{"gene":"NPSR1","run_date":"2026-04-29T11:37:57","timeline":{"discoveries":[{"year":2005,"finding":"NPSR1 (GPRA) isoforms A and B are G protein-coupled receptors; only the full-length variants GPRA-A and GPRA-B with 7-transmembrane topology are transported to the plasma membrane, while truncated variants are retained in intracellular compartments. Isoform-specific activation of GPRA-A with its agonist NPS results in significant inhibition of cell growth.","method":"Immunohistochemistry, in situ hybridization, cell-based functional assays with NPS stimulation","journal":"American journal of respiratory cell and molecular biology","confidence":"Medium","confidence_rationale":"Tier 2-3 — direct localization and functional assay in single lab with multiple methods","pmids":["15947423"],"is_preprint":false},{"year":2006,"finding":"NPS stimulation of NPSR1 activates downstream gene targets including MMP10, INHBA (activin A), IL8, and EPHA2 in a dose-dependent manner; Gene Ontology analysis revealed enrichment of 'cell proliferation', 'morphogenesis', and 'immune response' pathways, with a common co-regulated pathway including JUN/FOS oncogene homologs, early growth response genes, nuclear receptor subfamily 4 members, and dual specificity phosphatases.","method":"Microarray analysis, quantitative RT-PCR, immunoassay, immunohistochemistry","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods (microarray, qRT-PCR, immunoassay) in single lab","pmids":["16926187"],"is_preprint":false},{"year":2006,"finding":"NPSR1 (GPRA)-deficient mice show an attenuated bronchoconstriction response to thromboxane (a cholinergic receptor-dependent agent) but not to methacholine, suggesting NPSR1 contributes to neurally mediated bronchoconstriction mechanisms.","method":"GPRA-knockout mouse model, airway resistance measurements","journal":"American journal of physiology. Lung cellular and molecular physiology","confidence":"Medium","confidence_rationale":"Tier 2 — clean KO with specific physiological phenotype readout","pmids":["16829631"],"is_preprint":false},{"year":2010,"finding":"NPSR1 is essential for mediating NPS effects in vivo: NPSR1-deficient mice fail to exhibit NPS-induced hyperlocomotion, anxiolysis, or corticosterone release after intracerebroventricular NPS administration, establishing NPSR1 as the required receptor for these NPS-induced behavioral and neuroendocrine effects.","method":"NPSR1 gene-targeted (knockout) mice, ICV NPS administration, behavioral assays (open-field, forced swim, Morris water maze), corticosterone measurement","journal":"Psychoneuroendocrinology","confidence":"High","confidence_rationale":"Tier 2 — clean KO with multiple orthogonal behavioral and endocrine phenotype readouts","pmids":["20171785"],"is_preprint":false},{"year":2011,"finding":"NPSR1-A and NPSR1-B isoforms signal through the same downstream pathways (cAMP/PKA, MAPK/JNK, MAPK/ERK) and regulate largely the same gene set after NPS stimulation, but NPSR1-A induces stronger signaling effects than NPSR1-B; one notable exception is CD69 (a marker of regulatory T cells), which shows higher induction by NPSR1-B.","method":"HEK-293 cell overexpression, NPS concentration-response analysis, qRT-PCR, cAMP assay, Ca²⁺ assay, pathway-specific reporter assays (cAMP/PKA, MAPK/JNK, MAPK/ERK), genome-scale Affymetrix expression arrays","journal":"BMC pulmonary medicine","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal signaling assays in single lab with genome-scale profiling","pmids":["21707994"],"is_preprint":false},{"year":2011,"finding":"Multiple NPSR1 SNPs affect receptor function: a promoter SNP (rs2530547) significantly affects NPSR1 mRNA levels in human leukocytes; three non-synonymous coding SNPs (rs324981 [Ile107Asn], rs34705969 [Cys197Phe], rs727162 [Arg241Ser]) show quantitative differences in NPS-induced cAMP/PKA signaling and genome-wide transcriptional responses; the Cys197Phe variant exhibits a loss-of-function phenotype.","method":"Luciferase reporter assays, qRT-PCR of human leukocytes, NPS-induced genome-wide transcriptional profiling, CRE-dependent luciferase activity assays, molecular modelling","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1-2 — multiple functional assays (reporter, transcriptomics, signaling) with defined variants","pmids":["22216302"],"is_preprint":false},{"year":2013,"finding":"RORA and NPSR1 interact biologically: NPSR1 stimulation activates a pathway including RORA and other circadian clock genes; overexpression of RORA decreases NPSR1 promoter activity; Rora mRNA expression is lower in lung tissue of Npsr1-deficient mice during early hours of the light period, suggesting a regulatory feedback loop between these genes.","method":"Cell-based NPSR1 stimulation, RORA overexpression with NPSR1 promoter luciferase assay, Npsr1 knockout mouse lung gene expression analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2-3 — multiple methods (cell reporter, KO mouse) but cross-lab validation limited","pmids":["23565190"],"is_preprint":false},{"year":2015,"finding":"In primary hippocampal neurons expressing NPSR1, NPS stimulation induces calcium mobilization from the endoplasmic reticulum via IP3 and ryanodine receptors, followed by activation of store-operated calcium channels mediating extracellular calcium entry.","method":"NPSR1 expression in primary hippocampal cultures, single-cell calcium imaging","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — direct calcium imaging in neurons with pharmacological dissection of pathway components","pmids":["25714705"],"is_preprint":false},{"year":2014,"finding":"NPS stimulation of NPSR1-A overexpressing SH-SY5Y neuroblastoma cells activates MAPK pathways, circadian activity, focal adhesion, TGF-beta, and cytokine-cytokine interaction gene pathways, as determined by transcriptome analysis.","method":"NPSR1-A overexpression in SH-SY5Y cells, NPS stimulation, transcriptome analysis, immunohistochemistry","journal":"Virchows Archiv : an international journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 — transcriptome-level pathway analysis after NPS stimulation in cell model","pmids":["24915894"],"is_preprint":false},{"year":2008,"finding":"LPS stimulation upregulates NPSR1-A protein and mRNA levels in monocytes, indicating that NPSR1 expression is regulated by innate immune signaling.","method":"LPS stimulation of monocytes, FACS for NPSR1 protein, quantitative real-time PCR for NPSR1 mRNA","journal":"Journal of medical genetics","confidence":"Medium","confidence_rationale":"Tier 2-3 — direct in vitro experiment with two