{"gene":"NPY1R","run_date":"2026-04-29T11:37:57","timeline":{"discoveries":[{"year":2003,"finding":"Chronic intracerebroventricular NPY infusion induces hyperphagia and obesity in mice lacking either Npy1r or Npy5r, demonstrating biological redundancy between Y1 and Y5 receptor signaling in NPY-mediated control of food intake.","method":"Chronic ICV NPY infusion in Npy1r and Npy5r knockout mice with measurement of food intake, fat pad weight, and plasma hormones","journal":"Endocrinology","confidence":"High","confidence_rationale":"Tier 2 — clean KO with defined metabolic phenotype, replicated across two receptor knockout lines","pmids":["14525913"],"is_preprint":false},{"year":2020,"finding":"Maternal deprivation increases Npy1r expression in medial prefrontal cortex neurons; pharmacological blockade of NPY1R signaling during electrophysiological recordings demonstrated that NPY1R enhances GABAergic currents in care-deprived mice, linking NPY1R to inhibitory synaptic control of prefrontal circuits.","method":"RNAseq for gene expression, electrophysiological recordings with NPY1R antagonist in maternally deprived mice","journal":"Neuropsychopharmacology","confidence":"High","confidence_rationale":"Tier 2 — electrophysiology with pharmacological blockade directly linking NPY1R to GABAergic currents, supported by RNAseq validation","pmids":["32492699"],"is_preprint":false},{"year":2020,"finding":"Conditional inactivation of Npy1r in forebrain excitatory neurons (limbic system) causes sex-dependent metabolic and behavioral phenotypes: male knockout mice show HPA axis hyperactivation, anxiety, reduced body weight, and reduced WAT mass, while female knockouts show increased WAT and compensatory reduction of AgRP in the arcuate nucleus, indicating estrogen-dependent resilience mechanisms.","method":"Conditional knockout mice (Npy1rrfb), behavioral testing, HPA axis measurements, WAT weighing, immunohistochemistry for AgRP","journal":"Hormones and behavior","confidence":"High","confidence_rationale":"Tier 2 — clean conditional KO with multiple defined metabolic and behavioral phenotypic readouts","pmids":["32755609"],"is_preprint":false},{"year":2018,"finding":"Conditional inactivation of Npy1r in Y5R-containing neurons causes impaired behavioral flexibility (reversal learning), decreased serotonergic fibers in orbitofrontal cortex (OFC), and increased baseline OFC pyramidal neuron activity; escitalopram treatment normalized OFC activity and restored behavioral flexibility, placing NPY1R-Y5R co-expression upstream of OFC serotonergic tone regulation.","method":"Conditional knockout (Npy1rY5R-/- mice), Morris water maze and water T-maze reversal tasks, c-Fos immunohistochemistry, 5-HT fiber quantification, escitalopram pharmacological rescue","journal":"Neuropharmacology","confidence":"High","confidence_rationale":"Tier 2 — conditional KO with multiple behavioral readouts, pharmacological rescue, and neurochemical validation","pmids":["29353053"],"is_preprint":false},{"year":2023,"finding":"Spinal dorsal horn NPY1R-expressing interneurons (Y1-INs) are necessary for neuropathic hypersensitivity after peripheral nerve injury; Y1-INs segregate into three subpopulations (Grp/Npy1r, Npff/Npy1r, Cck/Npy1r), and specifically Grp/Npy1r interneurons mediate neuropathic pain analgesia by intrathecal Y1 agonist [Leu31,Pro34]-NPY.","method":"Fluorescence in situ hybridization (FISH) for subpopulation characterization, chemogenetic inhibition (DREADDs), conditional Npy1r deletion from CCK-INs and NPFF-INs, intrathecal Y1 agonist administration in peripheral nerve injury models","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 — multiple genetic and pharmacological approaches, chemogenetics, conditional KO, confirmed across mouse, non-human primate, and human tissue","pmids":["37824208"],"is_preprint":false},{"year":2020,"finding":"MCM3AP-AS1 lncRNA recruits DNMT1/DNMT3A/DNMT3B to the NPY1R promoter, promoting its methylation and transcriptional silencing, thereby activating the MAPK pathway to promote prostate cancer cell proliferation, invasion, and migration.","method":"RNA immunoprecipitation, RNA pull-down, chromatin immunoprecipitation (ChIP), methylation-specific PCR, lentiviral overexpression/knockdown, xenograft tumor model","journal":"Molecular therapy. Nucleic acids","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (RIP, RNA pull-down, ChIP, MSP) identifying the writer complex and functional consequence","pmids":["32193153"],"is_preprint":false},{"year":2022,"finding":"NPY1R mediates the inhibitory action of NPY on estradiol-stimulated growth of ER-positive breast cancer cells; NPY treatment reduced estradiol-stimulated cell growth, an effect reversed by NPY1R antagonist BIBP-3226.","method":"Pharmacological antagonism with BIBP-3226, NPY treatment of ER+ BC cells, xenograft models, proteogenomics","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 — pharmacological rescue experiment with antagonist in cell and xenograft models, single lab","pmids":["35121782"],"is_preprint":false},{"year":2025,"finding":"Pancreas-specific and whole-body knockout of Npy1r significantly decreases liver metastasis in a genetically engineered mouse model of pancreatic cancer (KPR172HC); NPY1R antagonist BIBO3304 reduces migratory capacity on cell-derived matrices and decreases liver metastasis in an intrasplenic metastasis model.","method":"Conditional and whole-body Npy1r knockout in autochthonous KPR172HC mouse model, pharmacological inhibition with BIBO3304, intrasplenic metastasis model, migration assays","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 — genetic KO and pharmacological inhibition with concordant results across multiple in vivo models","pmids":["40073121"],"is_preprint":false},{"year":2025,"finding":"NPY dose-dependently attenuates lipolysis and cAMP signaling in primary human subcutaneous adipocytes via NPY1R; adipocyte NPY1R expression is reduced after weight loss and correlates positively with body fat percentage, acting as a cell-autonomous brake on lipolysis.","method":"Single nuclei RNA sequencing of human subcutaneous WAT pre/post lifestyle intervention, pharmacological NPY treatment in primary human adipocytes, meta-analysis of 23 clinical studies, cAMP signaling measurement","journal":"Molecular metabolism","confidence":"High","confidence_rationale":"Tier 2 — direct pharmacological experiment in primary human adipocytes with cAMP readout, confirmed by