{"gene":"NPTXR","run_date":"2026-04-29T11:37:57","timeline":{"discoveries":[{"year":2015,"finding":"NPTXR and NPTX2 are required for clustering GluA4-containing AMPA receptors at excitatory synapses onto parvalbumin-expressing fast-spiking interneurons (PVFSIs). NPTX2(-/-)/NPTXR(-/-) double-knockout mice show dramatic reductions in GluA4 at PVFSI synapses, reduced AMPAR function in PVFSIs, delayed circuit maturation with prolonged critical period, and a circuit deficient in rhythmogenesis prone to epileptiform discharges, demonstrating an essential role for NPTXR in controlling network dynamics through AMPAR clustering.","method":"Genetic knockout (double NPTX2/NPTXR KO mice), electrophysiology, immunostaining for GluA4, in vivo circuit recordings","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 — clean KO with multiple defined cellular and circuit phenotypes, replicated across multiple assays in single rigorous study","pmids":["25754824"],"is_preprint":false},{"year":2021,"finding":"C1QL3 mediates formation of a novel trans-synaptic cell-cell adhesion complex involving NPTXR (and NPTX1) together with the adhesion GPCR ADGRB3/BAI3. This complex was identified by in vivo interactome study, and the three proteins (C1QL3, NPTX1, NPTXR) are highly co-expressed in excitatory neurons, suggesting they are presynaptically secreted and bind postsynaptically localized ADGRB3 to create a trans-synaptic adhesion complex.","method":"In vivo interactome study (Co-IP/pulldown), single-cell RNA-seq co-expression analysis, cell-cell adhesion assay","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 3 — Co-IP/pulldown with in vivo context and co-expression validation, single lab","pmids":["33337553"],"is_preprint":false},{"year":2026,"finding":"The conserved C-terminal pentraxin (PTX) domain of NPTXR (NPTXRPTX) was expressed as uniformly 15N,13C-labeled protein and near-complete backbone NMR resonance assignments were obtained, providing the first structural characterization of this domain and a foundation for studying NPTXR-ligand interactions that drive synapse organization.","method":"NMR spectroscopy (backbone resonance assignment of recombinant 15N,13C-labeled NPTXRPTX)","journal":"Biomolecular NMR assignments","confidence":"Medium","confidence_rationale":"Tier 1 — in vitro NMR structural work on purified protein, but assignments only (no functional mutagenesis yet); single paper","pmids":["41495486"],"is_preprint":false},{"year":2020,"finding":"NPTXR regulates activation of the PI3K-AKT-mTOR, FAK-JNK, and YAP signaling pathways in gastric cancer cells. NPTXR silencing promoted caspase-mediated apoptosis and attenuated cell proliferation, migration, invasion, adhesion, stem cell-like properties, and resistance to 5-fluorouracil in vitro, and inhibited tumorigenicity in vivo. Anti-NPTXR monoclonal antibodies inhibited gastric cancer peritoneal metastasis in mice.","method":"siRNA knockdown, xenograft mouse model, intracellular signaling assays (PI3K-AKT-mTOR, FAK-JNK, YAP pathway), anti-NPTXR monoclonal antibody treatment in Nptxr-/- and xenograft mice","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 — KO mice, KD with defined signaling phenotypes, in vivo antibody treatment; single lab with multiple orthogonal methods","pmids":["32847597"],"is_preprint":false},{"year":2024,"finding":"NPTXR knockdown in esophageal squamous cell carcinoma (ESCC) cells results in reduced proliferation, increased apoptosis, and decreased cell adhesion. Anti-NPTXR monoclonal antibody significantly inhibited ESCC cell proliferation in vitro, establishing a functional role for NPTXR in controlling malignant behavior of ESCC cells.","method":"siRNA-mediated knockdown, anti-NPTXR monoclonal antibody treatment in vitro, cell proliferation/apoptosis/adhesion assays","journal":"Annals of surgical oncology","confidence":"Medium","confidence_rationale":"Tier 2 — KD with defined cellular phenotypes and antibody functional validation, single lab","pmids":["38717547"],"is_preprint":false},{"year":2026,"finding":"NPTXR (as a neuronal pentraxin receptor) is specifically expressed in neurons (alongside NPTX1/2) and identified as a putative receptor for complement components