orthogonal measurement methods","pmids":["18285428"],"is_preprint":false},{"year":2017,"finding":"The combination of NPS and NPSR1 variants determines the magnitude of cAMP/PKA signal transduction and downstream gene expression: NPS-Val6/NPSR1-Ile107 produces the strongest activation while NPS-Leu6/NPSR1-Asn107 produces the weakest, demonstrating that NPS variants modify NPSR1 signaling.","method":"Transfected cells with different NPS/NPSR1 variant combinations, cAMP/PKA reporter assays, downstream gene expression analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — cell-based functional assays with multiple variant combinations","pmids":["28463995"],"is_preprint":false},{"year":2013,"finding":"DNA methylation and genetic variants in the NPSR1 promoter influence the binding of nuclear proteins to promoter DNA, as shown by EMSA, suggesting epigenetic regulation of NPSR1 expression.","method":"Electrophoretic Mobility Shift Assay (EMSA), EpiTYPER methylation analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — direct protein-DNA binding assay with variant and methylation manipulation","pmids":["23372674"],"is_preprint":false},{"year":2024,"finding":"NPSR1 promotes chronic colitis by regulating CD4+ T cell effector function: NPSR1 knockdown reduces CD4+ T cell-mediated immune responses and inhibits differentiation, decreases proliferation, increases apoptosis, enhances CCL2-induced migration in vitro, and reduces Th1 cell chemotaxis in vivo in a DSS-induced mouse colitis model.","method":"IBD patient biopsy analysis, DSS-induced mouse colitis model, NPSR1 knockdown (in vitro and in vivo), flow cytometry, EdU incorporation, Annexin V-FITC/PI staining, transwell assay, qRT-PCR, immunoblotting","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 — KD with multiple orthogonal readouts in both in vitro and in vivo models","pmids":["39332092"],"is_preprint":false},{"year":2025,"finding":"NPSR1 activation by NPS triggers signaling through both Gαq (calcium) and Gαs (cAMP) pathways, inducing expression of pro-inflammatory cytokines IL-6, PTGS2, IL-20, and CXCL8 in human fibroblasts with enforced NPSR1 expression; NPSR1 antagonism in mice reduces peritoneal TNF-α and increases resident macrophages in a zymosan-induced inflammation model.","method":"Cell-based calcium and cAMP signaling assays, NPSR1 antagonist treatment of human fibroblasts, in vitro pro-inflammatory marker expression, murine zymosan-induced peritoneal inflammation model","journal":"Bioorganic & medicinal chemistry letters","confidence":"Medium","confidence_rationale":"Tier 1-2 — in vitro signaling assays combined with in vivo pharmacological inhibition","pmids":["40752839"],"is_preprint":false},{"year":2021,"finding":"Chicken NPSR1, when expressed in vitro, is potently activated by NPS and stimulates calcium mobilization, cAMP/PKA, and MAPK/ERK signaling pathways, demonstrating functional conservation of the NPS-NPSR1 system across vertebrates.","method":"Cell-based luciferase reporter systems, calcium mobilization assays, cAMP assays in transfected cells expressing chicken NPSR1","journal":"Poultry science","confidence":"Medium","confidence_rationale":"Tier 1-2 — multiple in vitro signaling assays in reconstituted system; ortholog study consistent with mammalian NPSR1 function","pmids":["34634709"],"is_preprint":false}],"current_model":"NPSR1 is a G protein-coupled receptor (existing in at least two isoforms, -A and -B, with distinct C-termini) that, upon activation by its endogenous ligand neuropeptide S (NPS), signals through both Gαs (cAMP/PKA) and Gαq (IP3/calcium) pathways—mobilizing ER calcium via IP3 and ryanodine receptors followed by store-operated calcium entry—and also activates MAPK/ERK and MAPK/JNK cascades, leading to transcriptional responses that regulate cell proliferation, immune function, circadian clock genes (including a feedback loop with RORA), and pro-inflammatory cytokine expression; in vivo, NPSR1 is required for NPS-induced locomotion, anxiolysis, and HPA axis activation, and regulates CD4+ T cell effector function in intestinal inflammation."},"narrative":{"teleology":[{"year":2005,"claim":"Establishing that NPSR1 isoforms are functional GPCRs requiring full seven-transmembrane topology for plasma membrane targeting resolved whether the multiple splice variants all signal at the cell surface, and linked NPSR1-A activation to growth inhibition.","evidence":"Immunohistochemistry, in situ hybridization, and cell-based NPS stimulation assays in heterologous cells","pmids":["15947423"],"confidence":"Medium","gaps":["Growth inhibition observed in a single cell model; tissue-specific relevance unclear","Mechanism of growth inhibition not dissected"]},{"year":2006,"claim":"Identification of NPS-NPSR1 downstream transcriptional targets (MMP10, INHBA, IL8, EPHA2, JUN/FOS) and enriched pathways (cell proliferation, immune response, morphogenesis) established that NPSR1 is not merely a signaling relay but drives broad transcriptional reprogramming.","evidence":"Microarray, qRT-PCR, and immunoassay after NPS stimulation of NPSR1-expressing cells","pmids":["16926187"],"confidence":"Medium","gaps":["Target gene regulation not validated by loss-of-function approaches","Physiological cell type context not tested"]},{"year":2006,"claim":"Demonstration that NPSR1-deficient mice have attenuated thromboxane-induced bronchoconstriction provided the first in vivo evidence that NPSR1 modulates airway physiology through neural pathways.","evidence":"NPSR1-knockout mouse, airway resistance measurements with thromboxane and methacholine challenge","pmids":["16829631"],"confidence":"Medium","gaps":["Neurally mediated mechanism inferred but not directly demonstrated","Methacholine response unaffected, limiting generality of airway role"]},{"year":2008,"claim":"Finding that LPS upregulates NPSR1 expression in monocytes connected NPSR1 to innate immune activation, suggesting its expression is dynamically regulated during inflammation.","evidence":"LPS stimulation of monocytes with FACS and qRT-PCR readouts","pmids":["18285428"],"confidence":"Medium","gaps":["Transcription factor mediating LPS-induced NPSR1 upregulation not identified","Functional consequence of upregulation on monocyte biology not tested"]},{"year":2010,"claim":"Definitive demonstration that NPSR1 is required for NPS-induced hyperlocomotion, anxiolysis, and corticosterone release resolved whether alternative receptors could mediate NPS effects in the CNS.","evidence":"NPSR1-knockout mice with ICV NPS administration, open-field, forced swim, Morris water