meta-analysis","pmids":["41412283"],"is_preprint":false},{"year":2024,"finding":"NPY1R forms heteroreceptor complexes with TrkB in the hippocampal dentate gyrus; co-administration of NPY1R agonist and ketamine enhanced NPY1R-TrkB complex formation (detected by proximity ligation assay), increased BDNF expression, and promoted neuroblast proliferation and memory consolidation.","method":"In situ proximity ligation assay, immunohistochemistry for PCNA and DCX, intracerebroventricular administration, object-in-place memory task","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 3 — proximity ligation assay suggesting co-localization/complex formation, single lab, acknowledged as requiring further validation","pmids":["38667284"],"is_preprint":false},{"year":2024,"finding":"NPY1R forms heteroreceptor complexes with GALR2 in the dentate gyrus of the dorsal hippocampus; co-activation of NPY1R and GALR2 with agonists increases neuroblast proliferation and enhances memory consolidation in rats.","method":"In situ proximity ligation assay for NPY1R-GALR2 co-localization, intracerebroventricular injections of agonists, PCNA and DCX neurogenesis markers, object-in-place memory task","journal":"Frontiers in cellular neuroscience","confidence":"Medium","confidence_rationale":"Tier 3 — proximity ligation assay for complex, single lab with functional behavioral readout","pmids":["38425430"],"is_preprint":false},{"year":2025,"finding":"UHRF1 binds to the NPY1R promoter and promotes its methylation, leading to NPY1R transcriptional suppression; UHRF1 deficiency causes NPY1R upregulation, which attenuates cAMP/PKA/CREB signaling in intestinal epithelial cells, thereby enhancing NF-κB activation and proinflammatory responses that compromise intestinal epithelial barrier integrity.","method":"ChIP for UHRF1 binding to NPY1R promoter, Uhrf1 conditional KO mouse model, human IBD cell models, cAMP/PKA/CREB and NF-κB signaling measurements, barrier integrity assays","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 — ChIP demonstrating direct promoter binding, KO mouse model, and defined downstream signaling cascade","pmids":["41657307"],"is_preprint":false},{"year":2024,"finding":"TK (tyrosine kinase)-mediated phosphorylation of NPY1R protein modulates its activity; TKI treatment decreases IA formation and suppresses the contractile-to-synthetic phenotype transition of VSMCs, inflammatory response and M1 macrophage polarization in intracranial aneurysm mice; NPY1R overexpression promotes M1 macrophage polarization and VSMC phenotypic switching; macrophage ablation abolished NPY1R overexpression-mediated IA progression.","method":"Co-immunoprecipitation (Co-IP) for TK-NPY1R interaction, western blot, RT-qPCR, flow cytometry, ELISA, macrophage ablation in mouse IA model","journal":"Neuropeptides","confidence":"Medium","confidence_rationale":"Tier 3 — Co-IP for PTM identification, supported by in vivo macrophage ablation rescue, single lab","pmids":["39353356"],"is_preprint":false},{"year":2026,"finding":"In the spinal dorsal horn, MOR signaling in NPY1R+ neurons is required for morphine analgesia under inflammatory pain conditions; NPY synergistically enhances morphine analgesia through NPY1R, as shown by abolition of the effect with NPY1R antagonism or Npy1r knockout; NPY1R+ interneuron hyperexcitability from inflammation is suppressed by morphine via increased rheobase, hyperpolarized resting membrane potential, and reduced action potential firing.","method":"Chemogenetics (DREADDs), conditional Oprm1 knockout in NPY1R+ neurons (AAV-Npy1r-Cre-EGFP), intrathecal NPY + antagonist, Npy1r-/- mice, in situ hybridization, whole-cell patch clamp recordings from spinal cord slices","journal":"Brain : a journal of neurology","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal genetic and electrophysiological approaches in same study establishing mechanism","pmids":["41738433"],"is_preprint":false},{"year":2025,"finding":"NPY1R is expressed on a subset of colorectal stem cells predominantly in the middle and distal colorectum (LGR5+ cells); selective dysregulation of Wnt signaling in NPY1R+ stem cells using CreERT2 drives colon cancer initiation predominantly in the rectum, establishing NPY1R+ cells as a source of colon cancer.","method":"NPY1R-CreERT2 mouse lines, conditional Wnt signaling activation in NPY1R+ cells, combination with oncogenic Kras and Trp53 loss, histopathology","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 — genetic lineage tracing with CreERT2 driver establishing NPY1R+ stem cells as colon cancer origin, multiple genetic combinations","pmids":["40897804"],"is_preprint":false},{"year":2025,"finding":"Transient intracerebroventricular siRNA knockdown of NPY1R disrupts NPY1R-GALR2 and NPY1R-TrkB heteroreceptor complexes in the ventral hippocampus without affecting hippocampal neurogenesis or depressive-like behavior, indicating compensatory mechanisms that preserve hippocampal plasticity when NPY1R is transiently reduced.","method":"ICV siRNA knockdown, in situ proximity ligation assay, PCNA immunolabeling, BDNF immunohistochemistry, forced swim test","journal":"Journal of psychopharmacology","confidence":"Medium","confidence_rationale":"Tier 3 — siRNA knockdown with PLA for complex disruption, single lab, negative phenotypic result","pmids":["41307298"],"is_preprint":false},{"year":2025,"finding":"In the ventral hippocampus CA1 region, NPY1R-expressing neurons and NPY2R-expressing neurons form two physically non-overlapping sub-ensembles; NPY released from GABAergic interneurons acts on NPY1R+ sub-ensembles to gate early fast stages of fear memory extinction, as demonstrated by CRISPR/Cas9-mediated NPY1R knockout.","method":"Activity-dependent single-cell transcriptomics, genetically encoded calcium and NPY sensors, CRISPR/Cas9 NPY1R knockout, bidirectional chemogenetic manipulation, cued fear memory and extinction behavioral paradigm","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — CRISPR KO with calcium imaging and behavioral readout in preprint, single lab","pmids":[],"is_preprint":true},{"year":2025,"finding":"In colonic L-cells (enteroendocrine cells), PYY acts on neighboring enterochromaffin cells via NPY1R to enhance serotonin release, contributing to increased gut pain sensitivity in females; this pathway is driven by ERα-mediated upregulation of Olfr78 on L-cells, increasing PYY release in response to acetate.","method":"Estrogen receptor signaling analysis, functional gut epithelial circuit dissection in mouse