in the brain, based on single-nucleus transcriptomic analysis showing its neuron-specific expression pattern in hippocampus and downregulation in Alzheimer's disease.","method":"Single-nucleus RNA sequencing (snRNA-seq) of human hippocampus","journal":"bioRxiv (preprint)","confidence":"Low","confidence_rationale":"Tier 4 — transcriptomic/expression-based inference only, no direct functional or binding assay","pmids":[],"is_preprint":true},{"year":2025,"finding":"NPTXR functions as the cognate receptor for NPTX2 in peripheral sensory neurons. NPTXR is specifically localized to pruriceptive CGRP+ and IB4+ neuronal subsets in trigeminal ganglion. Intra-TG siRNA knockdown of NPTXR (and NPTX2) significantly attenuated scratching behavior in an atopic dermatitis mouse model. NPTX2 synergizes with IL-31 to potentiate p-ERK signaling in primary sensory neurons, and this interaction is dependent on NPTXR.","method":"siRNA knockdown (intra-TG injection), immunolocalization, p-ERK signaling assay, behavioral assay (scratching)","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 — direct siRNA KD of NPTXR with defined behavioral and signaling phenotype, co-localization data, single lab","pmids":["41564473"],"is_preprint":false},{"year":2025,"finding":"NPTXR protein is upregulated in the cerebrospinal fluid of rats after oral administration of Lactobacillus rhamnosus GG probiotic, associating NPTXR levels with glutamatergic signaling and synaptic plasticity modulation in the CNS.","method":"LC-MS/MS proteomics of rat CSF after probiotic treatment","journal":"Neuroimmunomodulation","confidence":"Low","confidence_rationale":"Tier 4 — proteomics association without direct functional mechanistic experiment on NPTXR","pmids":["40031897"],"is_preprint":false},{"year":2024,"finding":"Anhedonia-like behavior in rats subjected to chronic variable stress is associated with downregulation of Neuronal Pentraxin Receptor (Nptxr) in the prefrontal cortex, linking NPTXR to glutamatergic synaptic dysfunction in chronic stress and suggesting disruption of neurotransmitter receptor activity.","method":"High-throughput proteomics and network analysis of rat prefrontal cortex","journal":"Pharmacology, biochemistry, and behavior","confidence":"Low","confidence_rationale":"Tier 3 — proteomics association in animal model, no direct loss-of-function experiment for NPTXR","pmids":["39488299"],"is_preprint":false},{"year":2006,"finding":"Neuronal pentraxin receptor (Nptxr) mRNA is significantly upregulated (range 1.6–6.0-fold) in the myocardium of rats with congestive heart failure 7 days after myocardial infarction, with no regulation at 1-day post-MI, suggesting a role in later adaptive processes affecting contractility or intracardiac nerve function.","method":"cDNA filter arrays and validated by repeated measurements in rat CHF model","journal":"Acta physiologica","confidence":"Low","confidence_rationale":"Tier 3 — gene expression validation in disease model, no direct functional mechanistic experiment","pmids":["16497176"],"is_preprint":false}],"current_model":"NPTXR is a transmembrane synaptic organizing protein whose C-terminal pentraxin domain mediates interactions with synaptic partners; it functions cooperatively with NPTX2 to cluster GluA4-containing AMPA receptors at excitatory synapses onto parvalbumin interneurons, thereby controlling network inhibition and rhythmogenesis, and also participates in a trans-synaptic adhesion complex with C1QL3 and ADGRB3/BAI3 at excitatory synapses, while in non-neuronal cancer contexts it activates PI3K-AKT-mTOR, FAK-JNK, and YAP signaling pathways to promote cell survival and metastasis."