maze, and plasma corticosterone measurement","pmids":["20171785"],"confidence":"High","gaps":["Brain region-specific requirement for NPSR1 not mapped","Downstream neural circuit mechanisms not elucidated"]},{"year":2011,"claim":"Parallel signaling analysis of NPSR1-A and NPSR1-B revealed shared coupling to cAMP/PKA, MAPK/JNK, and MAPK/ERK pathways but quantitative differences in potency, establishing that isoform-specific C-terminal sequences modulate signaling amplitude rather than pathway selectivity.","evidence":"HEK-293 overexpression, NPS dose-response, cAMP/Ca²⁺ assays, pathway reporters, Affymetrix expression arrays","pmids":["21707994"],"confidence":"High","gaps":["Structural basis for isoform-specific signaling amplitude differences unknown","Isoform-specific roles in native tissues not determined"]},{"year":2011,"claim":"Functional characterization of multiple NPSR1 coding and promoter SNPs showed that natural genetic variation quantitatively tunes receptor signaling output, with Cys197Phe acting as a loss-of-function variant, providing a mechanistic basis for NPSR1 disease associations.","evidence":"Luciferase reporters, cAMP assays, genome-wide transcriptional profiling of defined NPSR1 variant alleles","pmids":["22216302"],"confidence":"High","gaps":["Crystal structure not available to explain variant effects on receptor conformation","Population-level phenotypic consequences of individual variants not established"]},{"year":2013,"claim":"Discovery that NPSR1 activation induces RORA and circadian clock gene expression while RORA suppresses the NPSR1 promoter uncovered a reciprocal regulatory loop linking NPSR1 to circadian biology.","evidence":"Cell-based NPS stimulation, RORA overexpression with NPSR1 promoter-luciferase, Npsr1-KO mouse lung expression analysis","pmids":["23565190"],"confidence":"Medium","gaps":["Direct RORA binding to NPSR1 promoter not demonstrated by ChIP","Circadian behavioral consequences of disrupted loop not tested"]},{"year":2015,"claim":"Calcium imaging in primary hippocampal neurons delineated the full calcium signaling cascade downstream of NPSR1: IP3 receptor and ryanodine receptor-mediated ER release followed by store-operated calcium entry, providing the first neuronal characterization of NPSR1 calcium coupling.","evidence":"Single-cell calcium imaging in NPSR1-expressing hippocampal cultures with pharmacological pathway dissection","pmids":["25714705"],"confidence":"Medium","gaps":["NPSR1 endogenous expression level in hippocampal neurons not established","Downstream consequences of calcium mobilization for neuronal function not explored"]},{"year":2017,"claim":"Showing that natural NPS ligand variants (Val6 vs Leu6) differentially activate NPSR1 variant receptors established that signal output is determined by the combinatorial pairing of ligand and receptor polymorphisms.","evidence":"Transfected cells with NPS/NPSR1 variant combinations, cAMP/PKA reporter and gene expression readouts","pmids":["28463995"],"confidence":"Medium","gaps":["In vivo relevance of NPS variant-receptor variant interactions not tested","Binding affinity differences between ligand variants not directly measured"]},{"year":2024,"claim":"Demonstration that NPSR1 promotes CD4+ T cell effector function, differentiation, and Th1 chemotaxis in colitis models extended NPSR1 biology from innate immunity and neuronal signaling to adaptive immune regulation in intestinal inflammation.","evidence":"IBD patient biopsies, DSS-induced colitis model, NPSR1 knockdown with flow cytometry, EdU proliferation, apoptosis, and migration assays","pmids":["39332092"],"confidence":"Medium","gaps":["T cell-intrinsic versus indirect effects not fully separated","NPS ligand source in intestinal microenvironment not identified"]},{"year":2025,"claim":"Pharmacological NPSR1 antagonism reduced peritoneal TNF-α in vivo and blocked pro-inflammatory cytokine induction in vitro, providing proof-of-concept that NPSR1 is a druggable anti-inflammatory target.","evidence":"Cell-based calcium/cAMP assays, NPSR1 antagonist in human fibroblasts and murine zymosan peritonitis model","pmids":["40752839"],"confidence":"Medium","gaps":["Antagonist selectivity profile not fully characterized","Chronic disease model efficacy not tested"]},{"year":null,"claim":"Key unresolved questions include the structural basis of NPSR1 isoform-specific signaling, the identity of endogenous NPS sources in peripheral tissues, the cell-type-specific transcriptional programs driven by NPSR1 in native immune and neuronal contexts, and whether NPSR1 antagonism has therapeutic utility in chronic inflammatory or neuropsychiatric disease.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No high-resolution NPSR1 structure available","Endogenous NPS sources in peripheral inflammation unknown","Cell-type-resolved NPSR1 signaling in vivo not mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,3,4,7,13,14]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,5,7,10,13,14]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,9,12,13]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[3,7]},{"term_id":"R-HSA-9909396","term_label":"Circadian clock","supporting_discovery_ids":[6,8]}],"complexes":[],"partners":["NPS","RORA"],"other_free_text":[]},"mechanistic_narrative":"NPSR1 is a G protein-coupled receptor that transduces neuropeptide S (NPS) signaling to regulate arousal, anxiety, neuroendocrine stress responses, and immune-inflammatory processes. Existing as two major isoforms (NPSR1-A and NPSR1-B) with distinct C-termini but shared signaling capacity, ligand-activated NPSR1 couples to both Gαs (cAMP/PKA) and Gαq (IP3/calcium) pathways—mobilizing ER calcium via IP3 and ryanodine receptors followed by store-operated calcium entry—and activates MAPK/ERK and MAPK/JNK cascades, driving transcriptional programs encompassing immediate-early genes, circadian clock regulators including a feedback loop with RORA, and pro-inflammatory cytokines such as IL-6, CXCL8, and PTGS2 [PMID:21707994, PMID:25714705, PMID:40752839, PMID:23565190]. NPSR1 is required in vivo for NPS-induced hyperlocomotion, anxiolysis, and HPA axis activation [PMID:20171785], and promotes CD4+ T cell effector function and intestinal inflammation in colitis models [PMID:39332092]."