colon, PYY-NPY1R-EC cell paracrine signaling assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 3 — preprint with mechanistic pathway placement in gut circuit, awaiting peer review","pmids":[],"is_preprint":true}],"current_model":"NPY1R is a Gi-coupled neuropeptide Y receptor that mediates inhibitory signaling downstream of NPY/PYY; it functions in spinal dorsal horn interneurons (particularly Grp/Npy1r subpopulation) to gate neuropathic pain and synergize with opioid analgesia, in hypothalamic/limbic excitatory neurons to regulate energy homeostasis, HPA axis activity, anxiety, and behavioral flexibility via serotonergic OFC circuits, in adipocytes to brake lipolysis via cAMP suppression, in colonic enteroendocrine cells to modulate serotonin release, in hippocampal circuits to gate fear memory extinction via NPY1R+ sub-ensembles, and in colorectal LGR5+ stem cells as a colon cancer origin; its promoter is epigenetically regulated by DNMT-mediated methylation (recruited by MCM3AP-AS1 or UHRF1), and NPY1R forms functional heteroreceptor complexes with GALR2 and TrkB that support hippocampal neurogenesis and mood regulation."},"narrative":{"teleology":[{"year":2003,"claim":"Establishing that Y1 and Y5 receptors are functionally redundant for NPY-driven hyperphagia resolved whether either receptor alone was indispensable for central feeding control.","evidence":"Chronic ICV NPY infusion in Npy1r-KO and Npy5r-KO mice showing preserved hyperphagia and obesity in both lines","pmids":["14525913"],"confidence":"High","gaps":["Downstream signaling pathways mediating redundancy not defined","Brain region-specific versus global KO contributions unresolved"]},{"year":2018,"claim":"Demonstrating that NPY1R loss in Y5R-co-expressing neurons impairs reversal learning and reduces OFC serotonergic innervation established NPY1R as a regulator of cognitive flexibility through serotonergic circuits.","evidence":"Conditional Npy1rY5R-/- KO mice with reversal learning tasks, 5-HT fiber quantification, c-Fos mapping, and escitalopram rescue","pmids":["29353053"],"confidence":"High","gaps":["Mechanism by which NPY1R regulates serotonergic fiber density unknown","Whether cognitive deficits are developmental or acute not determined"]},{"year":2020,"claim":"Conditional forebrain excitatory neuron Npy1r deletion revealed sex-dependent roles in HPA axis regulation, anxiety, and adiposity, establishing NPY1R as a node integrating energy homeostasis with stress circuitry in a sexually dimorphic manner.","evidence":"Conditional KO (Npy1rrfb) mice with behavioral, endocrine, and metabolic phenotyping; AgRP immunohistochemistry","pmids":["32755609"],"confidence":"High","gaps":["Estrogen-dependent compensatory mechanisms not molecularly defined","Specific hypothalamic nuclei mediating the phenotype not isolated"]},{"year":2020,"claim":"Two independent studies established that NPY1R expression is controlled epigenetically: the lncRNA MCM3AP-AS1 recruits DNMTs to methylate the NPY1R promoter in prostate cancer, and NPY1R enhances GABAergic currents in prefrontal cortex neurons, broadening NPY1R's known regulatory mechanisms.","evidence":"RIP, RNA pull-down, ChIP, MSP in prostate cancer cells (MCM3AP-AS1 study); electrophysiology with NPY1R antagonist in maternally deprived mice (prefrontal cortex study)","pmids":["32193153","32492699"],"confidence":"High","gaps":["Whether epigenetic silencing of NPY1R is reversible in vivo not tested","Identity of the ion channel downstream of NPY1R mediating GABAergic enhancement unknown"]},{"year":2022,"claim":"Pharmacological blockade showed NPY1R mediates NPY's inhibition of estradiol-stimulated ER+ breast cancer growth, extending NPY1R's tumor-relevant roles beyond epigenetic silencing to growth-suppressive signaling.","evidence":"BIBP-3226 antagonist reversal of NPY growth inhibition in ER+ breast cancer cells and xenografts","pmids":["35121782"],"confidence":"Medium","gaps":["Downstream signaling pathway linking NPY1R to estradiol-stimulated growth inhibition not identified","Single lab, not replicated independently"]},{"year":2023,"claim":"Identification of three NPY1R+ spinal interneuron subtypes and selective demonstration that Grp/Npy1r interneurons mediate Y1-agonist analgesia in neuropathic pain resolved which dorsal horn population underlies NPY1R-dependent pain gating.","evidence":"FISH subpopulation mapping, DREADDs chemogenetic inhibition, conditional Npy1r deletion from CCK-INs and NPFF-INs, intrathecal Y1 agonist in nerve injury models","pmids":["37824208"],"confidence":"High","gaps":["Circuit connectivity of Grp/Npy1r interneurons to ascending pain pathways not mapped","Mechanism of Y1R signaling within these interneurons not delineated"]},{"year":2024,"claim":"Proximity ligation assays revealed that NPY1R forms heteroreceptor complexes with both GALR2 and TrkB in the hippocampal dentate gyrus, providing a structural basis for NPY1R's roles in neurogenesis and memory consolidation.","evidence":"In situ PLA for NPY1R-GALR2 and NPY1R-TrkB complexes, ICV agonist co-administration, PCNA/DCX neurogenesis markers, object-in-place memory tasks in rats","pmids":["38667284","38425430"],"confidence":"Medium","gaps":["PLA shows proximity but not direct binding; biochemical validation of heterodimers lacking","Stoichiometry and structural basis of heteroreceptor complexes unknown","Findings from single lab, not independently replicated"]},{"year":2024,"claim":"Tyrosine kinase-mediated phosphorylation of NPY1R was linked to VSMC phenotypic switching and M1 macrophage polarization in intracranial aneurysm, expanding NPY1R's post-translational regulation repertoire.","evidence":"Co-IP for TK-NPY1R interaction, NPY1R overexpression, macrophage ablation rescue in mouse intracranial aneurysm model","pmids":["39353356"],"confidence":"Medium","gaps":["Specific tyrosine residue(s) phosphorylated not identified","Single Co-IP without reciprocal validation","Mechanism linking phosphorylation to M1 polarization not defined"]},{"year":2025,"claim":"Multiple 2025 studies collectively established NPY1R as a cAMP-suppressive brake in adipocytes and intestinal epithelium, a marker of colon cancer-originating stem cells, and a synergistic partner with opioid receptors in spinal pain circuits, greatly expanding its peripheral and translational relevance.","evidence":"NPY treatment of primary human adipocytes with cAMP readout [PMID:41412283]; UHRF1 ChIP on NPY1R promoter with conditional KO and barrier assays [PMID:41657307]; NPY1R-CreERT2 lineage tracing with Wnt/Kras/p53 oncogenic activation [PMID:40897804]; conditional Oprm1 KO in NPY1R+ neurons with patch clamp and DREADDs [PMID:41738433]","pmids":["41412283","41657307","40897804","41738433"],"confidence":"High","gaps":["Gi-coupling specificity versus Gq or beta-arrestin bias in adipocytes not resolved","Whether NPY1R+ stem cell identity reflects a functional receptor role or is merely a marker for colon cancer origin unclear","Molecular mechanism of NPY1R-MOR synergy at signal transduction level not defined"]},{"year":null,"claim":"Key unresolved questions include the structural basis of NPY1R heteroreceptor complexes, the specific Gi-downstream effectors in each cell type, whether NPY1R post-translational modifications (phosphorylation sites, desensitization) differ across tissues, and whether NPY1R functional roles in colon cancer stem cells are receptor-activity-dependent or marker-only.","evidence":"","pmids":[],"confidence":"Low","gaps":["No crystal/cryo-EM structure of NPY1R or its heterocomplexes available","Tissue-specific signaling bias (Gi vs arrestin vs other effectors) not systematically compared","Functional necessity of NPY1R catalytic activity in LGR5+ colon cancer initiation not tested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1,2,3,4,8,13]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[4,8,9,10,14]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[11]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,2,4,8,11,13]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[1,3,4,13]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[5,7,14]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[5,11]}],"complexes":["NPY1R-GALR2 heteroreceptor complex","NPY1R-TrkB heteroreceptor complex"],"partners":["GALR2","NTRK2","UHRF1","DNMT1","OPRM1","NPY","PYY"],"other_free_text":[]},"mechanistic_narrative":"NPY1R is a Gi/o-coupled receptor for neuropeptide Y (NPY) and peptide YY (PYY) that transduces inhibitory signals across diverse neuronal, adipocyte, epithelial, and immune cell types to regulate energy homeostasis, pain processing, anxiety, behavioral flexibility, and gut function. In the central nervous system, NPY1R on forebrain excitatory neurons controls HPA axis activity, body weight, and white adipose tissue mass in a sex-dependent manner [PMID:32755609], gates neuropathic pain via spinal dorsal horn Grp/Npy1r interneurons that synergize with opioid analgesia [PMID:37824208, PMID:41738433], and regulates orbitofrontal serotonergic tone to support behavioral flexibility [PMID:29353053]. In peripheral tissues, NPY1R suppresses lipolysis through cAMP attenuation in adipocytes [PMID:41412283], marks LGR5+ colorectal stem cells that serve as a cell of origin for colon cancer upon Wnt pathway dysregulation [PMID:40897804], and its promoter is epigenetically silenced by DNMT recruitment via UHRF1 or the lncRNA MCM3AP-AS1, linking NPY1R expression levels to intestinal barrier integrity and prostate cancer progression [PMID:41657307, PMID:32193153]."},"prefetch_data":{"uniprot":{"accession":"P25929","full_name":"Neuropeptide Y receptor type 1","aliases":[],"length_aa":384,"mass_kda":44.4,"function":"Receptor for neuropeptide Y and peptide YY. The rank order of affinity of this receptor for pancreatic polypeptides is NPY > [Pro-34] PYY, PYY and [Leu-31, Pro-34] NPY > NPY (2-36) > [Ile-31, Gln-34] PP and PYY (3-36) > PP > NPY free acid","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/P25929/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NPY1R","classification":"Not Classified","n_dependent_lines":7,"n_total_lines":1208,"dependency_fraction":0.005794701986754967},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/NPY1R","total_profiled":1310},"omim":[{"mim_id":"609985","title":"PANIC DISORDER 3; PAND3","url":"https://www.omim.org/entry/609985"},{"mim_id":"607122","title":"PROKINETICIN RECEPTOR 1; PROKR1","url":"https://www.omim.org/entry/607122"},{"mim_id":"605569","title":"G PROTEIN-COUPLED RECEPTOR 83; GPR83","url":"https://www.omim.org/entry/605569"},{"mim_id":"601790","title":"PANCREATIC POLYPEPTIDE RECEPTOR 1; PPYR1","url":"https://www.omim.org/entry/601790"},{"mim_id":"601770","title":"NEUROPEPTIDE Y RECEPTOR Y6; NPY6R","url":"https://www.omim.org/entry/601770"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"lymphoid tissue","ntpm":112.7}],"url":"https://www.proteinatlas.org/search/NPY1R"},"hgnc":{"alias_symbol":[],"prev_symbol":["NPYR"]},"alphafold":{"accession":"P25929","domains":[{"cath_id":"1.20.1070.10","chopping":"44-333","consensus_level":"high","plddt":91.038,"start":44,"end":333}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P25929","model_url":"https://alphafold.ebi.ac.uk/files/AF-P25929-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P25929-F1-predicted_aligned_error_v6.png","plddt_mean":79.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NPY1R","jax_strain_url":"https://www.jax.org/strain/search?query=NPY1R"},"sequence":{"accession":"P25929","fasta_url":"https://rest.uniprot.org/uniprotkb/P25929.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P25929/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P25929"}},"corpus_meta":[{"pmid":"15090072","id":"PMC_15090072","title":"A case of autism with an interstitial deletion on 4q leading to hemizygosity for genes encoding for glutamine and glycine neurotransmitter receptor sub-units (AMPA 2, GLRA3, GLRB) and neuropeptide receptors NPY1R, NPY5R.","date":"2004","source":"BMC medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/15090072","citation_count":63,"is_preprint":false},{"pmid":"6533057","id":"PMC_6533057","title":"Nitrosamine carcinogenesis in 5120 rodents: chronic administration of sixteen different concentrations of NDEA, NDMA, NPYR and NPIP in the water of 4440 inbred rats, with parallel studies on NDEA alone of the effect of age of starting (3, 6 or 20 weeks) and of species (rats, mice or hamsters).","date":"1984","source":"IARC scientific publications","url":"https://pubmed.ncbi.nlm.nih.gov/6533057","citation_count":54,"is_preprint":false},{"pmid":"14525913","id":"PMC_14525913","title":"Chronic neuropeptide Y infusion into the lateral ventricle induces sustained feeding and obesity in mice lacking either Npy1r or Npy5r expression.","date":"2003","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/14525913","citation_count":38,"is_preprint":false},{"pmid":"32193153","id":"PMC_32193153","title":"MCM3AP-AS1 KD Inhibits