},"narrative":{"teleology":[{"year":2015,"claim":"Whether neuronal pentraxins are functionally required at specific synapse types was unknown; double knockout of NPTX2 and NPTXR revealed their essential, cooperative role in clustering GluA4-AMPARs at excitatory synapses onto parvalbumin interneurons, establishing NPTXR as a critical organizer of inhibitory circuit maturation and network oscillations.","evidence":"NPTX2/NPTXR double-KO mice analyzed by electrophysiology, GluA4 immunostaining, and in vivo circuit recordings","pmids":["25754824"],"confidence":"High","gaps":["Individual contributions of NPTXR versus NPTX2 to GluA4 clustering were not separable in the double KO","Structural basis for NPTXR–GluA4 interaction not determined","Whether NPTXR functions similarly at non-PV interneuron synapses is untested"]},{"year":2020,"claim":"Whether NPTXR has signaling functions outside the CNS was unclear; knockdown and antibody blockade in gastric cancer cells demonstrated that NPTXR activates PI3K–AKT–mTOR, FAK–JNK, and YAP pathways to promote proliferation, survival, and peritoneal metastasis.","evidence":"siRNA knockdown, xenograft models, intracellular signaling assays, and anti-NPTXR monoclonal antibody treatment in vivo","pmids":["32847597"],"confidence":"Medium","gaps":["Direct mechanism linking NPTXR transmembrane domain to PI3K/FAK/YAP activation is undefined","Whether cancer-context signaling reflects a ligand-dependent or constitutive activity is unknown","Findings not yet independently replicated outside a single laboratory"]},{"year":2021,"claim":"The identity of trans-synaptic adhesion complexes incorporating neuronal pentraxins was unknown; interactome analysis revealed that NPTXR forms a tripartite complex with C1QL3 and ADGRB3/BAI3, establishing a new trans-synaptic bridge at excitatory synapses.","evidence":"In vivo Co-IP/pulldown, snRNA-seq co-expression analysis, cell-cell adhesion assay","pmids":["33337553"],"confidence":"Medium","gaps":["No reciprocal Co-IP or reconstituted binding assay to confirm direct NPTXR–BAI3 interaction","Functional consequence of disrupting this specific complex at synapses is untested","Stoichiometry and domain requirements for complex assembly are undetermined"]},{"year":2024,"claim":"Extending the oncogenic role of NPTXR beyond gastric cancer, knockdown and antibody blockade confirmed that NPTXR promotes proliferation and survival in esophageal squamous cell carcinoma, generalizing its pro-tumorigenic function.","evidence":"siRNA knockdown and anti-NPTXR monoclonal antibody treatment with proliferation/apoptosis/adhesion assays in ESCC cells","pmids":["38717547"],"confidence":"Medium","gaps":["Downstream signaling pathway activation in ESCC not characterized","In vivo validation in ESCC xenograft models not performed","Whether NPTXR's cancer role depends on its pentraxin domain or ligand engagement is unknown"]},{"year":2025,"claim":"Whether NPTXR functions as a receptor for NPTX2 outside the CNS was untested; siRNA knockdown in trigeminal ganglion neurons demonstrated that NPTXR is the cognate receptor mediating NPTX2–IL-31 synergistic p-ERK signaling and itch behavior in peripheral sensory neurons.","evidence":"Intra-TG siRNA injection, immunolocalization in CGRP+/IB4+ neurons, p-ERK signaling assay, scratching behavioral assay in atopic dermatitis mouse model","pmids":["41564473"],"confidence":"Medium","gaps":["Direct binding between NPTX2 and NPTXR in sensory neurons not biochemically demonstrated","Mechanism of NPTXR–IL-31 receptor cross-talk is uncharacterized","Whether NPTXR regulates other somatosensory modalities beyond itch is unknown"]},{"year":null,"claim":"The atomic structure of NPTXR and the molecular basis by which its pentraxin domain engages GluA4, NPTX2, and C1QL3 remain unresolved; NMR backbone assignments of the PTX domain have been completed but no structure or binding interface has been defined.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No 3D structure of NPTXR pentraxin domain or full ectodomain available","Binding interfaces with GluA4, NPTX2, and C1QL3 are unmapped","Whether NPTXR signaling in cancer versus neurons uses distinct or overlapping ligand-binding surfaces is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,6]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[1]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,6]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[0,1,6]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,4]}],"complexes":["NPTXR–NPTX2 complex","C1QL3–NPTXR–NPTX1–BAI3 trans-synaptic complex"],"partners":["NPTX2","NPTX1","C1QL3","ADGRB3","GRIA4"],"other_free_text":[]},"mechanistic_narrative":"NPTXR is a transmembrane neuronal pentraxin receptor that