},"prefetch_data":{"uniprot":{"accession":"Q6W5P4","full_name":"Neuropeptide S receptor","aliases":["G-protein coupled receptor 154","G-protein coupled receptor PGR14","G-protein coupled receptor for asthma susceptibility"],"length_aa":371,"mass_kda":42.7,"function":"G-protein coupled receptor for neuropeptide S (NPS) (PubMed:15947423, PubMed:16720571, PubMed:16790440). Receptor activation by NPS initiates a G(q)/GNAQ-dependent phospholipase C-activating signaling pathway, resulting in Ca(2+) mobilization from intracellular stores and increased intracellular Ca(2+) levels (PubMed:15312648, PubMed:15947423, PubMed:16720571, PubMed:16790440, PubMed:25714705, PubMed:26865629). In addition to this pathway, NPS binding to its receptor activates cAMP/PKA signal transduction (PubMed:26865629). Finally, both pathways converge to activate ERK1/ERK2 phosphorylation and signaling cascade (PubMed:26865629). Inhibits cell growth in response to NPS binding (PubMed:15947423)","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q6W5P4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NPSR1","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/NPSR1","total_profiled":1310},"omim":[{"mim_id":"621336","title":"SHORT SLEEP, FAMILIAL NATURAL, 3; FNSS3","url":"https://www.omim.org/entry/621336"},{"mim_id":"613207","title":"ASTHMA-RELATED TRAITS, SUSCEPTIBILITY TO, 8; ASRT8","url":"https://www.omim.org/entry/613207"},{"mim_id":"612975","title":"SHORT SLEEP, FAMILIAL NATURAL, 1; FNSS1","url":"https://www.omim.org/entry/612975"},{"mim_id":"609513","title":"NEUROPEPTIDE S; NPS","url":"https://www.omim.org/entry/609513"},{"mim_id":"608596","title":"NPSR1 ANTISENSE RNA 1; NPSRAS1","url":"https://www.omim.org/entry/608596"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Not detected","tissue_distribution":"Not detected","driving_tissues":[],"url":"https://www.proteinatlas.org/search/NPSR1"},"hgnc":{"alias_symbol":["PGR14","GPRA"],"prev_symbol":["GPR154"]},"alphafold":{"accession":"Q6W5P4","domains":[{"cath_id":"1.20.1070.10","chopping":"46-249_263-334","consensus_level":"high","plddt":91.8299,"start":46,"end":334}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6W5P4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6W5P4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6W5P4-F1-predicted_aligned_error_v6.png","plddt_mean":81.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NPSR1","jax_strain_url":"https://www.jax.org/strain/search?query=NPSR1"},"sequence":{"accession":"Q6W5P4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6W5P4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6W5P4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6W5P4"}},"corpus_meta":[{"pmid":"15341643","id":"PMC_15341643","title":"The gprA and gprB genes encode putative G protein-coupled receptors required for self-fertilization in Aspergillus nidulans.","date":"2004","source":"Molecular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/15341643","citation_count":91,"is_preprint":false},{"pmid":"15947423","id":"PMC_15947423","title":"Characterization of GPRA, a novel G protein-coupled receptor related to asthma.","date":"2005","source":"American journal of respiratory cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/15947423","citation_count":77,"is_preprint":false},{"pmid":"20171785","id":"PMC_20171785","title":"Abnormal response to stress and impaired NPS-induced hyperlocomotion, anxiolytic effect and corticosterone increase in mice lacking NPSR1.","date":"2010","source":"Psychoneuroendocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/20171785","citation_count":61,"is_preprint":false},{"pmid":"16829631","id":"PMC_16829631","title":"Expression and function of NPSR1/GPRA in the lung before and after induction of asthma-like disease.","date":"2006","source":"American journal of physiology. Lung cellular and molecular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/16829631","citation_count":54,"is_preprint":false},{"pmid":"23630477","id":"PMC_23630477","title":"Contextual fear conditioning in virtual reality is affected by 5HTTLPR and NPSR1 polymorphisms: effects on fear-potentiated startle.","date":"2013","source":"Frontiers in behavioral neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/23630477","citation_count":40,"is_preprint":false},{"pmid":"23319044","id":"PMC_23319044","title":"Neuropeptide S receptor (NPSR1) gene variation modulates response inhibition and error monitoring.","date":"2013","source":"NeuroImage","url":"https://pubmed.ncbi.nlm.nih.gov/23319044","citation_count":35,"is_preprint":false},{"pmid":"17210045","id":"PMC_17210045","title":"Chromosome 7p linkage and GPR154 gene association in Italian families with allergic asthma.","date":"2007","source":"Clinical and experimental allergy : journal of the British Society for Allergy and Clinical 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asthma.","date":"2016","source":"Allergy","url":"https://pubmed.ncbi.nlm.nih.gov/27145233","citation_count":16,"is_preprint":false},{"pmid":"33289016","id":"PMC_33289016","title":"The promoting effects of hsa_circ_0050102 in pancreatic cancer and the molecular mechanism by targeting miR-1182/NPSR1.","date":"2021","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/33289016","citation_count":16,"is_preprint":false},{"pmid":"28463995","id":"PMC_28463995","title":"Neuropeptide S (NPS) variants modify the signaling and risk effects of NPS Receptor 1 (NPSR1) variants in asthma.","date":"2017","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/28463995","citation_count":13,"is_preprint":false},{"pmid":"35030041","id":"PMC_35030041","title":"NPSR1-AS1 activates the MAPK pathway to facilitate thyroid cancer cell malignant behaviors via recruiting ELAVL1 to stabilize NPSR1 mRNA.","date":"2022","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/35030041","citation_count":13,"is_preprint":false},{"pmid":"25091462","id":"PMC_25091462","title":"NPSR1 polymorphisms influence recurrent abdominal pain in children: a population-based study.","date":"2014","source":"Neurogastroenterology and motility","url":"https://pubmed.ncbi.nlm.nih.gov/25091462","citation_count":13,"is_preprint":false},{"pmid":"34634709","id":"PMC_34634709","title":"Neuropeptide S (NPS) and its receptor (NPSR1) in chickens: cloning, tissue expression, and functional analysis.","date":"2021","source":"Poultry science","url":"https://pubmed.ncbi.nlm.nih.gov/34634709","citation_count":11,"is_preprint":false},{"pmid":"17327822","id":"PMC_17327822","title":"Haplotype-defined linkage region for gPRA in Schapendoes dogs.","date":"2007","source":"Molecular vision","url":"https://pubmed.ncbi.nlm.nih.gov/17327822","citation_count":9,"is_preprint":false},{"pmid":"34406628","id":"PMC_34406628","title":"Highly expressed TLX1NB and NPSR1-AS1 lncRNAs could serve as diagnostic tools in colorectal cancer.","date":"2021","source":"Human