Affinage

NOS1

Nitric oxide synthase 1 · UniProt P29475

Length
1434 aa
Mass
161.0 kDa
Annotated
2026-06-10
100 papers in source corpus 36 papers cited in narrative 36 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NOS1 (nNOS) is a Ca2+/calmodulin-regulated nitric oxide synthase whose activity, subcellular targeting, and downstream signaling place it at a hub spanning neuronal excitotoxicity, synaptic plasticity, cardiac and renal physiology, muscle homeostasis, and neuroendocrine control (PMID:28123012, PMID:36197968). Its catalytic output is gated by phosphorylation and cofactor supply: activating Ser1412/Ser1417 phosphorylation downstream of an AMPK–LKB1 axis and of SGLT1- and ERα-driven inputs drives NO production (PMID:30867247, PMID:36470319, PMID:26174015), while NMDA-receptor-triggered calcineurin/PP1/PP2A dephosphorylation paradoxically raises nitrotyrosine-generating activity to promote neuronal death (PMID:14643384); tetrahydrobiopterin (BH4) availability set by GCH1 constitutively tunes activity in cardiomyocytes (PMID:22798524), and splice variant identity (nNOS-α vs -µ) determines the balance between NO and uncoupled superoxide output (PMID:28126743). NOS1 signals through scaffold-organized protein complexes: PDZ-domain coupling to PSD-95 links it to NMDAR-driven, NOS1AP–MKK3–p38 MAPK excitotoxic and pain signaling (PMID:23658158, PMID:29319606), while its interaction with CAPON drives Dexras1 S-nitrosylation and ERK–CREB–BDNF modulation underlying anxiety, depression, and amyloid-associated memory deficits (PMID:25129479, PMID:29577585, PMID:35664081). NO and reactive nitrogen species produced by NOS1 act on specific targets through S-nitrosylation of HDAC2 (suppressing interferon-stimulated genes for melanoma immune escape) and PTEN (activating AKT/mTOR), through tyrosine nitration of TRKB (a brake on plasticity), and through cGMP-dependent control of Ca2+ influx and GLUT-1-mediated cardiac glucose uptake (PMID:31805977, PMID:36682419, PMID:28243469, PMID:33494625, PMID:9330792). At the sarcolemma, NOS1 localization requires the intact sarcoglycan complex and the matrix proteoglycan biglycan, and its mislocalization to the sarcoplasm drives FoxO3-dependent muscle atrophy (PMID:12409321, PMID:16807372, PMID:30066461). NOS1 loss-of-function mutations cause congenital hypogonadotropic hypogonadism by impairing GnRH neuron function, a phenotype rescuable by inhaled NO during minipuberty (PMID:36197968).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1998 High

    Established that nNOS-expressing neurons are paradoxically protected from their own NO output, identifying MnSOD as the antioxidant shield that confers excitotoxic resistance.

    Evidence Antisense knockdown and adenoviral MnSOD transfer in cortical neuron cultures and MnSOD-/- mice

    PMID:9482791

    Open questions at the time
    • Does not define the molecular link between NO/superoxide flux and cell death in unprotected neurons
    • Does not address how MnSOD expression is restricted to nNOS neurons
  2. 2003 Medium

    Resolved how NMDA receptor activation upregulates NOS1 enzymatic activity, showing calcineurin- and PP1/PP2A-dependent dephosphorylation increases nitrotyrosine accumulation and drives cell-autonomous death.

    Evidence Pharmacological phosphatase/calcineurin inhibition with nitrotyrosine and TUNEL readouts in rat cortical neurons

    PMID:14643384

    Open questions at the time
    • Specific dephosphorylated residue(s) not mapped
    • Single-lab pharmacological dissection without genetic confirmation
  3. 2013 High

    Defined the NOS1AP–MKK3–p38 MAPK axis as the excitotoxic effector downstream of nNOS, and demonstrated a druggable PDZ interaction by neuroprotective peptide competition in vivo.

    Evidence Reciprocal Co-IP, siRNA, cell-permeable competing peptide in cortical neurons and a neonatal rat hypoxia-ischemia model

    PMID:23658158

    Open questions at the time
    • Does not establish stoichiometry of the nNOS–NOS1AP–MKK3 complex
    • Long-term outcomes of peptide intervention not assessed
  4. 2014 High

    Showed that the nNOS–CAPON scaffold interaction bidirectionally controls affective behavior via Dexras1 S-nitrosylation and ERK signaling, validating it as an anxiolytic/antidepressant target.

