Affinage

MTNR1A

Melatonin receptor type 1A · UniProt P48039

Length
350 aa
Mass
39.4 kDa
Annotated
2026-06-10
57 papers in source corpus 9 papers cited in narrative 9 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2004 Medium

    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

    PMID:15470001

    Open questions at the time
    • Does not establish downstream signaling output from these tissues
    • Diurnal transcript rhythm mechanism not addressed
    • Ortholog (ovine) expression pattern, not human
  2. 2008 Medium

    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

    PMID:18452558

    Open questions at the time
    • Signaling pathway mediating growth suppression not defined
    • Whether melatonin ligand is required for the anti-growth effect untested
  3. 2015 Medium

    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

    PMID:25613019

    Open questions at the time
    • Direct causal link between phosphorylation changes and arrestin recruitment not dissected
    • Performed in overexpression cell systems
  4. 2016 Low

    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

    PMID:27038909

    Open questions at the time
    • Statistical mediation only, no functional experiment on MTNR1A protein or mRNA
    • Causal role of MTNR1A in the disease not established
  5. 2017 Medium

    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

    PMID:28805353

    Open questions at the time
    • Downstream signaling cascade from receptor to apoptotic/steroidogenic genes not mapped
    • Contribution of MTNR1B not separated
  6. 2020 Medium

    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

    PMID:33095446

    Open questions at the time
    • No structural model linking residues to mechanism
    • Heterologous yeast system may not reflect native coupling
  7. 2020 Medium

    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

    PMID:32730662

    Open questions at the time
    • Mechanism coupling diurnal rhythm to hnRNPL binding activity unresolved
    • Whether this regulation operates outside renal tubular cells unknown
  8. 2020 Medium

    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

    PMID:32792587

    Open questions at the time
    • Survival signaling pathway downstream of the receptor not identified
    • Selectivity for rods over cones mechanistically unexplained
    • Ortholog study
  9. 2025 Low

    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

    PMID:39751706

    Open questions at the time
    • No MTNR1A knockout rescue to prove necessity
    • Mechanism linking receptor level to anti-inflammatory effect not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 2 GO:0048018 receptor ligand activity 1
Localization
GO:0005886 plasma membrane 2
Pathway
R-HSA-162582 Signal Transduction 2 R-HSA-8953854 Metabolism of RNA 1
Partners
ARRB2EXOSC10HNRNPL

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2015 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. Time-lapse confocal microscopy of MTNR1A-EGFP in living cells, FRET imaging (YFP-β-arrestin 2 / CFP-MTNR1A), phosphorylation assays Molecular neurobiology Medium 25613019
2020 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. RNAi screen, hnRNPL knockdown/overexpression, molecular binding assays (CA-repeat element), CREB phosphorylation assay, diurnal expression analysis in mouse kidney Journal of cellular physiology Medium 32730662
2020 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. In vivo CRISPR/Cas9 genomic editing in Xenopus tropicalis, histological analysis of retina, immunolocalization of Mel1a receptor protein Scientific reports Medium 32792587
2017 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. siRNA knockdown of MTNR1A in bovine granulosa cells, qRT-PCR, ELISA for progesterone/estradiol/inhibin Molecular reproduction and development Medium 28805353
2025 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. MTNR1A protein level measurement, LPS-induced neuroinflammation assay in human microglia, Ramelteon agonist comparison, humanized in vitro neuroinflammation model Inflammation Low 39751706
2020 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. Site-directed mutagenesis of human MTNR1A expressed in Saccharomyces cerevisiae GPCR biosensor with chimeric Gα protein and fluorescent reporter (ZsGreen) Biotechnology and bioengineering Medium 33095446
2008 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. Array-CGH, RT-PCR, 5-aza-2'-deoxycytidine demethylation treatment, bisulfite sequencing/methylation analysis, exogenous MTNR1A re-expression growth assay Cancer science Medium 18452558
2016 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. Genome-wide linkage scan, SNP association analysis, DNA methylation association analysis, mediation analysis in family-based cohorts The Journal of allergy and clinical immunology Low 27038909
2004 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. RT-PCR, in situ hybridization with 35S-labeled ovine MTNR1A riboprobe, comparison of day vs night tissue samples Biology of reproduction Medium 15470001

