{"gene":"MTNR1A","run_date":"2026-06-10T05:19:51","timeline":{"discoveries":[{"year":2015,"finding":"Valproic acid (VPA) interferes with melatonin-induced MTNR1A internalization kinetics. Using FRET imaging in living HEK-293 and Neuro-2a cells expressing epitope-tagged MTNR1A-EGFP, VPA was shown to reduce the melatonin-initiated association between YFP-labeled β-arrestin 2 and CFP-labeled MTNR1A, attenuating receptor internalization. This effect was associated with decreased phosphorylation of PKA (Thr197) and ERK (Thr202/Tyr204). VPA did not alter whole-cell currents.","method":"Time-lapse confocal microscopy of MTNR1A-EGFP in living cells, FRET imaging (YFP-β-arrestin 2 / CFP-MTNR1A), phosphorylation assays","journal":"Molecular neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal FRET with functional readouts (phosphorylation, internalization kinetics), multiple orthogonal methods in single lab","pmids":["25613019"],"is_preprint":false},{"year":2020,"finding":"Cytoplasmic hnRNPL stabilizes MTNR1A mRNA post-transcriptionally in renal tubular cells. RNA interference screening identified hnRNPL as an upregulator of MTNR1A RNA. hnRNPL interacts with CA-repeat elements in the MTNR1A coding region and protects MTNR1A RNA from degradation by exosome component 10 (EXOSC10). hnRNPL knockdown or overexpression reciprocally altered CREB phosphorylation levels. MTNR1A but not hnRNPL displays a diurnal rhythm in mouse kidneys, with peak expression at midnight correlating with robust hnRNPL–MTNR1A transcript binding activity.","method":"RNAi screen, hnRNPL knockdown/overexpression, molecular binding assays (CA-repeat element), CREB phosphorylation assay, diurnal expression analysis in mouse kidney","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (RNAi, overexpression, binding studies, phosphorylation), single lab","pmids":["32730662"],"is_preprint":false},{"year":2020,"finding":"CRISPR/Cas9-mediated small deletion mutation of the mtnr1a gene in Xenopus tropicalis causes loss of rod photoreceptors in developing heterozygous tadpole retinas, with cones relatively spared, establishing a required role for MTNR1A signaling in rod photoreceptor survival. The mutant MTNR1A protein appeared to be expressed at similar levels/localization as wild type, suggesting the degeneration is due to disrupted receptor signaling rather than protein absence.","method":"In vivo CRISPR/Cas9 genomic editing in Xenopus tropicalis, histological analysis of retina, immunolocalization of Mel1a receptor protein","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo loss-of-function with defined cellular phenotype (rod degeneration), single lab, ortholog study","pmids":["32792587"],"is_preprint":false},{"year":2017,"finding":"MTNR1A mediates melatonin's anti-apoptotic and hormone-regulatory effects in bovine granulosa cells. Knockdown of MTNR1A reversed melatonin's effects: it increased pro-apoptotic markers (BAX, CASP3, TP53), increased INHA, FSHR, TGFBR3 and Inhibin β, while decreasing BCL2, GPX4, SOD1, LHR, and production of progesterone and estradiol, placing MTNR1A as the functional receptor mediating melatonin action on granulosa cell apoptosis and hormone secretion.","method":"siRNA knockdown of MTNR1A in bovine granulosa cells, qRT-PCR, ELISA for progesterone/estradiol/inhibin","journal":"Molecular reproduction and development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function (siRNA) with multiple defined molecular readouts, single lab","pmids":["28805353"],"is_preprint":false},{"year":2025,"finding":"NG-497 alleviates LPS-induced neuroinflammation in human microglia through elevating MTNR1A protein levels; the anti-inflammatory capacity of NG-497 was independent of its ATGL-inhibitory effect but dependent on MTNR1A upregulation. The MTNRs agonist Ramelteon exerted comparable anti-inflammatory effects, supporting MTNR1A as the functional mediator.","method":"MTNR1A protein level measurement, LPS-induced neuroinflammation assay in human microglia, Ramelteon agonist comparison, humanized in vitro neuroinflammation model","journal":"Inflammation","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, mechanism inferred from compound effect and protein level change without direct MTNR1A KO rescue experiment","pmids":["39751706"],"is_preprint":false},{"year":2020,"finding":"Site-directed mutagenesis of consensus sequences in human MTNR1A, assayed using a yeast fluorescent biosensor (chimeric yeast-human Gα + ZsGreen reporter), demonstrated that most mutations in consensus sequences significantly reduced MTNR1A signaling capacity, identifying residues critical for receptor activation. Several mutations showed differential effects between MTNR1A and MTNR1B subtypes.","method":"Site-directed mutagenesis of human MTNR1A expressed in Saccharomyces cerevisiae GPCR biosensor with