Proliferation, Invasion, and Migration of PCa Cells via DNMT1/DNMT3 (A/B) Methylation-Mediated Upregulation of NPY1R.","date":"2020","source":"Molecular therapy. Nucleic acids","url":"https://pubmed.ncbi.nlm.nih.gov/32193153","citation_count":24,"is_preprint":false},{"pmid":"35121782","id":"PMC_35121782","title":"NPY1R exerts inhibitory action on estradiol-stimulated growth and predicts endocrine sensitivity and better survival in ER-positive breast cancer.","date":"2022","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/35121782","citation_count":21,"is_preprint":false},{"pmid":"9250411","id":"PMC_9250411","title":"A cyclic N7,C-8 guanine adduct of N-nitrosopyrrolidine (NPYR): formation in nucleic acids and excretion in the urine of NPYR-treated rats.","date":"1997","source":"Chemical research in toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/9250411","citation_count":20,"is_preprint":false},{"pmid":"32492699","id":"PMC_32492699","title":"Social subordination induced by early life adversity rewires inhibitory control of the prefrontal cortex via enhanced Npy1r signaling.","date":"2020","source":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/32492699","citation_count":16,"is_preprint":false},{"pmid":"37824208","id":"PMC_37824208","title":"Alleviation of neuropathic pain with neuropeptide Y requires spinal Npy1r interneurons that coexpress Grp.","date":"2023","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/37824208","citation_count":15,"is_preprint":false},{"pmid":"32755609","id":"PMC_32755609","title":"Conditional inactivation of Npy1r gene in mice induces sex-related differences of metabolic and behavioral functions.","date":"2020","source":"Hormones and behavior","url":"https://pubmed.ncbi.nlm.nih.gov/32755609","citation_count":11,"is_preprint":false},{"pmid":"32007578","id":"PMC_32007578","title":"Development and characterisation of a peptidergic N-and C-terminally stabilised mammalian NPY1R agonist which protects against diabetes induction.","date":"2020","source":"Biochimica et biophysica acta. 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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":25025,"output_tokens":4602,"usd":0.072053},"stage2":{"model":"claude-opus-4-6","input_tokens":8054,"output_tokens":2885,"usd":0.168593},"total_usd":0.240646,"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\": 2003,\n      \"finding\": \"Chronic intracerebroventricular NPY infusion induces hyperphagia and obesity in mice lacking either Npy1r or Npy5r, demonstrating biological redundancy between Y1 and Y5 receptor signaling in NPY-mediated control of food intake.\",\n      \"method\": \"Chronic ICV NPY infusion in Npy1r and Npy5r knockout mice with measurement of food intake, fat pad weight, and plasma hormones\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined metabolic phenotype, replicated across two receptor knockout lines\",\n      \"pmids\": [\"14525913\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Maternal deprivation increases Npy1r expression in medial prefrontal cortex neurons; pharmacological blockade of NPY1R signaling during electrophysiological recordings demonstrated that NPY1R enhances GABAergic currents in care-deprived mice, linking NPY1R to inhibitory synaptic control of prefrontal circuits.\",\n      \"method\": \"RNAseq for gene expression, electrophysiological recordings with NPY1R antagonist in maternally deprived mice\",\n      \"journal\": \"Neuropsychopharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — electrophysiology with pharmacological blockade directly linking NPY1R to GABAergic currents, supported by RNAseq validation\",\n      \"pmids\": [\"32492699\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Conditional inactivation of Npy1r in forebrain excitatory neurons (limbic system) causes sex-dependent metabolic and behavioral phenotypes: male knockout mice show HPA axis hyperactivation, anxiety, reduced body weight, and reduced WAT mass, while female knockouts show increased WAT and compensatory reduction of AgRP in the arcuate nucleus, indicating estrogen-dependent resilience mechanisms.\",\n      \"method\": \"Conditional knockout mice (Npy1rrfb), behavioral testing, HPA axis measurements, WAT weighing, immunohistochemistry for AgRP\",\n      \"journal\": \"Hormones and behavior\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean conditional KO with multiple defined metabolic and behavioral phenotypic readouts\",\n      \"pmids\": [\"32755609\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Conditional inactivation of Npy1r in Y5R-containing neurons causes impaired behavioral flexibility (reversal learning), decreased serotonergic fibers in orbitofrontal cortex (OFC), and increased baseline OFC pyramidal neuron activity; escitalopram treatment normalized OFC activity and restored behavioral flexibility, placing NPY1R-Y5R co-expression upstream of OFC serotonergic tone regulation.\",\n      \"method\": \"Conditional knockout (Npy1rY5R-/- mice), Morris water maze and water T-maze reversal tasks, c-Fos immunohistochemistry, 5-HT fiber quantification, escitalopram pharmacological rescue\",\n      \"journal\": \"Neuropharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with multiple behavioral readouts, pharmacological rescue, and neurochemical validation\",\n      \"pmids\": [\"29353053\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Spinal dorsal horn NPY1R-expressing interneurons (Y1-INs) are necessary for neuropathic hypersensitivity after peripheral nerve injury; Y1-INs segregate into three subpopulations (Grp/Npy1r, Npff/Npy1r, Cck/Npy1r), and specifically Grp/Npy1r interneurons mediate neuropathic pain analgesia by intrathecal Y1 agonist [Leu31,Pro34]-NPY.\",\n      \"method\": \"Fluorescence in situ hybridization (FISH) for subpopulation characterization, chemogenetic inhibition (DREADDs), conditional Npy1r deletion from CCK-INs and NPFF-INs, intrathecal Y1 agonist administration in peripheral nerve injury models\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple genetic and pharmacological approaches, chemogenetics, conditional KO, confirmed across mouse, non-human primate, and human tissue\",\n      \"pmids\": [\"37824208\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"MCM3AP-AS1 lncRNA recruits DNMT1/DNMT3A/DNMT3B to the NPY1R promoter, promoting its methylation and transcriptional silencing, thereby activating the MAPK pathway to promote prostate cancer cell proliferation, invasion, and migration.