    Evidence Viral overexpression/disruption, competing peptides, small-molecule blockers, and behavioral assays in mice

    PMID:25129479

    Open questions at the time
    • Brain-region specificity of the behavioral effect not fully delineated
    • Direct S-nitrosylation site on Dexras1 within this paradigm not mapped
  5. 2012 High

    Placed NOS1 downstream of GCH1/BH4 as the mediator of cardiac relaxation, linking cofactor supply to Ca2+ handling and contractility.

    Evidence Transgenic GCH1 overexpression with NOS1 inhibition, Ca2+ imaging, patch clamp, and contractility measurement in isolated hearts and myocytes

    PMID:22798524

    Open questions at the time
    • Molecular target of NOS1-derived NO in the Ca2+-handling apparatus not identified here
    • Does not distinguish NO vs S-nitrosylation mechanisms
  6. 2017 Medium

    Demonstrated that NOS1 splice-variant identity dictates the NO-versus-superoxide balance, providing a molecular basis for context-dependent oxidative output.

    Evidence EPR measurement of electron uncoupling and 8-nitroguanosine-cGMP detection in HEK293 cells expressing nNOS-α vs nNOS-µ

    PMID:28126743

    Open questions at the time
    • Physiological tissue contexts where each variant predominates not defined
    • Single-lab in vitro/cell measurements
  7. 2017 Medium

    Identified S-nitrosylation of PTEN and mitochondrial NOS1 translocation as a pro-survival mechanism in carcinoma cells, activating AKT/mTOR and limiting autophagy.

    Evidence Biotin-switch assay, NOS1 knockdown/inhibition with autophagy-inhibitor rescue and xenografts in nasopharyngeal carcinoma

    PMID:28243469

    Open questions at the time
    • PTEN S-nitrosylation site(s) not mapped
    • Single-lab evidence for Hsp90-dependent mitochondrial translocation
  8. 2019 High

    Established NOS1-mediated S-nitrosylation of HDAC2 as an epigenetic immune-evasion mechanism, linking NO directly to interferon-stimulated gene suppression and metastasis.

    Evidence Biotin-switch, ChIP-qPCR, HDAC2-C262A/C274A mutants, and xenograft melanoma models

    PMID:31805977

    Open questions at the time
    • Upstream regulation of NOS1 activity in melanoma not addressed
    • Generality across tumor types not tested
  9. 2018 High

    Showed NOS1-driven tyrosine nitration of TRKB Y816 functions as a molecular brake on neuronal plasticity by triggering receptor endocytosis and degradation.

    Evidence In vitro nitration assays, Y816 mutagenesis, endocytosis assays, and ocular dominance plasticity after in vivo nNOS inhibition

    PMID:36682419

    Open questions at the time
    • Enzymatic mediator of tyrosine nitration (peroxynitrite vs other) not defined in vivo
    • Does not address reversibility of TRKB nitration
  10. 2018 Medium

    Extended scaffold-disruption logic across multiple CNS pathologies, showing nNOS–PSD-95 and nNOS–NOS1AP coupling drive p38 MAPK in TBI, neuropathic pain, thalamic hemorrhage pain, and that PSD-95–nNOS/TrkB complex switching governs fear extinction.

    Evidence Co-IP, disruptor peptides (ZL006, TAT-GESV) and behavioral models in mice/rats

    PMID:29319606 PMID:29577585 PMID:30143658 PMID:30193808 PMID:31989159

    Open questions at the time
    • Mostly single-lab Co-IP plus pharmacology without genetic confirmation
    • Selectivity of disruptor compounds for specific PDZ interactions not exhaustively established
  11. 2013 High

    Established a renal physiological role, showing collecting-duct NOS1 is required for natriuresis and protection against salt-sensitive hypertension.

    Evidence AQP2-Cre conditional NOS1 knockout with dietary sodium challenge and telemetric blood pressure

    PMID:23608660

    Open questions at the time
    • Downstream tubular targets of NOS1-derived NO not identified
    • Does not address NOS1 regulation in collecting duct
  12. 2019 High

    Defined the SGLT1–NOS1 axis at the macula densa, linking luminal glucose sensing through NOS1 Ser1417 phosphorylation to tubuloglomerular feedback and hyperfiltration.