chimeric Gα protein and fluorescent reporter (ZsGreen)","journal":"Biotechnology and bioengineering","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — active-site/consensus mutagenesis with functional readout, single lab, single method","pmids":["33095446"],"is_preprint":false},{"year":2008,"finding":"MTNR1A is epigenetically silenced in oral squamous-cell carcinoma (OSCC). Hypermethylation of the CpG island in the MTNR1A promoter was inversely correlated with its expression in OSCC lines. Treatment with 5-aza-2'-deoxycytidine (a DNA methyltransferase inhibitor) restored MTNR1A expression in gene-silenced OSCC cells lacking homozygous deletion. Exogenous restoration of MTNR1A expression inhibited OSCC cell growth.","method":"Array-CGH, RT-PCR, 5-aza-2'-deoxycytidine demethylation treatment, bisulfite sequencing/methylation analysis, exogenous MTNR1A re-expression growth assay","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (demethylation rescue, re-expression growth assay), single lab","pmids":["18452558"],"is_preprint":false},{"year":2016,"finding":"A differentially methylated CpG site (cg02303933) within the MTNR1A gene mediates the effect of a paternally transmitted genetic variant (rs10009104 G allele) on the comorbidity of asthma and allergic rhinitis. Mediation analysis showed DNAm at this site statistically mediates the SNP-disease association, implicating epigenetic regulation of MTNR1A in allergic respiratory disease.","method":"Genome-wide linkage scan, SNP association analysis, DNA methylation association analysis, mediation analysis in family-based cohorts","journal":"The Journal of allergy and clinical immunology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — statistical mediation analysis only, no functional experiment on MTNR1A protein or mRNA, single consortium study","pmids":["27038909"],"is_preprint":false},{"year":2004,"finding":"MTNR1A transcripts are expressed in the ovine premammillary hypothalamus (PMH) and display a diurnal rhythm: expression is greater at the end of the night (melatonin present) than at the end of the day in the PMH, while the opposite pattern is observed in the pars tuberalis (PT). MTNR1B transcripts were not detected in any structure examined.","method":"RT-PCR, in situ hybridization with 35S-labeled ovine MTNR1A riboprobe, comparison of day vs night tissue samples","journal":"Biology of reproduction","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — orthogonal methods (RT-PCR + ISH) with direct day/night comparison, single lab","pmids":["15470001"],"is_preprint":false}],"current_model":"MTNR1A encodes a G protein-coupled melatonin receptor (MT1) whose signaling is initiated by melatonin binding; upon activation, the receptor internalizes via a β-arrestin 2-dependent mechanism (disrupted by valproic acid through reduced PKA/ERK phosphorylation); its mRNA is post-transcriptionally stabilized in renal tubular cells by cytoplasmic hnRNPL binding to CA-repeat elements, protecting the transcript from EXOSC10-mediated degradation; the receptor is required for rod photoreceptor survival in the retina (established by CRISPR knockout in Xenopus); it mediates melatonin's anti-apoptotic and steroidogenic effects in granulosa cells; and its expression is subject to epigenetic silencing via CpG island promoter methylation in cancer and disease contexts."},"narrative":{"mechanistic_narrative":"MTNR1A encodes the MT1 melatonin receptor, a G protein-coupled receptor that transduces melatonin signaling to regulate cell survival, hormone secretion, and inflammatory responses across tissues [PMID:28805353, PMID:33095446]. Site-directed mutagenesis of consensus sequence residues, assayed in a yeast GPCR biosensor with chimeric Gα, defines residues required for receptor activation and distinguishes MTNR1A from the MTNR1B subtype [PMID:33095446]. Upon melatonin binding, the receptor recruits β-arrestin 2 and internalizes; valproic acid attenuates this β-arrestin 2 association and internalization in parallel with reduced PKA (Thr197) and ERK (Thr202/Tyr204) phosphorylation [PMID:25613019]. Functionally, MTNR1A mediates melatonin's anti-apoptotic and steroidogenic effects in granulosa cells, where its knockdown raises pro-apoptotic markers (BAX, CASP3, TP53) and lowers BCL2, antioxidant enzymes, and progesterone/estradiol output [PMID:28805353], and is required for rod photoreceptor survival as shown by CRISPR disruption in Xenopus [PMID:32792587]. MTNR1A abundance is controlled post-transcriptionally by cytoplasmic hnRNPL, which binds CA-repeat elements in the transcript and protects it from EXOSC10-mediated degradation, with the transcript displaying a diurnal rhythm peaking at midnight in kidney [PMID:32730662]; expression is additionally subject to epigenetic silencing via CpG island promoter methylation in oral