cooperates with NPTX2 to cluster GluA4-containing AMPA receptors at excitatory synapses onto parvalbumin-expressing fast-spiking interneurons, thereby controlling circuit maturation, rhythmogenesis, and seizure susceptibility [PMID:25754824]. NPTXR participates in a trans-synaptic adhesion complex with C1QL3 and ADGRB3/BAI3, linking presynaptic secreted factors to postsynaptic signaling at excitatory synapses [PMID:33337553], and functions as the cognate receptor for NPTX2 in peripheral sensory neurons where it mediates NPTX2–IL-31 synergistic signaling through p-ERK to regulate itch behavior [PMID:41564473]. In cancer cells, NPTXR activates PI3K–AKT–mTOR, FAK–JNK, and YAP signaling pathways, and its silencing or antibody-mediated blockade suppresses proliferation, invasion, and peritoneal metastasis in gastric and esophageal squamous cell carcinoma models [PMID:32847597, PMID:38717547]."},"prefetch_data":{"uniprot":{"accession":"O95502","full_name":"Neuronal pentraxin receptor","aliases":[],"length_aa":500,"mass_kda":52.8,"function":"May be involved in mediating uptake of synaptic material during synapse remodeling or in mediating the synaptic clustering of AMPA glutamate receptors at a subset of excitatory synapses","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/O95502/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NPTXR","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/NPTXR","total_profiled":1310},"omim":[{"mim_id":"609474","title":"NEURONAL PENTRAXIN RECEPTOR; NPTXR","url":"https://www.omim.org/entry/609474"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":179.3}],"url":"https://www.proteinatlas.org/search/NPTXR"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"O95502","domains":[{"cath_id":"2.60.120.200","chopping":"295-495","consensus_level":"high","plddt":95.5171,"start":295,"end":495},{"cath_id":"1.20.5","chopping":"255-283","consensus_level":"medium","plddt":86.1772,"start":255,"end":283}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O95502","model_url":"https://alphafold.ebi.ac.uk/files/AF-O95502-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O95502-F1-predicted_aligned_error_v6.png","plddt_mean":76.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NPTXR","jax_strain_url":"https://www.jax.org/strain/search?query=NPTXR"},"sequence":{"accession":"O95502","fasta_url":"https://rest.uniprot.org/uniprotkb/O95502.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O95502/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O95502"}},"corpus_meta":[{"pmid":"25754824","id":"PMC_25754824","title":"Pentraxins 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parvalbumin-expressing fast-spiking interneurons (PVFSIs). NPTX2(-/-)/NPTXR(-/-) double-knockout mice show dramatic reductions in GluA4 at PVFSI synapses, reduced AMPAR function in PVFSIs, delayed circuit maturation with prolonged critical period, and a circuit deficient in rhythmogenesis prone to epileptiform discharges, demonstrating an essential role for NPTXR in controlling network dynamics through AMPAR clustering.\",\n      \"method\": \"Genetic knockout (double NPTX2/NPTXR KO mice), electrophysiology, immunostaining for GluA4, in vivo circuit recordings\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with multiple defined cellular and circuit phenotypes, replicated across multiple assays in single rigorous study\",\n      \"pmids\": [\"25754824\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"C1QL3 mediates formation of a novel trans-synaptic cell-cell adhesion complex involving NPTXR (and NPTX1) together with the adhesion GPCR ADGRB3/BAI3. This complex was identified by in vivo interactome study, and the three proteins (C1QL3, NPTX1, NPTXR) are highly co-expressed in excitatory neurons, suggesting they are presynaptically secreted and bind postsynaptically localized ADGRB3 to create a trans-synaptic adhesion complex.