    Evidence Macula densa-specific NOS1 knockout, microperfusion/micropuncture, GFR measurement, and SGLT1 inhibition

    PMID:30867247

    Open questions at the time
    • Kinase mediating Ser1417 phosphorylation downstream of SGLT1 not identified
    • Translation to human diabetic hyperfiltration not directly tested
  13. 2021 High

    Connected NOS1 to insulin-independent cardiac glucose uptake via NO/sGC/PKG-driven GLUT-1 surface density, and to NOS1AP-genotype-dependent arrhythmogenesis through ion-channel regulation.

    Evidence CRISPR nNOS knockout in GCH1-Tg mice, glucose uptake assays, and LQT1 patient hiPSC-CMs with guinea pig cardiomyocyte electrophysiology

    PMID:32061134 PMID:33494625

    Open questions at the time
    • Mechanism by which NOS1AP SNPs reduce NOS1 expression/co-localization not fully resolved
    • Direct ion-channel S-nitrosylation targets not mapped
  14. 2018 High

    Defined sarcolemmal NOS1 localization as a determinant of muscle homeostasis, showing the sarcoglycan complex and biglycan target NOS1 to the membrane and that its sarcoplasmic redistribution drives FoxO3-dependent atrophy.

    Evidence Sarcoglycan-deficient and biglycan-null models, biglycan protein injection, unloading models, and in vivo nNOS inhibition with FoxO3 nuclear localization readouts

    PMID:12409321 PMID:16807372 PMID:30066461 PMID:31043586

    Open questions at the time
    • Mechanism translating displaced NOS1 activity into FoxO3 nuclear entry not fully mapped
    • Role of nNOS–GSNOR S-nitrosylation homeostasis in atrophy not causally established
  15. 2017 High

    Identified NOS1-expressing interneurons in the nucleus accumbens as drivers of MMP-dependent synaptic potentiation underlying cocaine relapse, defining a discrete circuit role.

    Evidence NO-sensitive electrodes, DREADD activation/silencing, caspase ablation, electrophysiology, and reinstatement behavior in rodents

    PMID:28123012

    Open questions at the time
    • Molecular MMP substrates underlying potentiation not identified
    • Generalization to other reward circuits not tested
  16. 2021 Medium

    Extended NOS1 function to innate immunity and hematopoiesis, showing NO directs AP-1 composition for macrophage polarization and promotes C/EBPα-dependent granulopoiesis via G-CSFR–STAT3.

    Evidence Pharmacological NOS1 inhibition in macrophages and in vivo, nNOS overexpression in K562, and human CD34+ HSPC differentiation

    PMID:28013342 PMID:33771575

    Open questions at the time
    • Direct molecular targets of NO in AP-1 subunit switching not defined
    • Largely single-lab pharmacological evidence
  17. 2022 High

    Established NOS1 as a human disease gene for congenital hypogonadotropic hypogonadism through GnRH neuron dysfunction, with a developmentally timed estrogen-ERα input activating NOS1 during minipuberty and inhaled NO rescuing the phenotype.

    Evidence Whole-exome sequencing with mutant activity assays, Nos1-KO phenotyping, time-window NO inhibition/rescue, and ERα-blockade with phospho-Ser1412 readouts

    PMID:36197968 PMID:36470319

    Open questions at the time
    • Downstream NO targets in GnRH neurons not identified
    • Mechanism of extragonadal estrogen production driving ERα input not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the diverse phosphorylation, scaffolding, splice-variant, and cofactor inputs are integrated to set NOS1's choice between NO, superoxide, and specific S-nitrosylation/nitration targets within a given cell type remains unresolved.
  • No unified model linking variant/cofactor state to target selection
  • Tissue-specific interactomes not systematically mapped
  • Reversibility and turnover of nitrosylation/nitration marks largely uncharacterized in vivo

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016491 oxidoreductase activity 3 GO:0060089 molecular transducer activity 3 GO:0060090 molecular adaptor activity 3 GO:0140096 catalytic activity, acting on a protein 3
Localization
GO:0005886 plasma membrane 4 GO:0005739 mitochondrion 2 GO:0005829 cytosol 1
Pathway
R-HSA-112316 Neuronal System 3 R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-168256 Immune System 2
Partners
BIGLYCANCAPONGSNORHDAC2NOS1APPSD-95PTENTRKB
Complex memberships
dystrophin–sarcoglycan–syntrophin complexnNOS–PSD-95–NOS1AP complex