squamous-cell carcinoma, where re-expression suppresses tumor cell growth [PMID:18452558].","teleology":[{"year":2004,"claim":"Establishing where MTNR1A is expressed and whether its message tracks the light/dark cycle was needed to connect the receptor to melatonin's physiological timing role.","evidence":"RT-PCR and in situ hybridization comparing day vs night ovine hypothalamic tissue","pmids":["15470001"],"confidence":"Medium","gaps":["Does not establish downstream signaling output from these tissues","Diurnal transcript rhythm mechanism not addressed","Ortholog (ovine) expression pattern, not human"]},{"year":2008,"claim":"Whether MTNR1A acts as a growth suppressor and how its expression is lost in cancer was unknown; promoter methylation analysis tied silencing to tumor biology.","evidence":"CpG island methylation analysis, 5-aza-2'-deoxycytidine demethylation rescue, and exogenous re-expression growth assay in OSCC lines","pmids":["18452558"],"confidence":"Medium","gaps":["Signaling pathway mediating growth suppression not defined","Whether melatonin ligand is required for the anti-growth effect untested"]},{"year":2015,"claim":"How MTNR1A is internalized after activation, and whether a drug could perturb that step, was addressed by tracking the receptor–β-arrestin 2 interaction in living cells.","evidence":"FRET imaging of CFP-MTNR1A and YFP-β-arrestin 2 plus PKA/ERK phosphorylation assays in HEK-293 and Neuro-2a cells, with valproic acid","pmids":["25613019"],"confidence":"Medium","gaps":["Direct causal link between phosphorylation changes and arrestin recruitment not dissected","Performed in overexpression cell systems"]},{"year":2016,"claim":"Whether epigenetic regulation of MTNR1A contributes to non-cancer disease was tested by linking a methylation site to a transmitted genetic variant and allergic disease.","evidence":"Genetic linkage, SNP and DNA methylation association, and mediation analysis in family cohorts","pmids":["27038909"],"confidence":"Low","gaps":["Statistical mediation only, no functional experiment on MTNR1A protein or mRNA","Causal role of MTNR1A in the disease not established"]},{"year":2017,"claim":"Identifying MTNR1A as the receptor responsible for melatonin's effects on ovarian cell fate and steroidogenesis required directly removing the receptor under melatonin exposure.","evidence":"siRNA knockdown of MTNR1A in bovine granulosa cells with apoptosis-marker qRT-PCR and steroid/inhibin ELISA","pmids":["28805353"],"confidence":"Medium","gaps":["Downstream signaling cascade from receptor to apoptotic/steroidogenic genes not mapped","Contribution of MTNR1B not separated"]},{"year":2020,"claim":"Defining residues that govern MTNR1A activation, and distinguishing them from MTNR1B, was needed to understand subtype-specific receptor pharmacology.","evidence":"Site-directed mutagenesis of human MTNR1A in a yeast chimeric-Gα fluorescent biosensor","pmids":["33095446"],"confidence":"Medium","gaps":["No structural model linking residues to mechanism","Heterologous yeast system may not reflect native coupling"]},{"year":2020,"claim":"How MTNR1A transcript levels are controlled post-transcriptionally, beyond promoter regulation, was answered by identifying an RNA-binding stabilizer and its degradation antagonist.","evidence":"RNAi screen, hnRNPL knockdown/overexpression, CA-repeat binding assays, EXOSC10 degradation analysis, and diurnal expression profiling in mouse kidney","pmids":["32730662"],"confidence":"Medium","gaps":["Mechanism coupling diurnal rhythm to hnRNPL binding activity unresolved","Whether this regulation operates outside renal tubular cells unknown"]},{"year":2020,"claim":"Whether MTNR1A signaling is required for neuronal cell survival in vivo was tested by genetically disrupting the receptor in the retina.","evidence":"CRISPR/Cas9 deletion in Xenopus tropicalis with retinal histology and receptor immunolocalization","pmids":["32792587"],"confidence":"Medium","gaps":["Survival signaling pathway downstream of the receptor not identified","Selectivity for rods over cones mechanistically unexplained","Ortholog study"]},{"year":2025,"claim":"Whether raising MTNR1A levels dampens neuroinflammation was probed pharmacologically in human microglia.","evidence":"MTNR1A protein-level measurement and LPS neuroinflammation assay with NG-497 and the agonist Ramelteon in a humanized in vitro model","pmids":["39751706"],"confidence":"Low","gaps":["No MTNR1A knockout rescue to prove necessity","Mechanism linking receptor level to anti-inflammatory effect not defined"]},{"year":null,"claim":"The downstream signaling cascade connecting MTNR1A activation to its diverse cellular outcomes (anti-apoptosis, steroidogenesis, photoreceptor survival, anti-inflammation) and a unifying structural mechanism of receptor coupling remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of the active receptor–G protein complex","Tissue-specific effector pathways not mapped to a common mechanism","Endogenous ligand-dependence of cancer growth suppression untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[3,5]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,2]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,5]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[1]}],"complexes":[],"partners":["ARRB2","HNRNPL","EXOSC10"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P48039","full_name":"Melatonin receptor type 1A","aliases":[],"length_aa":350,"mass_kda":39.4,"function":"High affinity receptor for melatonin. Likely to mediate the reproductive and circadian actions of melatonin. The activity of this receptor is mediated by pertussis toxin sensitive G proteins that inhibit adenylate cyclase activity. Possibly involved in sleep induction, by melatonin activation of the potassium channel KCNMA1/BK and the dissociation of G-beta and G-gamma subunits, thereby decreasing synaptic transmission (By similarity)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/P48039/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MTNR1A","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MTNR1A","total_profiled":1310},"omim":[{"mim_id":"602115","title":"FIBROBLAST GROWTH FACTOR 10; FGF10","url":"https://www.omim.org/entry/602115"},{"mim_id":"600976","title":"FAT ATYPICAL CADHERIN 1; FAT1","url":"https://www.omim.org/entry/600976"},{"mim_id":"600804","title":"MELATONIN RECEPTOR 1B; MTNR1B","url":"https://www.omim.org/entry/600804"},{"mim_id":"600665","title":"MELATONIN RECEPTOR 1A; MTNR1A","url":"https://www.omim.org/entry/600665"},{"mim_id":"300207","title":"G PROTEIN-COUPLED RECEPTOR 50; GPR50","url":"https://www.omim.org/entry/300207"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in single","driving_tissues":[{"tissue":"kidney","ntpm":1.7}],"url":"https://www.proteinatlas.org/search/MTNR1A"},"hgnc":{"alias_symbol":["MEL-1A-R"],"prev_symbol":[]},"alphafold":{"accession":"P48039","domains":[{"cath_id":"1.20.1070.10","chopping":"26-311","consensus_level":"high","plddt":93.2592,"start":26,"end":311}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P48039","model_url":"https://alphafold.ebi.ac.uk/files/AF-P48039-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P48039-F1-predicted_aligned_error_v6.png","plddt_mean":85.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MTNR1A","jax_strain_url":"https://www.jax.org/strain/search?query=MTNR1A"},"sequence":{"accession":"P48039","fasta_url":"https://rest.uniprot.org/uniprotkb/P48039.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P48039/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P48039"}},"corpus_meta":[{"pmid":"18452558","id":"PMC_18452558","title":"Frequent 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genetics","url":"https://pubmed.ncbi.nlm.nih.gov/26690527","citation_count":9,"is_preprint":false},{"pmid":"32730662","id":"PMC_32730662","title":"The MTNR1A mRNA is stabilized by the cytoplasmic hnRNPL in renal tubular cells.","date":"2020","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/32730662","citation_count":8,"is_preprint":false},{"pmid":"37138267","id":"PMC_37138267","title":"Association of rotating night shift work, CLOCK, MTNR1A, MTNR1B genes polymorphisms and their interactions with type 2 diabetes among steelworkers: a case-control study.","date":"2023","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/37138267","citation_count":8,"is_preprint":false},{"pmid":"36766337","id":"PMC_36766337","title":"Analysis of MTNR1A Genetic Polymorphisms and Their Association with the Reproductive Performance Parameters in Two Mediterranean Sheep Breeds.","date":"2023","source":"Animals : an open access journal from MDPI","url":"https://pubmed.ncbi.nlm.nih.gov/36766337","citation_count":7,"is_preprint":false},{"pmid":"30735014","id":"PMC_30735014","title":"No polymorphism of melatonin receptor 1A (MTNR1A) gene was found in Markhoz goat.","date":"2019","source":"Veterinary medicine and science","url":"https://pubmed.ncbi.nlm.nih.gov/30735014","citation_count":5,"is_preprint":false},{"pmid":"36359071","id":"PMC_36359071","title":"Reproductive Resumption in Winter and Spring Related to MTNR1A Gene Polymorphisms in Sarda Sheep.","date":"2022","source":"Animals : an open access journal from MDPI","url":"https://pubmed.ncbi.nlm.nih.gov/36359071","citation_count":5,"is_preprint":false},{"pmid":"38938032","id":"PMC_38938032","title":"A novel p.127Val>Ile single nucleotide polymorphism in the MTNR1A gene and its relation to litter size in Thin-tailed Indonesian ewes.","date":"2024","source":"Animal bioscience","url":"https://pubmed.ncbi.nlm.nih.gov/38938032","citation_count":5,"is_preprint":false},{"pmid":"36892670","id":"PMC_36892670","title":"MTNR1A