\",\n      \"method\": \"RNA immunoprecipitation, RNA pull-down, chromatin immunoprecipitation (ChIP), methylation-specific PCR, lentiviral overexpression/knockdown, xenograft tumor model\",\n      \"journal\": \"Molecular therapy. Nucleic acids\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (RIP, RNA pull-down, ChIP, MSP) identifying the writer complex and functional consequence\",\n      \"pmids\": [\"32193153\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NPY1R mediates the inhibitory action of NPY on estradiol-stimulated growth of ER-positive breast cancer cells; NPY treatment reduced estradiol-stimulated cell growth, an effect reversed by NPY1R antagonist BIBP-3226.\",\n      \"method\": \"Pharmacological antagonism with BIBP-3226, NPY treatment of ER+ BC cells, xenograft models, proteogenomics\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological rescue experiment with antagonist in cell and xenograft models, single lab\",\n      \"pmids\": [\"35121782\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Pancreas-specific and whole-body knockout of Npy1r significantly decreases liver metastasis in a genetically engineered mouse model of pancreatic cancer (KPR172HC); NPY1R antagonist BIBO3304 reduces migratory capacity on cell-derived matrices and decreases liver metastasis in an intrasplenic metastasis model.\",\n      \"method\": \"Conditional and whole-body Npy1r knockout in autochthonous KPR172HC mouse model, pharmacological inhibition with BIBO3304, intrasplenic metastasis model, migration assays\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO and pharmacological inhibition with concordant results across multiple in vivo models\",\n      \"pmids\": [\"40073121\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NPY dose-dependently attenuates lipolysis and cAMP signaling in primary human subcutaneous adipocytes via NPY1R; adipocyte NPY1R expression is reduced after weight loss and correlates positively with body fat percentage, acting as a cell-autonomous brake on lipolysis.\",\n      \"method\": \"Single nuclei RNA sequencing of human subcutaneous WAT pre/post lifestyle intervention, pharmacological NPY treatment in primary human adipocytes, meta-analysis of 23 clinical studies, cAMP signaling measurement\",\n      \"journal\": \"Molecular metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct pharmacological experiment in primary human adipocytes with cAMP readout, confirmed by meta-analysis\",\n      \"pmids\": [\"41412283\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NPY1R forms heteroreceptor complexes with TrkB in the hippocampal dentate gyrus; co-administration of NPY1R agonist and ketamine enhanced NPY1R-TrkB complex formation (detected by proximity ligation assay), increased BDNF expression, and promoted neuroblast proliferation and memory consolidation.\",\n      \"method\": \"In situ proximity ligation assay, immunohistochemistry for PCNA and DCX, intracerebroventricular administration, object-in-place memory task\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — proximity ligation assay suggesting co-localization/complex formation, single lab, acknowledged as requiring further validation\",\n      \"pmids\": [\"38667284\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NPY1R forms heteroreceptor complexes with GALR2 in the dentate gyrus of the dorsal hippocampus; co-activation of NPY1R and GALR2 with agonists increases neuroblast proliferation and enhances memory consolidation in rats.\",\n      \"method\": \"In situ proximity ligation assay for NPY1R-GALR2 co-localization, intracerebroventricular injections of agonists, PCNA and DCX neurogenesis markers, object-in-place memory task\",\n      \"journal\": \"Frontiers in cellular neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — proximity ligation assay for complex, single lab with functional behavioral readout\",\n      \"pmids\": [\"38425430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"UHRF1 binds to the NPY1R promoter and promotes its methylation, leading to NPY1R transcriptional suppression; UHRF1 deficiency causes NPY1R upregulation, which attenuates cAMP/PKA/CREB signaling in intestinal epithelial cells, thereby enhancing NF-κB activation and proinflammatory responses that compromise intestinal epithelial barrier integrity.\",\n      \"method\": \"ChIP for UHRF1 binding to NPY1R promoter, Uhrf1 conditional KO mouse model, human IBD cell models, cAMP/PKA/CREB and NF-κB signaling measurements, barrier integrity assays\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP demonstrating direct promoter binding, KO mouse model, and defined downstream signaling cascade\",\n      \"pmids\": [\"41657307\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TK (tyrosine kinase)-mediated phosphorylation of NPY1R protein modulates its activity; TKI treatment decreases IA formation and suppresses the contractile-to-synthetic phenotype transition of VSMCs, inflammatory response and M1 macrophage polarization in intracranial aneurysm mice; NPY1R overexpression promotes M1 macrophage polarization and VSMC phenotypic switching; macrophage ablation abolished NPY1R overexpression-mediated IA progression.\",\n      \"method\": \"Co-immunoprecipitation (Co-IP) for TK-NPY1R interaction, western blot, RT-qPCR, flow cytometry, ELISA, macrophage ablation in mouse IA model\",\n      \"journal\": \"Neuropeptides\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP for PTM identification, supported by in vivo macrophage ablation rescue, single lab\",\n      \"pmids\": [\"39353356\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"In the spinal dorsal horn, MOR signaling in NPY1R+ neurons is required for morphine analgesia under inflammatory pain conditions; NPY synergistically enhances morphine analgesia through NPY1R, as shown by abolition of the effect with NPY1R antagonism or Npy1r knockout; NPY1R+ interneuron hyperexcitability from inflammation is suppressed by morphine via increased rheobase, hyperpolarized resting membrane potential, and reduced action potential firing.\",\n      \"method\": \"Chemogenetics (DREADDs), conditional Oprm1 knockout in NPY1R+ neurons (AAV-Npy1r-Cre-EGFP), intrathecal NPY + antagonist, Npy1r-/- mice, in situ hybridization, whole-cell patch clamp recordings from spinal cord slices\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal genetic and electrophysiological approaches in same study establishing mechanism\",\n      \"pmids\": [\"41738433\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NPY1R is expressed on a subset of colorectal stem cells predominantly in the middle and distal colorectum (LGR5+ cells); selective dysregulation of Wnt signaling in NPY1R+ stem cells using CreERT2 drives colon cancer initiation predominantly in the rectum, establishing NPY1R+ cells as a source of colon cancer.