cell","url":"https://pubmed.ncbi.nlm.nih.gov/34406628","citation_count":9,"is_preprint":false},{"pmid":"31132388","id":"PMC_31132388","title":"Investigating the Contribution of NPSR1, IL-6 and BDNF Polymorphisms to Depressive and Anxiety Symptoms in Hemodialysis Patients.","date":"2019","source":"Progress in neuro-psychopharmacology & biological psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/31132388","citation_count":8,"is_preprint":false},{"pmid":"31734525","id":"PMC_31734525","title":"Association of NPSR1 gene variation and neural activity in patients with panic disorder and agoraphobia and healthy controls.","date":"2019","source":"NeuroImage. Clinical","url":"https://pubmed.ncbi.nlm.nih.gov/31734525","citation_count":8,"is_preprint":false},{"pmid":"22548958","id":"PMC_22548958","title":"NPSR1 gene is associated with reduced risk of rheumatoid arthritis.","date":"2012","source":"The Journal of rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/22548958","citation_count":8,"is_preprint":false},{"pmid":"30927345","id":"PMC_30927345","title":"Nocturnal asthma is affected by genetic interactions between RORA and NPSR1.","date":"2019","source":"Pediatric pulmonology","url":"https://pubmed.ncbi.nlm.nih.gov/30927345","citation_count":7,"is_preprint":false},{"pmid":"23680103","id":"PMC_23680103","title":"The functional coding variant Asn107Ile of the neuropeptide S receptor gene (NPSR1) influences age at onset of obsessive-compulsive disorder.","date":"2013","source":"The international journal of neuropsychopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/23680103","citation_count":7,"is_preprint":false},{"pmid":"30190127","id":"PMC_30190127","title":"Association of NPSR1 rs324981 polymorphism and treatment response to antidepressants in Chinese Han population with generalized anxiety disorder.","date":"2018","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/30190127","citation_count":7,"is_preprint":false},{"pmid":"32846769","id":"PMC_32846769","title":"Gene polymorphisms (rs324957, rs324981) in NPSR1 are associated with increased risk of primary insomnia: A cross-sectional study.","date":"2020","source":"Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32846769","citation_count":5,"is_preprint":false},{"pmid":"12927076","id":"PMC_12927076","title":"Analysis of PDE6D and PDE6G genes for generalised progressive retinal atrophy (gPRA) mutations in dogs.","date":"2003","source":"Genetics, selection, evolution : GSE","url":"https://pubmed.ncbi.nlm.nih.gov/12927076","citation_count":5,"is_preprint":false},{"pmid":"24439655","id":"PMC_24439655","title":"Interaction of NPSR1 genotypes and probiotics in the manifestation of atopic eczema in early childhood.","date":"2014","source":"Allergologia et immunopathologia","url":"https://pubmed.ncbi.nlm.nih.gov/24439655","citation_count":4,"is_preprint":false},{"pmid":"35914393","id":"PMC_35914393","title":"The association between genetic variability in the NPS/NPSR1 system and chronic stress responses: A gene-environment-(quasi-) experiment.","date":"2022","source":"Psychoneuroendocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/35914393","citation_count":4,"is_preprint":false},{"pmid":"19325992","id":"PMC_19325992","title":"Lack of association between neuropeptide S receptor 1 gene (NPSR1) and eczema in five European populations.","date":"2009","source":"Acta dermato-venereologica","url":"https://pubmed.ncbi.nlm.nih.gov/19325992","citation_count":4,"is_preprint":false},{"pmid":"39332092","id":"PMC_39332092","title":"NPSR1 promotes chronic colitis through regulating CD4+ T cell effector function in inflammatory bowel disease.","date":"2024","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/39332092","citation_count":1,"is_preprint":false},{"pmid":"17285544","id":"PMC_17285544","title":"[Study on the association of single nucleotide polymorphisms and haplotypes of GPR154 gene with allergic asthma in Han nationality in Hubei Chinese population].","date":"2007","source":"Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/17285544","citation_count":1,"is_preprint":false},{"pmid":"40752839","id":"PMC_40752839","title":"Design of a peripherally biased NPSR1 antagonist for neuropeptide S induced inflammation.","date":"2025","source":"Bioorganic & medicinal chemistry letters","url":"https://pubmed.ncbi.nlm.nih.gov/40752839","citation_count":0,"is_preprint":false},{"pmid":"9657245","id":"PMC_9657245","title":"Factor G pathway reactive activity (GPRA) after surgery for abdominal aortic aneurysm.","date":"1998","source":"International angiology : a journal of the International Union of Angiology","url":"https://pubmed.ncbi.nlm.nih.gov/9657245","citation_count":0,"is_preprint":false},{"pmid":"41558152","id":"PMC_41558152","title":"LncRNA NPSR1-AS1 affects the malignant biological behavior of bladder cancer through miR-199a-3p and the clinical value of urine-derived lncRNA NPSR1-AS1.","date":"2026","source":"Urologic oncology","url":"https://pubmed.ncbi.nlm.nih.gov/41558152","citation_count":0,"is_preprint":false},{"pmid":"39167471","id":"PMC_39167471","title":"Impact of NPSR1 gene variation on the neural correlates of phasic and sustained fear in spider phobia-an imaging genetics and independent replication approach.","date":"2024","source":"Social cognitive and affective neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/39167471","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":27122,"output_tokens":3609,"usd":0.067751},"stage2":{"model":"claude-opus-4-6","input_tokens":7033,"output_tokens":2845,"usd":0.159435},"total_usd":0.227186,"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\": 2005,\n      \"finding\": \"NPSR1 (GPRA) isoforms A and B are G protein-coupled receptors; only the full-length variants GPRA-A and GPRA-B with 7-transmembrane topology are transported to the plasma membrane, while truncated variants are retained in intracellular compartments. Isoform-specific activation of GPRA-A with its agonist NPS results in significant inhibition of cell growth.\",\n      \"method\": \"Immunohistochemistry, in situ hybridization, cell-based functional assays with NPS stimulation\",\n      \"journal\": \"American journal of respiratory cell and molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — direct localization and functional assay in single lab with multiple methods\",\n      \"pmids\": [\"15947423\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"NPS stimulation of NPSR1 activates downstream gene targets including MMP10, INHBA (activin A), IL8, and EPHA2 in a dose-dependent manner; Gene Ontology analysis revealed enrichment of 'cell proliferation', 'morphogenesis', and 'immune response' pathways, with a common co-regulated pathway including JUN/FOS oncogene homologs, early growth response genes, nuclear receptor subfamily 4 members, and dual specificity phosphatases.