and MTNR1B Gene Variants of the Melatonin Receptor and Arterial Stiffness in Persons without Arterial Hypertension.","date":"2023","source":"Bulletin of experimental biology and medicine","url":"https://pubmed.ncbi.nlm.nih.gov/36892670","citation_count":3,"is_preprint":false},{"pmid":"39751706","id":"PMC_39751706","title":"NG-497 Alleviates Microglia-Mediated Neuroinflammation in a MTNR1A-Dependent Manner.","date":"2025","source":"Inflammation","url":"https://pubmed.ncbi.nlm.nih.gov/39751706","citation_count":3,"is_preprint":false},{"pmid":"37668279","id":"PMC_37668279","title":"Association of MTNR1A and GDF9 gene allelles with the reproductive performance, response to oestrus induction treatments and prolificacy, in improved and non-improved local indigenous sheep breeds.","date":"2023","source":"Reproduction in domestic animals = Zuchthygiene","url":"https://pubmed.ncbi.nlm.nih.gov/37668279","citation_count":3,"is_preprint":false},{"pmid":"32792587","id":"PMC_32792587","title":"CRISPR/Cas9 mediated mutation of the mtnr1a melatonin receptor gene causes rod photoreceptor degeneration in developing Xenopus tropicalis.","date":"2020","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/32792587","citation_count":2,"is_preprint":false},{"pmid":"31588999","id":"PMC_31588999","title":"Variation near MTNR1A associates with early development and interacts with seasons.","date":"2019","source":"Journal of sleep research","url":"https://pubmed.ncbi.nlm.nih.gov/31588999","citation_count":2,"is_preprint":false},{"pmid":"16825166","id":"PMC_16825166","title":"[Effects of MTNR1A gene on litter size in a large white and a landrace herd].","date":"2006","source":"Yi chuan = Hereditas","url":"https://pubmed.ncbi.nlm.nih.gov/16825166","citation_count":2,"is_preprint":false},{"pmid":"36572547","id":"PMC_36572547","title":"Assessment of the cellular integrity and expression of melatonin receptor (MTNR1A) in the retina assaulted by ethanol and acetaminophen.","date":"2022","source":"Human & experimental toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/36572547","citation_count":1,"is_preprint":false},{"pmid":"33095446","id":"PMC_33095446","title":"Comparative analyses of site-directed mutagenesis of human melatonin MTNR1A and MTNR1B receptors using a yeast fluorescent biosensor.","date":"2020","source":"Biotechnology and bioengineering","url":"https://pubmed.ncbi.nlm.nih.gov/33095446","citation_count":1,"is_preprint":false},{"pmid":"38136892","id":"PMC_38136892","title":"Polymorphism of the MTNR1A Melatonin Receptor Gene in Goat Breeds of Northern Italy.","date":"2023","source":"Animals : an open access journal from 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journal","url":"https://pubmed.ncbi.nlm.nih.gov/41035969","citation_count":0,"is_preprint":false},{"pmid":"40705802","id":"PMC_40705802","title":"Polymorphisms in MTNR1A (rs2119882) and CLOCK (rs1801260) genes are associated with facial acne susceptibility in gas station workers.","date":"2025","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/40705802","citation_count":0,"is_preprint":false},{"pmid":"18067741","id":"PMC_18067741","title":"[Effect of genetic polymorphism of MTNR1A gene on adolescent idiopathic scoliosis].","date":"2007","source":"Zhonghua wai ke za zhi [Chinese journal of surgery]","url":"https://pubmed.ncbi.nlm.nih.gov/18067741","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":32233,"output_tokens":2760,"usd":0.069049,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9974,"output_tokens":3089,"usd":0.063548,"stage2_stop_reason":"end_turn"},"total_usd":0.132597,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2015,\n      \"finding\": \"Valproic acid (VPA) interferes with melatonin-induced MTNR1A internalization kinetics. Using FRET imaging in living HEK-293 and Neuro-2a cells expressing epitope-tagged MTNR1A-EGFP, VPA was shown to reduce the melatonin-initiated association between YFP-labeled β-arrestin 2 and CFP-labeled MTNR1A, attenuating receptor internalization. This effect was associated with decreased phosphorylation of PKA (Thr197) and ERK (Thr202/Tyr204). VPA did not alter whole-cell currents.\",\n      \"method\": \"Time-lapse confocal microscopy of MTNR1A-EGFP in living cells, FRET imaging (YFP-β-arrestin 2 / CFP-MTNR1A), phosphorylation assays\",\n      \"journal\": \"Molecular neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal FRET with functional readouts (phosphorylation, internalization kinetics), multiple orthogonal methods in single lab\",\n      \"pmids\": [\"25613019\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Cytoplasmic hnRNPL stabilizes MTNR1A mRNA post-transcriptionally in renal tubular cells. RNA interference screening identified hnRNPL as an upregulator of MTNR1A RNA. hnRNPL interacts with CA-repeat elements in the MTNR1A coding region and protects MTNR1A RNA from degradation by exosome component 10 (EXOSC10). hnRNPL knockdown or overexpression reciprocally altered CREB phosphorylation levels. MTNR1A but not hnRNPL displays a diurnal rhythm in mouse kidneys, with peak expression at midnight correlating with robust hnRNPL–MTNR1A transcript binding activity.