\",\n      \"method\": \"NPY1R-CreERT2 mouse lines, conditional Wnt signaling activation in NPY1R+ cells, combination with oncogenic Kras and Trp53 loss, histopathology\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic lineage tracing with CreERT2 driver establishing NPY1R+ stem cells as colon cancer origin, multiple genetic combinations\",\n      \"pmids\": [\"40897804\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Transient intracerebroventricular siRNA knockdown of NPY1R disrupts NPY1R-GALR2 and NPY1R-TrkB heteroreceptor complexes in the ventral hippocampus without affecting hippocampal neurogenesis or depressive-like behavior, indicating compensatory mechanisms that preserve hippocampal plasticity when NPY1R is transiently reduced.\",\n      \"method\": \"ICV siRNA knockdown, in situ proximity ligation assay, PCNA immunolabeling, BDNF immunohistochemistry, forced swim test\",\n      \"journal\": \"Journal of psychopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — siRNA knockdown with PLA for complex disruption, single lab, negative phenotypic result\",\n      \"pmids\": [\"41307298\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In the ventral hippocampus CA1 region, NPY1R-expressing neurons and NPY2R-expressing neurons form two physically non-overlapping sub-ensembles; NPY released from GABAergic interneurons acts on NPY1R+ sub-ensembles to gate early fast stages of fear memory extinction, as demonstrated by CRISPR/Cas9-mediated NPY1R knockout.\",\n      \"method\": \"Activity-dependent single-cell transcriptomics, genetically encoded calcium and NPY sensors, CRISPR/Cas9 NPY1R knockout, bidirectional chemogenetic manipulation, cued fear memory and extinction behavioral paradigm\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — CRISPR KO with calcium imaging and behavioral readout in preprint, single lab\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In colonic L-cells (enteroendocrine cells), PYY acts on neighboring enterochromaffin cells via NPY1R to enhance serotonin release, contributing to increased gut pain sensitivity in females; this pathway is driven by ERα-mediated upregulation of Olfr78 on L-cells, increasing PYY release in response to acetate.\",\n      \"method\": \"Estrogen receptor signaling analysis, functional gut epithelial circuit dissection in mouse colon, PYY-NPY1R-EC cell paracrine signaling assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — preprint with mechanistic pathway placement in gut circuit, awaiting peer review\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"NPY1R is a Gi-coupled neuropeptide Y receptor that mediates inhibitory signaling downstream of NPY/PYY; it functions in spinal dorsal horn interneurons (particularly Grp/Npy1r subpopulation) to gate neuropathic pain and synergize with opioid analgesia, in hypothalamic/limbic excitatory neurons to regulate energy homeostasis, HPA axis activity, anxiety, and behavioral flexibility via serotonergic OFC circuits, in adipocytes to brake lipolysis via cAMP suppression, in colonic enteroendocrine cells to modulate serotonin release, in hippocampal circuits to gate fear memory extinction via NPY1R+ sub-ensembles, and in colorectal LGR5+ stem cells as a colon cancer origin; its promoter is epigenetically regulated by DNMT-mediated methylation (recruited by MCM3AP-AS1 or UHRF1), and NPY1R forms functional heteroreceptor complexes with GALR2 and TrkB that support hippocampal neurogenesis and mood regulation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"NPY1R is a Gi/o-coupled receptor for neuropeptide Y (NPY) and peptide YY (PYY) that transduces inhibitory signals across diverse neuronal, adipocyte, epithelial, and immune cell types to regulate energy homeostasis, pain processing, anxiety, behavioral flexibility, and gut function. In the central nervous system, NPY1R on forebrain excitatory neurons controls HPA axis activity, body weight, and white adipose tissue mass in a sex-dependent manner [PMID:32755609], gates neuropathic pain via spinal dorsal horn Grp/Npy1r interneurons that synergize with opioid analgesia [PMID:37824208, PMID:41738433], and regulates orbitofrontal serotonergic tone to support behavioral flexibility [PMID:29353053]. In peripheral tissues, NPY1R suppresses lipolysis through cAMP attenuation in adipocytes [PMID:41412283], marks LGR5+ colorectal stem cells that serve as a cell of origin for colon cancer upon Wnt pathway dysregulation [PMID:40897804], and its promoter is epigenetically silenced by DNMT recruitment via UHRF1 or the lncRNA MCM3AP-AS1, linking NPY1R expression levels to intestinal barrier integrity and prostate cancer progression [PMID:41657307, PMID:32193153].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Establishing that Y1 and Y5 receptors are functionally redundant for NPY-driven hyperphagia resolved whether either receptor alone was indispensable for central feeding control.\",\n      \"evidence\": \"Chronic ICV NPY infusion in Npy1r-KO and Npy5r-KO mice showing preserved hyperphagia and obesity in both lines\",\n      \"pmids\": [\"14525913\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream signaling pathways mediating redundancy not defined\", \"Brain region-specific versus global KO contributions unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrating that NPY1R loss in Y5R-co-expressing neurons impairs reversal learning and reduces OFC serotonergic innervation established NPY1R as a regulator of cognitive flexibility through serotonergic circuits.\",\n      \"evidence\": \"Conditional Npy1rY5R-/- KO mice with reversal learning tasks, 5-HT fiber quantification, c-Fos mapping, and escitalopram rescue\",\n      \"pmids\": [\"29353053\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which NPY1R regulates serotonergic fiber density unknown\", \"Whether cognitive deficits are developmental or acute not determined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Conditional forebrain excitatory neuron Npy1r deletion revealed sex-dependent roles in HPA axis regulation, anxiety, and adiposity, establishing NPY1R as a node integrating energy homeostasis with stress circuitry in a sexually dimorphic manner.