Source papers

Stage 0 corpus · 57 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 Frequent silencing of a putative tumor suppressor gene melatonin receptor 1 A (MTNR1A) in oral squamous-cell carcinoma. Cancer science 79 18452558
1995 Mapping of the gene for the Mel1a-melatonin receptor to human chromosome 4 (MTNR1A) and mouse chromosome 8 (Mtnr1a). Genomics 71 7558006
2004 MTNR1A melatonin receptors in the ovine premammillary hypothalamus: day-night variation in the expression of the transcripts. Biology of reproduction 39 15470001
2013 Association between genetic variations in MTNR1A and MTNR1B genes and gestational diabetes mellitus in Han Chinese women. Gynecologic and obstetric investigation 37 24157813
2012 Characterisation of the Melatonin Receptor 1A (MTNR1A) gene in the Rasa Aragonesa sheep breed: association with reproductive seasonality. Animal reproduction science 32 22809454
2017 MTNR1A and MTNR1B gene polymorphisms in women with gestational diabetes. Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology 31 28084098
2017 The role of Melatonin receptor MTNR1A in the action of Melatonin on bovine granulosa cells. Molecular reproduction and development 29 28805353
2011 A polymorphism at the melatonin receptor 1A (MTNR1A) gene in Sarda ewes affects fertility after AI in the spring. Reproduction, fertility, and development 25 21211471
2018 SNP rs403212791 in exon 2 of the MTNR1A gene is associated with reproductive seasonality in the Rasa aragonesa sheep breed. Theriogenology 24 29475126
2008 Relationship between MTNR1A melatonin receptor gene polymorphism and seasonal reproduction in different goat breeds. Animal reproduction science 23 18243602
2008 Lack of association between the promoter polymorphism of the MTNR1A gene and adolescent idiopathic scoliosis. Spine 23 18794763
2016 DNA methylation within melatonin receptor 1A (MTNR1A) mediates paternally transmitted genetic variant effect on asthma plus rhinitis. The Journal of allergy and clinical immunology 22 27038909
2010 Effect of genotype at the MTNR1A locus and melatonin treatment on first conception in Sarda ewe lambs. Theriogenology 22 20708235
2011 The melatonin receptor 1A (MTNR1A) gene is associated with recurrent and idiopathic calcium nephrolithiasis. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 21 21652546
2020 Reproductive performance in three Slovenian sheep breeds with different alleles for the MTNR1A gene. Animal reproduction science 19 32414462
2016 Influences of melatonin treatment, melatonin receptor 1A (MTNR1A) and kisspeptin (KiSS-1) gene polymorphisms on first conception in Sarda ewe lambs. Reproduction, fertility, and development 18 25375207
2011 Characterization of the Mediterranean Italian buffaloes melatonin receptor 1A (MTNR1A) gene and its association with reproductive seasonality. Theriogenology 18 21497385
2014 Sequence analysis and identification of new variations in the coding sequence of melatonin receptor gene (MTNR1A) of Indian Chokla sheep breed. Meta gene 17 25606429
2018 Reproductive response to male joining with ewes with different allelic variants of the MTNR1A gene. Animal reproduction science 15 30553547
2008 Pig melatonin receptor 1a (MTNR1A) genotype is associated with seasonal variation of sow litter size. Animal reproduction science 15 19181464
2021 Detection of Polymorphisms in the MTNR1A Gene and Their Association with Reproductive Performance in Awassi Ewes. Animals : an open access journal from MDPI 14 33672405
2012 Association between melatonin receptor 1A (MTNR1A) gene polymorphism and the reproductive performance of Mediterranean Italian buffaloes. Reproduction, fertility, and development 14 22935159
2020 New polymorphisms at MTNR1A gene and their association with reproductive resumption in sarda breed sheep. Theriogenology 13 33049568
2022 Expression and distribution of MTNR1A in the hypothalamus-pituitary-gonadal axis of Tibetan sheep during the estrous cycle. Gene 12 35835405
2018 Polymorphism of melatonin receptor (MTNR1A) gene and its association with seasonal reproduction in water buffalo (Bubalus bubalis). Animal reproduction science 12 30384994
2020 Polymorphisms of the melatonin receptor 1A (MTNR1A) gene influence the age at first mating in autumn-born ram-lambs and sexual activity of adult rams in spring. Theriogenology 11 32799126
2019 Expression of MTNR1A, steroid (ERα, ERβ, and PR) receptor gene transcripts, and the concentration of melatonin and steroid hormones in the ovarian follicles of buffalo. Domestic animal endocrinology 11 31421986
2015 Valproic Acid Influences MTNR1A Intracellular Trafficking and Signaling in a β-Arrestin 2-Dependent Manner. Molecular neurobiology 11 25613019