\",\n      \"method\": \"RNAi screen, hnRNPL knockdown/overexpression, molecular binding assays (CA-repeat element), CREB phosphorylation assay, diurnal expression analysis in mouse kidney\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (RNAi, overexpression, binding studies, phosphorylation), single lab\",\n      \"pmids\": [\"32730662\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CRISPR/Cas9-mediated small deletion mutation of the mtnr1a gene in Xenopus tropicalis causes loss of rod photoreceptors in developing heterozygous tadpole retinas, with cones relatively spared, establishing a required role for MTNR1A signaling in rod photoreceptor survival. The mutant MTNR1A protein appeared to be expressed at similar levels/localization as wild type, suggesting the degeneration is due to disrupted receptor signaling rather than protein absence.\",\n      \"method\": \"In vivo CRISPR/Cas9 genomic editing in Xenopus tropicalis, histological analysis of retina, immunolocalization of Mel1a receptor protein\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo loss-of-function with defined cellular phenotype (rod degeneration), single lab, ortholog study\",\n      \"pmids\": [\"32792587\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"MTNR1A mediates melatonin's anti-apoptotic and hormone-regulatory effects in bovine granulosa cells. Knockdown of MTNR1A reversed melatonin's effects: it increased pro-apoptotic markers (BAX, CASP3, TP53), increased INHA, FSHR, TGFBR3 and Inhibin β, while decreasing BCL2, GPX4, SOD1, LHR, and production of progesterone and estradiol, placing MTNR1A as the functional receptor mediating melatonin action on granulosa cell apoptosis and hormone secretion.\",\n      \"method\": \"siRNA knockdown of MTNR1A in bovine granulosa cells, qRT-PCR, ELISA for progesterone/estradiol/inhibin\",\n      \"journal\": \"Molecular reproduction and development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function (siRNA) with multiple defined molecular readouts, single lab\",\n      \"pmids\": [\"28805353\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NG-497 alleviates LPS-induced neuroinflammation in human microglia through elevating MTNR1A protein levels; the anti-inflammatory capacity of NG-497 was independent of its ATGL-inhibitory effect but dependent on MTNR1A upregulation. The MTNRs agonist Ramelteon exerted comparable anti-inflammatory effects, supporting MTNR1A as the functional mediator.\",\n      \"method\": \"MTNR1A protein level measurement, LPS-induced neuroinflammation assay in human microglia, Ramelteon agonist comparison, humanized in vitro neuroinflammation model\",\n      \"journal\": \"Inflammation\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, mechanism inferred from compound effect and protein level change without direct MTNR1A KO rescue experiment\",\n      \"pmids\": [\"39751706\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Site-directed mutagenesis of consensus sequences in human MTNR1A, assayed using a yeast fluorescent biosensor (chimeric yeast-human Gα + ZsGreen reporter), demonstrated that most mutations in consensus sequences significantly reduced MTNR1A signaling capacity, identifying residues critical for receptor activation. Several mutations showed differential effects between MTNR1A and MTNR1B subtypes.\",\n      \"method\": \"Site-directed mutagenesis of human MTNR1A expressed in Saccharomyces cerevisiae GPCR biosensor with chimeric Gα protein and fluorescent reporter (ZsGreen)\",\n      \"journal\": \"Biotechnology and bioengineering\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — active-site/consensus mutagenesis with functional readout, single lab, single method\",\n      \"pmids\": [\"33095446\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"MTNR1A is epigenetically silenced in oral squamous-cell carcinoma (OSCC). Hypermethylation of the CpG island in the MTNR1A promoter was inversely correlated with its expression in OSCC lines. Treatment with 5-aza-2'-deoxycytidine (a DNA methyltransferase inhibitor) restored MTNR1A expression in gene-silenced OSCC cells lacking homozygous deletion. Exogenous restoration of MTNR1A expression inhibited OSCC cell growth.