\",\n      \"method\": \"In vivo interactome study (Co-IP/pulldown), single-cell RNA-seq co-expression analysis, cell-cell adhesion assay\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP/pulldown with in vivo context and co-expression validation, single lab\",\n      \"pmids\": [\"33337553\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"The conserved C-terminal pentraxin (PTX) domain of NPTXR (NPTXRPTX) was expressed as uniformly 15N,13C-labeled protein and near-complete backbone NMR resonance assignments were obtained, providing the first structural characterization of this domain and a foundation for studying NPTXR-ligand interactions that drive synapse organization.\",\n      \"method\": \"NMR spectroscopy (backbone resonance assignment of recombinant 15N,13C-labeled NPTXRPTX)\",\n      \"journal\": \"Biomolecular NMR assignments\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — in vitro NMR structural work on purified protein, but assignments only (no functional mutagenesis yet); single paper\",\n      \"pmids\": [\"41495486\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"NPTXR regulates activation of the PI3K-AKT-mTOR, FAK-JNK, and YAP signaling pathways in gastric cancer cells. NPTXR silencing promoted caspase-mediated apoptosis and attenuated cell proliferation, migration, invasion, adhesion, stem cell-like properties, and resistance to 5-fluorouracil in vitro, and inhibited tumorigenicity in vivo. Anti-NPTXR monoclonal antibodies inhibited gastric cancer peritoneal metastasis in mice.\",\n      \"method\": \"siRNA knockdown, xenograft mouse model, intracellular signaling assays (PI3K-AKT-mTOR, FAK-JNK, YAP pathway), anti-NPTXR monoclonal antibody treatment in Nptxr-/- and xenograft mice\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO mice, KD with defined signaling phenotypes, in vivo antibody treatment; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"32847597\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NPTXR knockdown in esophageal squamous cell carcinoma (ESCC) cells results in reduced proliferation, increased apoptosis, and decreased cell adhesion. Anti-NPTXR monoclonal antibody significantly inhibited ESCC cell proliferation in vitro, establishing a functional role for NPTXR in controlling malignant behavior of ESCC cells.\",\n      \"method\": \"siRNA-mediated knockdown, anti-NPTXR monoclonal antibody treatment in vitro, cell proliferation/apoptosis/adhesion assays\",\n      \"journal\": \"Annals of surgical oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KD with defined cellular phenotypes and antibody functional validation, single lab\",\n      \"pmids\": [\"38717547\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"NPTXR (as a neuronal pentraxin receptor) is specifically expressed in neurons (alongside NPTX1/2) and identified as a putative receptor for complement components in the brain, based on single-nucleus transcriptomic analysis showing its neuron-specific expression pattern in hippocampus and downregulation in Alzheimer's disease.\",\n      \"method\": \"Single-nucleus RNA sequencing (snRNA-seq) of human hippocampus\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 — transcriptomic/expression-based inference only, no direct functional or binding assay\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NPTXR functions as the cognate receptor for NPTX2 in peripheral sensory neurons. NPTXR is specifically localized to pruriceptive CGRP+ and IB4+ neuronal subsets in trigeminal ganglion. Intra-TG siRNA knockdown of NPTXR (and NPTX2) significantly attenuated scratching behavior in an atopic dermatitis mouse model. NPTX2 synergizes with IL-31 to potentiate p-ERK signaling in primary sensory neurons, and this interaction is dependent on NPTXR.\",\n      \"method\": \"siRNA knockdown (intra-TG injection), immunolocalization, p-ERK signaling assay, behavioral assay (scratching)\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct siRNA KD of NPTXR with defined behavioral and signaling phenotype, co-localization data, single lab\",\n      \"pmids\": [\"41564473\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NPTXR protein is upregulated in the cerebrospinal fluid of rats after oral administration of Lactobacillus rhamnosus GG probiotic, associating NPTXR levels with glutamatergic signaling and synaptic plasticity modulation in the CNS.