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 MnSOD is enriched in nNOS neurons and is required for their resistance to NMDA-mediated neurotoxicity; antisense knockdown of MnSOD renders nNOS neurons susceptible to NMDA toxicity, and adenoviral MnSOD transfer restores resistance in MnSOD-/- cultures. Antisense knockdown, adenoviral gene transfer, cortical neuron cultures, MnSOD-/- mice The Journal of neuroscience High 9482791
2012 FMRP activates translation of NOS1 in the developing human neocortex by interacting with coding-region binding motifs on human NOS1 mRNA (absent from mouse Nos1 mRNA); NOS1 protein is severely reduced in developing human FXS brain but not in FMRP-deficient mice. Co-immunoprecipitation, polyribosome fractionation, postmortem human tissue, FMRP-KO mouse tissue Cell High 22579290
2013 Excitotoxic stimulation recruits NOS1AP to nNOS in cortical neurons; NOS1AP interacts with p38MAPK-activating kinase MKK3, and competing with the nNOS–NOS1AP PDZ interaction reduces p38MAPK activation and subsequent neuronal death. A cell-permeable competing peptide doubled surviving tissue in a neonatal rat hypoxia-ischemia model. Co-IP, siRNA knockdown, cell-permeable competing peptide, rat cortical neuron culture, in vivo neonatal HI model The Journal of neuroscience High 23658158
2019 NOS1 S-nitrosylates HDAC2 at Cys262/Cys274, reducing HDAC2 binding to STAT1, impairing HDAC2 recruitment to ISG promoters, decreasing H4K16 deacetylation, and suppressing interferon-stimulated gene expression to promote melanoma immune escape and lung metastasis. Biotin-switch S-nitrosylation assay, Co-IP, ChIP-qPCR, luciferase reporter, HDAC2-C262A/C274A site mutant, xenograft mouse model, flow cytometry Journal of experimental & clinical cancer research High 31805977
2003 NMDA receptor activation decreases nNOS phosphorylation via calcineurin- and PP1/PP2A-dependent dephosphorylation, increasing nNOS enzymatic activity (measured by nitrotyrosine accumulation) and driving neuron death in a cell-autonomous pathway. Quantitative digital microscopy, NMDA receptor antagonists, calcineurin/phosphatase inhibitors, nitrotyrosine immunostaining, TUNEL assay in rat cortical neurons Neurobiology of aging Medium 14643384
2014 Augmenting nNOS–CAPON interaction in mouse hippocampus causes anxiogenic behavior; disrupting it produces anxiolytic effects. The anxiogenic mechanism involves Dexras1 S-nitrosylation and downstream ERK signaling. Small-molecule blockers of nNOS–CAPON binding recapitulate the anxiolytic effect. Viral overexpression, competing peptides (Tat-CAPON-12C), small-molecule binding blockers, behavioral assays (chronic mild stress model), co-IP, western blot Nature medicine High 25129479
2018 nNOS-induced nitration of tyrosine 816 on TRKB inhibits TRKB phosphorylation and PLCγ1 binding, triggers clathrin-dependent TRKB endocytosis via AP-2, and promotes lysosomal TRKB degradation, constituting a molecular brake on neuronal plasticity. Chronic nNOS inhibition in vivo reduced TRKB nitration and promoted ocular dominance plasticity. In vitro nitration assays, site-specific mutagenesis (Y816), co-IP, endocytosis assays, nNOS inhibitor in vivo, monocular deprivation plasticity paradigm Progress in neurobiology High 36682419
2017 NOS1 S-nitrosylates PTEN, activating the AKT/mTOR pathway to inhibit excessive autophagy and promote survival of nasopharyngeal carcinoma cells; Hsp90 inhibitor geldanamycin blocks NOS1 mitochondrial translocation and reverses apoptosis resistance. Biotin-switch S-nitrosylation assay, NOS1 siRNA/pharmacological inhibition, autophagy inhibitor rescue, in vivo xenograft, western blot Cell death discovery Medium 28243469
2002 Sarcolemmal nNOS expression is dramatically reduced in sarcoglycan-deficient muscular dystrophy (alpha-, beta-, delta-, gamma-sarcoglycan mutations) even when dystrophin and syntrophin are present, demonstrating that the intact sarcoglycan-sarcospan complex is required to maintain nNOS at the sarcolemma. Western blot, immunofluorescence in animal models and patient biopsy tissue FASEB journal Medium 12409321