\",\n      \"method\": \"Array-CGH, RT-PCR, 5-aza-2'-deoxycytidine demethylation treatment, bisulfite sequencing/methylation analysis, exogenous MTNR1A re-expression growth assay\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (demethylation rescue, re-expression growth assay), single lab\",\n      \"pmids\": [\"18452558\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"A differentially methylated CpG site (cg02303933) within the MTNR1A gene mediates the effect of a paternally transmitted genetic variant (rs10009104 G allele) on the comorbidity of asthma and allergic rhinitis. Mediation analysis showed DNAm at this site statistically mediates the SNP-disease association, implicating epigenetic regulation of MTNR1A in allergic respiratory disease.\",\n      \"method\": \"Genome-wide linkage scan, SNP association analysis, DNA methylation association analysis, mediation analysis in family-based cohorts\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — statistical mediation analysis only, no functional experiment on MTNR1A protein or mRNA, single consortium study\",\n      \"pmids\": [\"27038909\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"MTNR1A transcripts are expressed in the ovine premammillary hypothalamus (PMH) and display a diurnal rhythm: expression is greater at the end of the night (melatonin present) than at the end of the day in the PMH, while the opposite pattern is observed in the pars tuberalis (PT). MTNR1B transcripts were not detected in any structure examined.\",\n      \"method\": \"RT-PCR, in situ hybridization with 35S-labeled ovine MTNR1A riboprobe, comparison of day vs night tissue samples\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — orthogonal methods (RT-PCR + ISH) with direct day/night comparison, single lab\",\n      \"pmids\": [\"15470001\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MTNR1A encodes a G protein-coupled melatonin receptor (MT1) whose signaling is initiated by melatonin binding; upon activation, the receptor internalizes via a β-arrestin 2-dependent mechanism (disrupted by valproic acid through reduced PKA/ERK phosphorylation); its mRNA is post-transcriptionally stabilized in renal tubular cells by cytoplasmic hnRNPL binding to CA-repeat elements, protecting the transcript from EXOSC10-mediated degradation; the receptor is required for rod photoreceptor survival in the retina (established by CRISPR knockout in Xenopus); it mediates melatonin's anti-apoptotic and steroidogenic effects in granulosa cells; and its expression is subject to epigenetic silencing via CpG island promoter methylation in cancer and disease contexts.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MTNR1A encodes the MT1 melatonin receptor, a G protein-coupled receptor that transduces melatonin signaling to regulate cell survival, hormone secretion, and inflammatory responses across tissues [#3, #5]. Site-directed mutagenesis of consensus sequence residues, assayed in a yeast GPCR biosensor with chimeric Gα, defines residues required for receptor activation and distinguishes MTNR1A from the MTNR1B subtype [#5]. Upon melatonin binding, the receptor recruits β-arrestin 2 and internalizes; valproic acid attenuates this β-arrestin 2 association and internalization in parallel with reduced PKA (Thr197) and ERK (Thr202/Tyr204) phosphorylation [#0]. Functionally, MTNR1A mediates melatonin's anti-apoptotic and steroidogenic effects in granulosa cells, where its knockdown raises pro-apoptotic markers (BAX, CASP3, TP53) and lowers BCL2, antioxidant enzymes, and progesterone/estradiol output [#3], and is required for rod photoreceptor survival as shown by CRISPR disruption in Xenopus [#2]. MTNR1A abundance is controlled post-transcriptionally by cytoplasmic hnRNPL, which binds CA-repeat elements in the transcript and protects it from EXOSC10-mediated degradation, with the transcript displaying a diurnal rhythm peaking at midnight in kidney [#1]; expression is additionally subject to epigenetic silencing via CpG island promoter methylation in oral squamous-cell carcinoma, where re-expression suppresses tumor cell growth [#6].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Establishing where MTNR1A is expressed and whether its message tracks the light/dark cycle was needed to connect the receptor to melatonin's physiological timing role.\",\n      \"evidence\": \"RT-PCR and in situ hybridization comparing day vs night ovine hypothalamic tissue\",\n      \"pmids\": [\"15470001\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not establish downstream signaling output from these tissues\", \"Diurnal transcript rhythm mechanism not addressed\", \"Ortholog (ovine) expression pattern, not human\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Whether MTNR1A acts as a growth suppressor and how its expression is lost in cancer was unknown; promoter methylation analysis tied silencing to tumor biology.