\",\n      \"method\": \"Microarray analysis, quantitative RT-PCR, immunoassay, immunohistochemistry\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (microarray, qRT-PCR, immunoassay) in single lab\",\n      \"pmids\": [\"16926187\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"NPSR1 (GPRA)-deficient mice show an attenuated bronchoconstriction response to thromboxane (a cholinergic receptor-dependent agent) but not to methacholine, suggesting NPSR1 contributes to neurally mediated bronchoconstriction mechanisms.\",\n      \"method\": \"GPRA-knockout mouse model, airway resistance measurements\",\n      \"journal\": \"American journal of physiology. Lung cellular and molecular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with specific physiological phenotype readout\",\n      \"pmids\": [\"16829631\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"NPSR1 is essential for mediating NPS effects in vivo: NPSR1-deficient mice fail to exhibit NPS-induced hyperlocomotion, anxiolysis, or corticosterone release after intracerebroventricular NPS administration, establishing NPSR1 as the required receptor for these NPS-induced behavioral and neuroendocrine effects.\",\n      \"method\": \"NPSR1 gene-targeted (knockout) mice, ICV NPS administration, behavioral assays (open-field, forced swim, Morris water maze), corticosterone measurement\",\n      \"journal\": \"Psychoneuroendocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with multiple orthogonal behavioral and endocrine phenotype readouts\",\n      \"pmids\": [\"20171785\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"NPSR1-A and NPSR1-B isoforms signal through the same downstream pathways (cAMP/PKA, MAPK/JNK, MAPK/ERK) and regulate largely the same gene set after NPS stimulation, but NPSR1-A induces stronger signaling effects than NPSR1-B; one notable exception is CD69 (a marker of regulatory T cells), which shows higher induction by NPSR1-B.\",\n      \"method\": \"HEK-293 cell overexpression, NPS concentration-response analysis, qRT-PCR, cAMP assay, Ca²⁺ assay, pathway-specific reporter assays (cAMP/PKA, MAPK/JNK, MAPK/ERK), genome-scale Affymetrix expression arrays\",\n      \"journal\": \"BMC pulmonary medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal signaling assays in single lab with genome-scale profiling\",\n      \"pmids\": [\"21707994\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Multiple NPSR1 SNPs affect receptor function: a promoter SNP (rs2530547) significantly affects NPSR1 mRNA levels in human leukocytes; three non-synonymous coding SNPs (rs324981 [Ile107Asn], rs34705969 [Cys197Phe], rs727162 [Arg241Ser]) show quantitative differences in NPS-induced cAMP/PKA signaling and genome-wide transcriptional responses; the Cys197Phe variant exhibits a loss-of-function phenotype.\",\n      \"method\": \"Luciferase reporter assays, qRT-PCR of human leukocytes, NPS-induced genome-wide transcriptional profiling, CRE-dependent luciferase activity assays, molecular modelling\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple functional assays (reporter, transcriptomics, signaling) with defined variants\",\n      \"pmids\": [\"22216302\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"RORA and NPSR1 interact biologically: NPSR1 stimulation activates a pathway including RORA and other circadian clock genes; overexpression of RORA decreases NPSR1 promoter activity; Rora mRNA expression is lower in lung tissue of Npsr1-deficient mice during early hours of the light period, suggesting a regulatory feedback loop between these genes.\",\n      \"method\": \"Cell-based NPSR1 stimulation, RORA overexpression with NPSR1 promoter luciferase assay, Npsr1 knockout mouse lung gene expression analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — multiple methods (cell reporter, KO mouse) but cross-lab validation limited\",\n      \"pmids\": [\"23565190\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"In primary hippocampal neurons expressing NPSR1, NPS stimulation induces calcium mobilization from the endoplasmic reticulum via IP3 and ryanodine receptors, followed by activation of store-operated calcium channels mediating extracellular calcium entry.\",\n      \"method\": \"NPSR1 expression in primary hippocampal cultures, single-cell calcium imaging\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct calcium imaging in neurons with pharmacological dissection of pathway components\",\n      \"pmids\": [\"25714705\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"NPS stimulation of NPSR1-A overexpressing SH-SY5Y neuroblastoma cells activates MAPK pathways, circadian activity, focal adhesion, TGF-beta, and cytokine-cytokine interaction gene pathways, as determined by transcriptome analysis.\",\n      \"method\": \"NPSR1-A overexpression in SH-SY5Y cells, NPS stimulation, transcriptome analysis, immunohistochemistry\",\n      \"journal\": \"Virchows Archiv : an international journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — transcriptome-level pathway analysis after NPS stimulation in cell model\",\n      \"pmids\": [\"24915894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"LPS stimulation upregulates NPSR1-A protein and mRNA levels in monocytes, indicating that NPSR1 expression is regulated by innate immune signaling.\",\n      \"method\": \"LPS stimulation of monocytes, FACS for NPSR1 protein, quantitative real-time PCR for NPSR1 mRNA\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — direct in vitro experiment with two orthogonal measurement methods\",\n      \"pmids\": [\"18285428\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The combination of NPS and NPSR1 variants determines the magnitude of cAMP/PKA signal transduction and downstream gene expression: NPS-Val6/NPSR1-Ile107 produces the strongest activation while NPS-Leu6/NPSR1-Asn107 produces the weakest, demonstrating that NPS variants modify NPSR1 signaling.\",\n      \"method\": \"Transfected cells with different NPS/NPSR1 variant combinations, cAMP/PKA reporter assays, downstream gene expression analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — cell-based functional assays with multiple variant combinations\",\n      \"pmids\": [\"28463995\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"DNA methylation and genetic variants in the NPSR1 promoter influence the binding of nuclear proteins to promoter DNA, as shown by EMSA, suggesting epigenetic regulation of NPSR1 expression.