2006 Biglycan, an extracellular matrix molecule, regulates sarcolemmal localization of nNOS, dystrobrevin, and syntrophin; purified biglycan induces nNOS redistribution to the plasma membrane in cultured muscle cells, and biglycan protein injection into biglycan-null muscle restores sarcolemmal nNOS. Biglycan-null mouse analysis, purified biglycan addition to cultured muscle cells, intramuscular biglycan protein injection, immunofluorescence FASEB journal Medium 16807372
2012 Cardiac-myocyte GTP cyclohydrolase 1 (GCH1) overexpression increases intracellular BH4 and constitutively increases NOS1 activity; NOS1 inhibition abolishes GCH1-dependent differences in ICaL density, PLB Ser16 phosphorylation, Ca2+ decay rate, and myocardial relaxation, placing NOS1 as the downstream mediator of BH4-dependent cardiac relaxation. Transgenic mouse model, NOS1 inhibition (SMTC), isolated hearts, field-stimulated cardiomyocytes, Ca2+ imaging, patch clamp Circulation research High 22798524
2021 BH4-mediated nNOS activity in cardiomyocytes drives insulin-independent glucose uptake via NO/sGC/PKG-dependent increase in GLUT-1 plasmalemmal density; CRISPR/Cas9 knockout of nNOS in mGCH1-Tg mice abolishes BH4-dependent protection of LV function in diabetes. CRISPR/Cas9 nNOS KO, transgenic GCH1 overexpression, echocardiography, glucose uptake assay, HEK cell S-nitrosoglutathione treatment, 31P-MRS Circulation research High 33494625
2019 SGLT1 at the macula densa senses luminal glucose, upregulating NOS1 expression and Ser1417 phosphorylation; macula densa-specific NOS1 knockout abolishes glucose-stimulated NO production, blunting of TGF response, and GFR elevation, establishing a SGLT1-NOS1 axis in hyperglycemia-induced glomerular hyperfiltration. Macula densa-specific NOS1 knockout mice (AQP2-Cre × NOS1-flox), microperfusion, micropuncture, FITC-inulin GFR, SGLT1 inhibitor, western blot Journal of the American Society of Nephrology High 30867247
2013 Collecting duct (CD)-specific deletion of NOS1 causes impaired natriuresis/diuresis and salt-sensitive hypertension under high-sodium diet, demonstrating that CD NOS1 is required for fluid-electrolyte homeostasis. AQP2-Cre × NOS1-flox conditional KO mice, dietary sodium challenge, urine electrolyte/NOx measurement, telemetric blood pressure Hypertension High 23608660
2017 nNOS interneurons in the nucleus accumbens core (~1% of neurons) receive mGluR5-activated glutamate spillover, produce NO, and drive matrix metalloproteinase (MMP-2/9) activation and transient synaptic potentiation (AMPA current increase) in MSNs, thereby mediating cue-induced cocaine relapse. NO-sensitive electrodes, chemogenetic (DREADD) activation/silencing of nNOS interneurons, transgenic caspase ablation, MMP assay, whole-cell electrophysiology, rodent self-administration/reinstatement model The Journal of neuroscience High 28123012
2018 Contextual fear extinction induces a shift from PSD-95–nNOS to PSD-95–TrkB association in dorsal hippocampus (CA3); disrupting PSD-95–nNOS coupling in dorsal CA3 upregulates ERK phosphorylation and BDNF, promotes BDNF–TrkB–PSD-95 association, and enhances fear extinction. Co-immunoprecipitation, western blot, stereotaxic nNOS–PSD-95 disruptor peptide injection, behavioral fear conditioning/extinction paradigm Scientific reports Medium 30143658
2020 Disrupting the nNOS–PSD-95 interaction with ZL006 inhibits nNOS-PSD95 binding, reduces p38 MAPK activation and apoptotic marker expression (active caspase-3, PARP-1), and improves neurological, sensorimotor, and cognitive outcomes after traumatic brain injury in mice. Co-IP, cortical neuronal cultures (glutamate excitotoxicity), mouse CCI model, TUNEL/phospho-p38 immunostaining, western blot, behavioral tests Cerebral cortex Medium 31989159