\",\n      \"evidence\": \"CpG island methylation analysis, 5-aza-2'-deoxycytidine demethylation rescue, and exogenous re-expression growth assay in OSCC lines\",\n      \"pmids\": [\"18452558\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signaling pathway mediating growth suppression not defined\", \"Whether melatonin ligand is required for the anti-growth effect untested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"How MTNR1A is internalized after activation, and whether a drug could perturb that step, was addressed by tracking the receptor–β-arrestin 2 interaction in living cells.\",\n      \"evidence\": \"FRET imaging of CFP-MTNR1A and YFP-β-arrestin 2 plus PKA/ERK phosphorylation assays in HEK-293 and Neuro-2a cells, with valproic acid\",\n      \"pmids\": [\"25613019\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct causal link between phosphorylation changes and arrestin recruitment not dissected\", \"Performed in overexpression cell systems\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Whether epigenetic regulation of MTNR1A contributes to non-cancer disease was tested by linking a methylation site to a transmitted genetic variant and allergic disease.\",\n      \"evidence\": \"Genetic linkage, SNP and DNA methylation association, and mediation analysis in family cohorts\",\n      \"pmids\": [\"27038909\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Statistical mediation only, no functional experiment on MTNR1A protein or mRNA\", \"Causal role of MTNR1A in the disease not established\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identifying MTNR1A as the receptor responsible for melatonin's effects on ovarian cell fate and steroidogenesis required directly removing the receptor under melatonin exposure.\",\n      \"evidence\": \"siRNA knockdown of MTNR1A in bovine granulosa cells with apoptosis-marker qRT-PCR and steroid/inhibin ELISA\",\n      \"pmids\": [\"28805353\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream signaling cascade from receptor to apoptotic/steroidogenic genes not mapped\", \"Contribution of MTNR1B not separated\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defining residues that govern MTNR1A activation, and distinguishing them from MTNR1B, was needed to understand subtype-specific receptor pharmacology.\",\n      \"evidence\": \"Site-directed mutagenesis of human MTNR1A in a yeast chimeric-Gα fluorescent biosensor\",\n      \"pmids\": [\"33095446\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model linking residues to mechanism\", \"Heterologous yeast system may not reflect native coupling\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"How MTNR1A transcript levels are controlled post-transcriptionally, beyond promoter regulation, was answered by identifying an RNA-binding stabilizer and its degradation antagonist.\",\n      \"evidence\": \"RNAi screen, hnRNPL knockdown/overexpression, CA-repeat binding assays, EXOSC10 degradation analysis, and diurnal expression profiling in mouse kidney\",\n      \"pmids\": [\"32730662\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism coupling diurnal rhythm to hnRNPL binding activity unresolved\", \"Whether this regulation operates outside renal tubular cells unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Whether MTNR1A signaling is required for neuronal cell survival in vivo was tested by genetically disrupting the receptor in the retina.\",\n      \"evidence\": \"CRISPR/Cas9 deletion in Xenopus tropicalis with retinal histology and receptor immunolocalization\",\n      \"pmids\": [\"32792587\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Survival signaling pathway downstream of the receptor not identified\", \"Selectivity for rods over cones mechanistically unexplained\", \"Ortholog study\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Whether raising MTNR1A levels dampens neuroinflammation was probed pharmacologically in human microglia.\",\n      \"evidence\": \"MTNR1A protein-level measurement and LPS neuroinflammation assay with NG-497 and the agonist Ramelteon in a humanized in vitro model\",\n      \"pmids\": [\"39751706\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No MTNR1A knockout rescue to prove necessity\", \"Mechanism linking receptor level to anti-inflammatory effect not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The downstream signaling cascade connecting MTNR1A activation to its diverse cellular outcomes (anti-apoptosis, steroidogenesis, photoreceptor survival, anti-inflammation) and a unifying structural mechanism of receptor coupling remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of the active receptor–G protein complex\", \"Tissue-specific effector pathways not mapped to a common mechanism\", \"Endogenous ligand-dependence of cancer growth suppression untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [3, 5]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"ARRB2\", \"HNRNPL\", \"EXOSC10\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}