2015 Assessment of Genetic Variability in the Coding Sequence of Melatonin Receptor Gene (MTNR1A) in Tropical Arid Sheep Breeds of India. Reproduction in domestic animals = Zuchthygiene 11 25708518
2010 Analysis of genetic variations in the human melatonin receptor (MTNR1A, MTNR1B) genes and antipsychotics-induced tardive dyskinesia in schizophrenia. The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry 10 20726823
2023 Melatonin receptor 1A (MTNR1A) gene linkage and association to type 2 diabetes in Italian families. European review for medical and pharmacological sciences 9 37259752
2021 MTNR1A gene polymorphisms and reproductive recovery after seasonal anoestrus in different Mediterranean sheep breeds. Animal reproduction science 9 34922186
2019 Genotype of MTNR1A gene regulates the conception rate following melatonin treatment in water buffalo. Theriogenology 9 30711643
2015 Association study and expression analysis of MTNR1A as a candidate gene for body measurement and meat quality traits in Qinchuan cattle. Gene 9 26067916
2015 Characterization of MTNR1A gene in terms of genetic variability in a panel of subtemperate and subtropical Indian sheep breeds. Journal of genetics 9 26690527
2014 Association between melatonin receptor 1A (MTNR1A) gene single-nucleotide polymorphisms and the velvet antler yield of Sika deer. Molecular biology reports 9 24595444
2012 MTNR1A receptor expression in normal and pathological human salivary glands. Anticancer research 9 23155241
2023 Association of rotating night shift work, CLOCK, MTNR1A, MTNR1B genes polymorphisms and their interactions with type 2 diabetes among steelworkers: a case-control study. BMC genomics 8 37138267
2020 The MTNR1A mRNA is stabilized by the cytoplasmic hnRNPL in renal tubular cells. Journal of cellular physiology 8 32730662
2023 Analysis of MTNR1A Genetic Polymorphisms and Their Association with the Reproductive Performance Parameters in Two Mediterranean Sheep Breeds. Animals : an open access journal from MDPI 7 36766337
2024 A novel p.127Val>Ile single nucleotide polymorphism in the MTNR1A gene and its relation to litter size in Thin-tailed Indonesian ewes. Animal bioscience 5 38938032
2022 Reproductive Resumption in Winter and Spring Related to MTNR1A Gene Polymorphisms in Sarda Sheep. Animals : an open access journal from MDPI 5 36359071
2019 No polymorphism of melatonin receptor 1A (MTNR1A) gene was found in Markhoz goat. Veterinary medicine and science 5 30735014
2025 NG-497 Alleviates Microglia-Mediated Neuroinflammation in a MTNR1A-Dependent Manner. Inflammation 3 39751706
2023 MTNR1A and MTNR1B Gene Variants of the Melatonin Receptor and Arterial Stiffness in Persons without Arterial Hypertension. Bulletin of experimental biology and medicine 3 36892670
2023 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. Reproduction in domestic animals = Zuchthygiene 3 37668279
2020 CRISPR/Cas9 mediated mutation of the mtnr1a melatonin receptor gene causes rod photoreceptor degeneration in developing Xenopus tropicalis. Scientific reports 2 32792587
2019 Variation near MTNR1A associates with early development and interacts with seasons. Journal of sleep research 2 31588999
2006 [Effects of MTNR1A gene on litter size in a large white and a landrace herd]. Yi chuan = Hereditas 2 16825166
2022 Assessment of the cellular integrity and expression of melatonin receptor (MTNR1A) in the retina assaulted by ethanol and acetaminophen. Human & experimental toxicology 1 36572547
2020 Comparative analyses of site-directed mutagenesis of human melatonin MTNR1A and MTNR1B receptors using a yeast fluorescent biosensor. Biotechnology and bioengineering 1 33095446
2026 Epigenetic Shifts in MTNR1A, MTNR1B and Fn14 and Their Links to Preeclampsia Risk. Annals of human genetics 0 42257518
2025 Antioxidant components of ram seminal plasma are influenced by age, season, and the RsaI polymorphism of the MTNR1A gene. Animal reproduction science 0 40328208
2025 Polymorphisms in MTNR1A (rs2119882) and CLOCK (rs1801260) genes are associated with facial acne susceptibility in gas station workers. PloS one 0 40705802
2025 Manipulating seasonality by using PMSG and Kisspeptin hormones and the impact of the MTNR1A gene on reproduction efficiency in ewes. Open veterinary journal 0 41035969
2023 Polymorphism of the MTNR1A Melatonin Receptor Gene in Goat Breeds of Northern Italy. Animals : an open access journal from MDPI 0 38136892
2007 [Effect of genetic polymorphism of MTNR1A gene on adolescent idiopathic scoliosis]. Zhonghua wai ke za zhi [Chinese journal of surgery] 0 18067741

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