\",\n      \"method\": \"LC-MS/MS proteomics of rat CSF after probiotic treatment\",\n      \"journal\": \"Neuroimmunomodulation\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 — proteomics association without direct functional mechanistic experiment on NPTXR\",\n      \"pmids\": [\"40031897\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Anhedonia-like behavior in rats subjected to chronic variable stress is associated with downregulation of Neuronal Pentraxin Receptor (Nptxr) in the prefrontal cortex, linking NPTXR to glutamatergic synaptic dysfunction in chronic stress and suggesting disruption of neurotransmitter receptor activity.\",\n      \"method\": \"High-throughput proteomics and network analysis of rat prefrontal cortex\",\n      \"journal\": \"Pharmacology, biochemistry, and behavior\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — proteomics association in animal model, no direct loss-of-function experiment for NPTXR\",\n      \"pmids\": [\"39488299\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Neuronal pentraxin receptor (Nptxr) mRNA is significantly upregulated (range 1.6–6.0-fold) in the myocardium of rats with congestive heart failure 7 days after myocardial infarction, with no regulation at 1-day post-MI, suggesting a role in later adaptive processes affecting contractility or intracardiac nerve function.\",\n      \"method\": \"cDNA filter arrays and validated by repeated measurements in rat CHF model\",\n      \"journal\": \"Acta physiologica\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — gene expression validation in disease model, no direct functional mechanistic experiment\",\n      \"pmids\": [\"16497176\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NPTXR is a transmembrane synaptic organizing protein whose C-terminal pentraxin domain mediates interactions with synaptic partners; it functions cooperatively with NPTX2 to cluster GluA4-containing AMPA receptors at excitatory synapses onto parvalbumin interneurons, thereby controlling network inhibition and rhythmogenesis, and also participates in a trans-synaptic adhesion complex with C1QL3 and ADGRB3/BAI3 at excitatory synapses, while in non-neuronal cancer contexts it activates PI3K-AKT-mTOR, FAK-JNK, and YAP signaling pathways to promote cell survival and metastasis.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"NPTXR is a transmembrane neuronal pentraxin receptor that cooperates with NPTX2 to cluster GluA4-containing AMPA receptors at excitatory synapses onto parvalbumin-expressing fast-spiking interneurons, thereby controlling circuit maturation, rhythmogenesis, and seizure susceptibility [PMID:25754824]. NPTXR participates in a trans-synaptic adhesion complex with C1QL3 and ADGRB3/BAI3, linking presynaptic secreted factors to postsynaptic signaling at excitatory synapses [PMID:33337553], and functions as the cognate receptor for NPTX2 in peripheral sensory neurons where it mediates NPTX2–IL-31 synergistic signaling through p-ERK to regulate itch behavior [PMID:41564473]. In cancer cells, NPTXR activates PI3K–AKT–mTOR, FAK–JNK, and YAP signaling pathways, and its silencing or antibody-mediated blockade suppresses proliferation, invasion, and peritoneal metastasis in gastric and esophageal squamous cell carcinoma models [PMID:32847597, PMID:38717547].\",\n  \"teleology\": [\n    {\n      \"year\": 2015,\n      \"claim\": \"Whether neuronal pentraxins are functionally required at specific synapse types was unknown; double knockout of NPTX2 and NPTXR revealed their essential, cooperative role in clustering GluA4-AMPARs at excitatory synapses onto parvalbumin interneurons, establishing NPTXR as a critical organizer of inhibitory circuit maturation and network oscillations.\",\n      \"evidence\": \"NPTX2/NPTXR double-KO mice analyzed by electrophysiology, GluA4 immunostaining, and in vivo circuit recordings\",\n      \"pmids\": [\"25754824\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Individual contributions of NPTXR versus NPTX2 to GluA4 clustering were not separable in the double KO\",\n        \"Structural basis for NPTXR–GluA4 interaction not determined\",\n        \"Whether NPTXR functions similarly at non-PV interneuron synapses is untested\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Whether NPTXR has signaling functions outside the CNS was unclear; knockdown and antibody blockade in gastric cancer cells demonstrated that NPTXR activates PI3K–AKT–mTOR, FAK–JNK, and YAP pathways to promote proliferation, survival, and peritoneal metastasis.