\",\n      \"evidence\": \"Conditional KO (Npy1rrfb) mice with behavioral, endocrine, and metabolic phenotyping; AgRP immunohistochemistry\",\n      \"pmids\": [\"32755609\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Estrogen-dependent compensatory mechanisms not molecularly defined\", \"Specific hypothalamic nuclei mediating the phenotype not isolated\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Two independent studies established that NPY1R expression is controlled epigenetically: the lncRNA MCM3AP-AS1 recruits DNMTs to methylate the NPY1R promoter in prostate cancer, and NPY1R enhances GABAergic currents in prefrontal cortex neurons, broadening NPY1R's known regulatory mechanisms.\",\n      \"evidence\": \"RIP, RNA pull-down, ChIP, MSP in prostate cancer cells (MCM3AP-AS1 study); electrophysiology with NPY1R antagonist in maternally deprived mice (prefrontal cortex study)\",\n      \"pmids\": [\"32193153\", \"32492699\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether epigenetic silencing of NPY1R is reversible in vivo not tested\", \"Identity of the ion channel downstream of NPY1R mediating GABAergic enhancement unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Pharmacological blockade showed NPY1R mediates NPY's inhibition of estradiol-stimulated ER+ breast cancer growth, extending NPY1R's tumor-relevant roles beyond epigenetic silencing to growth-suppressive signaling.\",\n      \"evidence\": \"BIBP-3226 antagonist reversal of NPY growth inhibition in ER+ breast cancer cells and xenografts\",\n      \"pmids\": [\"35121782\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream signaling pathway linking NPY1R to estradiol-stimulated growth inhibition not identified\", \"Single lab, not replicated independently\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identification of three NPY1R+ spinal interneuron subtypes and selective demonstration that Grp/Npy1r interneurons mediate Y1-agonist analgesia in neuropathic pain resolved which dorsal horn population underlies NPY1R-dependent pain gating.\",\n      \"evidence\": \"FISH subpopulation mapping, DREADDs chemogenetic inhibition, conditional Npy1r deletion from CCK-INs and NPFF-INs, intrathecal Y1 agonist in nerve injury models\",\n      \"pmids\": [\"37824208\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Circuit connectivity of Grp/Npy1r interneurons to ascending pain pathways not mapped\", \"Mechanism of Y1R signaling within these interneurons not delineated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Proximity ligation assays revealed that NPY1R forms heteroreceptor complexes with both GALR2 and TrkB in the hippocampal dentate gyrus, providing a structural basis for NPY1R's roles in neurogenesis and memory consolidation.\",\n      \"evidence\": \"In situ PLA for NPY1R-GALR2 and NPY1R-TrkB complexes, ICV agonist co-administration, PCNA/DCX neurogenesis markers, object-in-place memory tasks in rats\",\n      \"pmids\": [\"38667284\", \"38425430\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"PLA shows proximity but not direct binding; biochemical validation of heterodimers lacking\", \"Stoichiometry and structural basis of heteroreceptor complexes unknown\", \"Findings from single lab, not independently replicated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Tyrosine kinase-mediated phosphorylation of NPY1R was linked to VSMC phenotypic switching and M1 macrophage polarization in intracranial aneurysm, expanding NPY1R's post-translational regulation repertoire.\",\n      \"evidence\": \"Co-IP for TK-NPY1R interaction, NPY1R overexpression, macrophage ablation rescue in mouse intracranial aneurysm model\",\n      \"pmids\": [\"39353356\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific tyrosine residue(s) phosphorylated not identified\", \"Single Co-IP without reciprocal validation\", \"Mechanism linking phosphorylation to M1 polarization not defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Multiple 2025 studies collectively established NPY1R as a cAMP-suppressive brake in adipocytes and intestinal epithelium, a marker of colon cancer-originating stem cells, and a synergistic partner with opioid receptors in spinal pain circuits, greatly expanding its peripheral and translational relevance.\",\n      \"evidence\": \"NPY treatment of primary human adipocytes with cAMP readout [PMID:41412283]; UHRF1 ChIP on NPY1R promoter with conditional KO and barrier assays [PMID:41657307]; NPY1R-CreERT2 lineage tracing with Wnt/Kras/p53 oncogenic activation [PMID:40897804]; conditional Oprm1 KO in NPY1R+ neurons with patch clamp and DREADDs [PMID:41738433]\",\n      \"pmids\": [\"41412283\", \"41657307\", \"40897804\", \"41738433\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Gi-coupling specificity versus Gq or beta-arrestin bias in adipocytes not resolved\", \"Whether NPY1R+ stem cell identity reflects a functional receptor role or is merely a marker for colon cancer origin unclear\", \"Molecular mechanism of NPY1R-MOR synergy at signal transduction level not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis of NPY1R heteroreceptor complexes, the specific Gi-downstream effectors in each cell type, whether NPY1R post-translational modifications (phosphorylation sites, desensitization) differ across tissues, and whether NPY1R functional roles in colon cancer stem cells are receptor-activity-dependent or marker-only.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No crystal/cryo-EM structure of NPY1R or its heterocomplexes available\", \"Tissue-specific signaling bias (Gi vs arrestin vs other effectors) not systematically compared\", \"Functional necessity of NPY1R catalytic activity in LGR5+ colon cancer initiation not tested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1, 2, 3, 4, 8, 13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [4, 8, 9, 10, 14]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 2, 4, 8, 11, 13]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [1, 3, 4, 13]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [5, 7, 14]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [5, 11]}\n    ],\n    \"complexes\": [\n      \"NPY1R-GALR2 heteroreceptor complex\",\n      \"NPY1R-TrkB heteroreceptor complex\"\n    ],\n    \"partners\": [\n      \"GALR2\",\n      \"NTRK2\",\n      \"UHRF1\",\n      \"DNMT1\",\n      \"OPRM1\",\n      \"NPY\",\n      \"PYY\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}