibition of cAMP and activation of PI3K, MAPK, NFAT, and mTORC1 cascades. Encoded by a two-exon gene on chromosome 4q31 with an intronless coding region, NPY2R inhibits cAMP production upon ligand binding and, in a tissue-dependent manner, engages mTORC1–S6K1–SMAD–Runx2 signaling to drive chondrocyte hypertrophy in articular cartilage [PMID:32101625] or PI3K/MAPK/NFAT signaling in podocytes to regulate cell migration and albuminuria [PMID:32561647]. In the nervous system, NPY2R activation reduces food intake and gastric emptying [PMID:40619099], mediates late-phase fear memory extinction in hippocampal sub-ensembles, and defines a population of pulmonary vagal sensory neurons that project to brainstem and periaqueductal gray to produce analgesia [PMID:40874463]. NPY2R also forms a complex with NPY5R and NFATc1 in sebaceous glands, positioning it upstream of the DYRK1A/NFATc1 transcriptional axis that controls sebum gene expression [PMID:37501148].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Cloning of the human NPY2R gene established it as a GPCR encoded by two exons on chromosome 4q31, resolving its genomic organization and evolutionary relationship to NPY1R via likely gene duplication.\",\n      \"evidence\": \"Gene cloning, Northern analysis, and chromosomal mapping of the human NPY2R locus\",\n      \"pmids\": [\"8975716\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No signal transduction pathway defined at this stage\", \"Tissue-specific expression patterns only partially characterized by Northern blot\", \"Ligand selectivity profile not fully delineated\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"A functional NPY2R promoter variant was linked to Huntington disease age of onset, and NPY2R agonism was shown to protect against mutant huntingtin-induced cell death, establishing a neuroprotective role for NPY2R signaling.\",\n      \"evidence\": \"Luciferase promoter reporter assays and cell death assays in PC12 cells expressing mutant huntingtin treated with NPY2R agonist NPY(3-36)\",\n      \"pmids\": [\"24121255\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Neuroprotective downstream mechanism not identified\", \"In vivo validation in Huntington disease models lacking\", \"Whether the promoter SNP effect is cell-type specific is unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Direct demonstration that NPY2R activation by PYY(3-36) inhibits cAMP production and can suppress adenosine-stimulated cAMP, defining the canonical Gi-coupled signaling output of the receptor.\",\n      \"evidence\": \"FRET-based real-time cAMP assay in living cells co-expressing NPY2R and adenosine A2B receptor\",\n      \"pmids\": [\"29491394\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"G-protein coupling specificity (Gi subtypes) not resolved\", \"Downstream effectors beyond cAMP inhibition not addressed\", \"Endogenous tissue context not tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Pharmacological studies in Xenopus tectum showed that NPY2R mediates suppression of prey-capture and food intake, establishing an evolutionarily conserved role for NPY2R in feeding and predator-avoidance behavior.\",\n      \"evidence\": \"Bilateral tectal microinjection of NPY and NPY2R-specific antagonist BIIE0246 with behavioral assays in Xenopus laevis\",\n      \"pmids\": [\"31271760\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Non-mammalian system; direct applicability to mammalian hypothalamic circuits uncertain\", \"Downstream intracellular signaling in tectal neurons not characterized\", \"Cell-type identity of NPY2R-expressing tectal neurons unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Two studies concurrently revealed tissue-specific NPY2R downstream signaling: in chondrocytes, NPY2R activates mTORC1–S6K1 which phosphorylates SMAD1/5/8 and promotes Runx2-driven hypertrophy; in podocytes, NPY2R engages PI3K, MAPK, and NFAT to modulate migration and albuminuria, demonstrating that NPY2R couples to distinct effector pathways depending on cell type.