\",\n      \"method\": \"Electrophoretic Mobility Shift Assay (EMSA), EpiTYPER methylation analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct protein-DNA binding assay with variant and methylation manipulation\",\n      \"pmids\": [\"23372674\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NPSR1 promotes chronic colitis by regulating CD4+ T cell effector function: NPSR1 knockdown reduces CD4+ T cell-mediated immune responses and inhibits differentiation, decreases proliferation, increases apoptosis, enhances CCL2-induced migration in vitro, and reduces Th1 cell chemotaxis in vivo in a DSS-induced mouse colitis model.\",\n      \"method\": \"IBD patient biopsy analysis, DSS-induced mouse colitis model, NPSR1 knockdown (in vitro and in vivo), flow cytometry, EdU incorporation, Annexin V-FITC/PI staining, transwell assay, qRT-PCR, immunoblotting\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KD with multiple orthogonal readouts in both in vitro and in vivo models\",\n      \"pmids\": [\"39332092\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NPSR1 activation by NPS triggers signaling through both Gαq (calcium) and Gαs (cAMP) pathways, inducing expression of pro-inflammatory cytokines IL-6, PTGS2, IL-20, and CXCL8 in human fibroblasts with enforced NPSR1 expression; NPSR1 antagonism in mice reduces peritoneal TNF-α and increases resident macrophages in a zymosan-induced inflammation model.\",\n      \"method\": \"Cell-based calcium and cAMP signaling assays, NPSR1 antagonist treatment of human fibroblasts, in vitro pro-inflammatory marker expression, murine zymosan-induced peritoneal inflammation model\",\n      \"journal\": \"Bioorganic & medicinal chemistry letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro signaling assays combined with in vivo pharmacological inhibition\",\n      \"pmids\": [\"40752839\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Chicken NPSR1, when expressed in vitro, is potently activated by NPS and stimulates calcium mobilization, cAMP/PKA, and MAPK/ERK signaling pathways, demonstrating functional conservation of the NPS-NPSR1 system across vertebrates.\",\n      \"method\": \"Cell-based luciferase reporter systems, calcium mobilization assays, cAMP assays in transfected cells expressing chicken NPSR1\",\n      \"journal\": \"Poultry science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple in vitro signaling assays in reconstituted system; ortholog study consistent with mammalian NPSR1 function\",\n      \"pmids\": [\"34634709\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NPSR1 is a G protein-coupled receptor (existing in at least two isoforms, -A and -B, with distinct C-termini) that, upon activation by its endogenous ligand neuropeptide S (NPS), signals through both Gαs (cAMP/PKA) and Gαq (IP3/calcium) pathways—mobilizing ER calcium via IP3 and ryanodine receptors followed by store-operated calcium entry—and also activates MAPK/ERK and MAPK/JNK cascades, leading to transcriptional responses that regulate cell proliferation, immune function, circadian clock genes (including a feedback loop with RORA), and pro-inflammatory cytokine expression; in vivo, NPSR1 is required for NPS-induced locomotion, anxiolysis, and HPA axis activation, and regulates CD4+ T cell effector function in intestinal inflammation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"NPSR1 is a G protein-coupled receptor that transduces neuropeptide S (NPS) signaling to regulate arousal, anxiety, neuroendocrine stress responses, and immune-inflammatory processes. Existing as two major isoforms (NPSR1-A and NPSR1-B) with distinct C-termini but shared signaling capacity, ligand-activated NPSR1 couples to both Gαs (cAMP/PKA) and Gαq (IP3/calcium) pathways—mobilizing ER calcium via IP3 and ryanodine receptors followed by store-operated calcium entry—and activates MAPK/ERK and MAPK/JNK cascades, driving transcriptional programs encompassing immediate-early genes, circadian clock regulators including a feedback loop with RORA, and pro-inflammatory cytokines such as IL-6, CXCL8, and PTGS2 [PMID:21707994, PMID:25714705, PMID:40752839, PMID:23565190]. NPSR1 is required in vivo for NPS-induced hyperlocomotion, anxiolysis, and HPA axis activation [PMID:20171785], and promotes CD4+ T cell effector function and intestinal inflammation in colitis models [PMID:39332092].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Establishing that NPSR1 isoforms are functional GPCRs requiring full seven-transmembrane topology for plasma membrane targeting resolved whether the multiple splice variants all signal at the cell surface, and linked NPSR1-A activation to growth inhibition.\",\n      \"evidence\": \"Immunohistochemistry, in situ hybridization, and cell-based NPS stimulation assays in heterologous cells\",\n      \"pmids\": [\"15947423\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Growth inhibition observed in a single cell model; tissue-specific relevance unclear\", \"Mechanism of growth inhibition not dissected\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identification of NPS-NPSR1 downstream transcriptional targets (MMP10, INHBA, IL8, EPHA2, JUN/FOS) and enriched pathways (cell proliferation, immune response, morphogenesis) established that NPSR1 is not merely a signaling relay but drives broad transcriptional reprogramming.\",\n      \"evidence\": \"Microarray, qRT-PCR, and immunoassay after NPS stimulation of NPSR1-expressing cells\",\n      \"pmids\": [\"16926187\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Target gene regulation not validated by loss-of-function approaches\", \"Physiological cell type context not tested\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstration that NPSR1-deficient mice have attenuated thromboxane-induced bronchoconstriction provided the first in vivo evidence that NPSR1 modulates airway physiology through neural pathways.\",\n      \"evidence\": \"NPSR1-knockout mouse, airway resistance measurements with thromboxane and methacholine challenge\",\n      \"pmids\": [\"16829631\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Neurally mediated mechanism inferred but not directly demonstrated\", \"Methacholine response unaffected, limiting generality of airway role\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Finding that LPS upregulates NPSR1 expression in monocytes connected NPSR1 to innate immune activation, suggesting its expression is dynamically regulated during inflammation.