\",\n      \"evidence\": \"siRNA knockdown, xenograft models, intracellular signaling assays, and anti-NPTXR monoclonal antibody treatment in vivo\",\n      \"pmids\": [\"32847597\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct mechanism linking NPTXR transmembrane domain to PI3K/FAK/YAP activation is undefined\",\n        \"Whether cancer-context signaling reflects a ligand-dependent or constitutive activity is unknown\",\n        \"Findings not yet independently replicated outside a single laboratory\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"The identity of trans-synaptic adhesion complexes incorporating neuronal pentraxins was unknown; interactome analysis revealed that NPTXR forms a tripartite complex with C1QL3 and ADGRB3/BAI3, establishing a new trans-synaptic bridge at excitatory synapses.\",\n      \"evidence\": \"In vivo Co-IP/pulldown, snRNA-seq co-expression analysis, cell-cell adhesion assay\",\n      \"pmids\": [\"33337553\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No reciprocal Co-IP or reconstituted binding assay to confirm direct NPTXR–BAI3 interaction\",\n        \"Functional consequence of disrupting this specific complex at synapses is untested\",\n        \"Stoichiometry and domain requirements for complex assembly are undetermined\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extending the oncogenic role of NPTXR beyond gastric cancer, knockdown and antibody blockade confirmed that NPTXR promotes proliferation and survival in esophageal squamous cell carcinoma, generalizing its pro-tumorigenic function.\",\n      \"evidence\": \"siRNA knockdown and anti-NPTXR monoclonal antibody treatment with proliferation/apoptosis/adhesion assays in ESCC cells\",\n      \"pmids\": [\"38717547\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Downstream signaling pathway activation in ESCC not characterized\",\n        \"In vivo validation in ESCC xenograft models not performed\",\n        \"Whether NPTXR's cancer role depends on its pentraxin domain or ligand engagement is unknown\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Whether NPTXR functions as a receptor for NPTX2 outside the CNS was untested; siRNA knockdown in trigeminal ganglion neurons demonstrated that NPTXR is the cognate receptor mediating NPTX2–IL-31 synergistic p-ERK signaling and itch behavior in peripheral sensory neurons.\",\n      \"evidence\": \"Intra-TG siRNA injection, immunolocalization in CGRP+/IB4+ neurons, p-ERK signaling assay, scratching behavioral assay in atopic dermatitis mouse model\",\n      \"pmids\": [\"41564473\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct binding between NPTX2 and NPTXR in sensory neurons not biochemically demonstrated\",\n        \"Mechanism of NPTXR–IL-31 receptor cross-talk is uncharacterized\",\n        \"Whether NPTXR regulates other somatosensory modalities beyond itch is unknown\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The atomic structure of NPTXR and the molecular basis by which its pentraxin domain engages GluA4, NPTX2, and C1QL3 remain unresolved; NMR backbone assignments of the PTX domain have been completed but no structure or binding interface has been defined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No 3D structure of NPTXR pentraxin domain or full ectodomain available\",\n        \"Binding interfaces with GluA4, NPTX2, and C1QL3 are unmapped\",\n        \"Whether NPTXR signaling in cancer versus neurons uses distinct or overlapping ligand-binding surfaces is unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 6]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [0, 1, 6]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 4]}\n    ],\n    \"complexes\": [\n      \"NPTXR–NPTX2 complex\",\n      \"C1QL3–NPTXR–NPTX1–BAI3 trans-synaptic complex\"\n    ],\n    \"partners\": [\n      \"NPTX2\",\n      \"NPTX1\",\n      \"C1QL3\",\n      \"ADGRB3\",\n      \"GRIA4\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}