\",\n      \"evidence\": \"NPY2R antagonist and rapamycin in chondrocytes with kinase-substrate interaction assays in vitro and intra-articular NPY in vivo [PMID:32101625]; PI3K/MAPK/NFAT signaling assays in podocytes, proteomics, NPY-KO mice, and NPY2R pharmacological inhibition in adriamycin nephropathy model [PMID:32561647]\",\n      \"pmids\": [\"32101625\", \"32561647\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How NPY2R selectively engages mTORC1 versus PI3K/MAPK/NFAT in different cell types is unknown\", \"Identity of the G-protein or adaptor mediating pathway divergence not defined\", \"Whether NPY2R signals through beta-arrestin in these contexts is untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Discovery that NPY2R forms a physical complex with NPY5R and NFATc1 in sebaceous glands placed NPY2R upstream of DYRK1A-regulated NFATc1 nuclear translocation and sebum gene transcription, revealing a non-canonical signaling mode involving receptor hetero-complexation.\",\n      \"evidence\": \"Co-immunoprecipitation, mass spectrometry, gel filtration for complex identification; ChIP-seq for NFATc1 genomic occupancy in sebocytes\",\n      \"pmids\": [\"37501148\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stoichiometry and direct versus indirect interaction between NPY2R and NPY5R not resolved\", \"Whether NPY2R–NPY5R complex signals differently from NPY2R alone is untested\", \"Functional consequence of disrupting the complex on sebaceous differentiation in vivo not shown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Single-cell transcriptomics and CRISPR knockout in ventral hippocampal CA1 demonstrated that NPY2R-expressing neuronal sub-ensembles are functionally distinct from NPY1R ensembles and specifically govern late-phase fear memory extinction, establishing a circuit-level role for NPY2R in memory stability.\",\n      \"evidence\": \"Activity-dependent scRNA-seq, genetically encoded NPY sensors, CRISPR/Cas9 NPY2R knockout, chemogenetic/optogenetic manipulation, and calcium imaging during fear conditioning in mice (preprint)\",\n      \"pmids\": [\"bio_10.1101_2024.05.09.593455\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint; not yet peer-reviewed\", \"Intracellular signaling cascade downstream of NPY2R in hippocampal extinction neurons not characterized\", \"Whether NPY2R modulates other forms of learning or only fear extinction is unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Two 2025 studies expanded NPY2R's physiological roles: a long-acting NPY2R agonist demonstrated dose-dependent anorexigenic and gastric emptying effects synergistic with GLP-1R/GCGR agonism in obesity, while a separate study identified Npy2r-expressing pulmonary vagal neurons as mediators of MSC-derived analgesic signaling via a lung-to-brain circuit through NTS and vlPAG.\",\n      \"evidence\": \"In vivo pharmacology with BI 1820237 in lean and diet-induced obese mice [PMID:40619099]; chemogenetic DREADD activation of Npy2r vagal neurons, circuit tracing, and pain behavior assays in murine models [PMID:40874463]\",\n      \"pmids\": [\"40619099\", \"40874463\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether NPY2R agonism has direct central versus peripheral anorexigenic effects is unresolved\", \"The ligand activating NPY2R on pulmonary vagal neurons (NPY versus PYY versus other) is not identified\", \"Human translational data for both anti-obesity and analgesic applications absent\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The mechanism by which NPY2R engages distinct downstream cascades (cAMP inhibition, mTORC1, PI3K/MAPK, NFAT) in a cell-type-specific manner — and whether this involves differential G-protein coupling, beta-arrestin recruitment, or receptor heteromerization — remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of NPY2R in complex with G-proteins or beta-arrestin\", \"Cell-type-specific signaling bias not mechanistically explained\", \"Role of NPY2R internalization and trafficking in signal diversification untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 2, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2, 3, 5]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [6, 7, 8]}\n    ],\n    \"complexes\": [\n      \"NPY2R–NPY5R–NFATc1 complex\"\n    ],\n    \"partners\": [\n      \"NPY5R\",\n      \"NFATc1\",\n      \"S6K1\",\n      \"P2RX2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}