\",\n      \"evidence\": \"LPS stimulation of monocytes with FACS and qRT-PCR readouts\",\n      \"pmids\": [\"18285428\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Transcription factor mediating LPS-induced NPSR1 upregulation not identified\", \"Functional consequence of upregulation on monocyte biology not tested\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Definitive demonstration that NPSR1 is required for NPS-induced hyperlocomotion, anxiolysis, and corticosterone release resolved whether alternative receptors could mediate NPS effects in the CNS.\",\n      \"evidence\": \"NPSR1-knockout mice with ICV NPS administration, open-field, forced swim, Morris water maze, and plasma corticosterone measurement\",\n      \"pmids\": [\"20171785\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Brain region-specific requirement for NPSR1 not mapped\", \"Downstream neural circuit mechanisms not elucidated\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Parallel signaling analysis of NPSR1-A and NPSR1-B revealed shared coupling to cAMP/PKA, MAPK/JNK, and MAPK/ERK pathways but quantitative differences in potency, establishing that isoform-specific C-terminal sequences modulate signaling amplitude rather than pathway selectivity.\",\n      \"evidence\": \"HEK-293 overexpression, NPS dose-response, cAMP/Ca²⁺ assays, pathway reporters, Affymetrix expression arrays\",\n      \"pmids\": [\"21707994\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for isoform-specific signaling amplitude differences unknown\", \"Isoform-specific roles in native tissues not determined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Functional characterization of multiple NPSR1 coding and promoter SNPs showed that natural genetic variation quantitatively tunes receptor signaling output, with Cys197Phe acting as a loss-of-function variant, providing a mechanistic basis for NPSR1 disease associations.\",\n      \"evidence\": \"Luciferase reporters, cAMP assays, genome-wide transcriptional profiling of defined NPSR1 variant alleles\",\n      \"pmids\": [\"22216302\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Crystal structure not available to explain variant effects on receptor conformation\", \"Population-level phenotypic consequences of individual variants not established\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Discovery that NPSR1 activation induces RORA and circadian clock gene expression while RORA suppresses the NPSR1 promoter uncovered a reciprocal regulatory loop linking NPSR1 to circadian biology.\",\n      \"evidence\": \"Cell-based NPS stimulation, RORA overexpression with NPSR1 promoter-luciferase, Npsr1-KO mouse lung expression analysis\",\n      \"pmids\": [\"23565190\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct RORA binding to NPSR1 promoter not demonstrated by ChIP\", \"Circadian behavioral consequences of disrupted loop not tested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Calcium imaging in primary hippocampal neurons delineated the full calcium signaling cascade downstream of NPSR1: IP3 receptor and ryanodine receptor-mediated ER release followed by store-operated calcium entry, providing the first neuronal characterization of NPSR1 calcium coupling.\",\n      \"evidence\": \"Single-cell calcium imaging in NPSR1-expressing hippocampal cultures with pharmacological pathway dissection\",\n      \"pmids\": [\"25714705\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"NPSR1 endogenous expression level in hippocampal neurons not established\", \"Downstream consequences of calcium mobilization for neuronal function not explored\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showing that natural NPS ligand variants (Val6 vs Leu6) differentially activate NPSR1 variant receptors established that signal output is determined by the combinatorial pairing of ligand and receptor polymorphisms.\",\n      \"evidence\": \"Transfected cells with NPS/NPSR1 variant combinations, cAMP/PKA reporter and gene expression readouts\",\n      \"pmids\": [\"28463995\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo relevance of NPS variant-receptor variant interactions not tested\", \"Binding affinity differences between ligand variants not directly measured\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstration that NPSR1 promotes CD4+ T cell effector function, differentiation, and Th1 chemotaxis in colitis models extended NPSR1 biology from innate immunity and neuronal signaling to adaptive immune regulation in intestinal inflammation.\",\n      \"evidence\": \"IBD patient biopsies, DSS-induced colitis model, NPSR1 knockdown with flow cytometry, EdU proliferation, apoptosis, and migration assays\",\n      \"pmids\": [\"39332092\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"T cell-intrinsic versus indirect effects not fully separated\", \"NPS ligand source in intestinal microenvironment not identified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Pharmacological NPSR1 antagonism reduced peritoneal TNF-α in vivo and blocked pro-inflammatory cytokine induction in vitro, providing proof-of-concept that NPSR1 is a druggable anti-inflammatory target.\",\n      \"evidence\": \"Cell-based calcium/cAMP assays, NPSR1 antagonist in human fibroblasts and murine zymosan peritonitis model\",\n      \"pmids\": [\"40752839\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Antagonist selectivity profile not fully characterized\", \"Chronic disease model efficacy not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis of NPSR1 isoform-specific signaling, the identity of endogenous NPS sources in peripheral tissues, the cell-type-specific transcriptional programs driven by NPSR1 in native immune and neuronal contexts, and whether NPSR1 antagonism has therapeutic utility in chronic inflammatory or neuropsychiatric disease.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No high-resolution NPSR1 structure available\", \"Endogenous NPS sources in peripheral inflammation unknown\", \"Cell-type-resolved NPSR1 signaling in vivo not mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 3, 4, 7, 13, 14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 5, 7, 10, 13, 14]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 9, 12, 13]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [3, 7]},\n      {\"term_id\": \"R-HSA-9909396\", \"supporting_discovery_ids\": [6, 8]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"NPS\",\n      \"RORA\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}