2018 nNOS–NOS1AP interaction is required for excitotoxic p38 MAPK signaling and neuropathic pain; a peptide inhibitor (TAT-GESV) disrupts nNOS–NOS1AP binding (but not nNOS–PSD95), blocks glutamate/glycine-induced neurotoxicity in cortical neurons, and suppresses paclitaxel- and nerve-injury-induced allodynia via blockade of p53-Ser15 phosphorylation downstream of p38 MAPK. In vitro binding assay, cortical neuron excitotoxicity, intrathecal peptide delivery, behavioral allodynia testing, western blot (phospho-p53) Pain Medium 29319606
2018 Disrupting PSD-95–nNOS interaction with ZL006 blocks hemorrhage-induced increase in PSD-95–nNOS binding and membrane translocation of nNOS in thalamic neurons, alleviating thalamic pain hypersensitivity when given before (but not after) hemorrhage. Co-IP, western blot, stereotaxic collagenase thalamic hemorrhage model, ZL006 systemic treatment, behavioral pain testing Neuropharmacology Medium 30193808
2018 nNOS–CAPON interaction is increased by Aβ treatment in vitro and in APP/PS1 mouse hippocampus; blocking nNOS–CAPON interaction rescues memory and dendritic impairments in 4-month-old APP/PS1 mice. Downstream mechanism involves S-nitrosylation of Dexras1 and inhibition of ERK–CREB–BDNF pathway. Co-IP, APP/PS1 transgenic mice, nNOS–CAPON competing peptides, behavioral memory tests, dendritic spine morphology, western blot Aging cell Medium 29577585
2022 Fluoxetine prevents chronic stress-induced nNOS–CAPON upregulation and coupling in the dentate gyrus; 5-HT1AR activation (by 8-OH-DPAT or elevated 5-HT) decreases nNOS–CAPON binding, and augmenting nNOS–CAPON binding neutralizes fluoxetine/5-HT1AR-induced synaptic plasticity (spine density, BDNF, ERK/CREB/synapsin phosphorylation) and anxiolytic/antidepressant effects. Co-IP, viral overexpression/competition constructs, 5-HT1AR agonist/antagonist pharmacology, CMS and CORT mouse models, dendritic spine analysis, behavioral tests Theranostics Medium 35664081
2021 NOS1AP SNPs (rs16847548, rs4657139) associated with arrhythmia risk reduce NOS1 expression and co-localization with NOS1AP in hiPSC-CMs from symptomatic LQT1 patients. NOS1 inhibition in guinea pig cardiomyocytes prolongs APD, enhances ICaL and INaL, slows Ca2+ decay, and induces delayed afterdepolarizations, establishing that NOS1AP SNPs cause NOS1 loss of function contributing to arrhythmogenesis. hiPSC-CMs from LQT1 patients with distinct NOS1AP genotypes, guinea pig cardiomyocyte NOS1 inhibition (SMTC, L-VNIO), action-potential clamp, patch clamp, Ca2+ fluorimetry Cardiovascular research High 32061134
2018 Unloading-induced redistribution of active nNOS from the sarcolemma to the sarcoplasm precedes myofiber atrophy and depends on mitochondrial-derived oxidant species; displaced nNOS activity drives FoxO3 nuclear translocation to initiate muscle atrophy. In vivo inhibition of nNOS before and during unloading prevents FoxO3 nuclear accumulation. Human bed-rest biopsies, rat unloading model, NADPH-diaphorase histochemistry, immunofluorescence, mitochondrial superoxide measurement, tropomyosin disulfide analysis, FoxO3 nuclear localization assay, in vivo nNOS inhibition The Journal of pathology High 30066461
2005 Adenoviral nNOS gene transfer into the cardiac vagus increases nNOS protein expression selectively in the right vagus within 9 hours and enhances baroreflex sensitivity and heart rate responses to right vagal stimulation in pigs, demonstrating NOS1-dependent facilitation of cardiac vagal neurotransmission in vivo. Adenoviral nNOS gene transfer in vivo (pig), western blot, baroreflex/vagal stimulation electrophysiology Journal of molecular and cellular cardiology Medium 15893765
2017 nNOS-derived NO facilitates Fos–Jun dimerization (AP-1) driving IL-12 and IL-23 expression in LPS-stimulated macrophages (TLR4-NOS1-AP1 axis); NOS1 inhibition switches AP-1 composition to ATF2–Jun, converting macrophages from IL-12high/IL-23high/IL-10low (M1) to IL-10high (M2) phenotype. Pharmacological NOS1 inhibition (TRIM), LPS-stimulated Raw 264.7 and THP1 macrophages, dimerization assays, cytokine measurement Inflammation research Medium 28013342
2019 nNOS is present in mitochondria of colon cancer cells; mitochondrial NOS1 suppresses mitochondrial superoxide and cisplatin-induced apoptosis by enhancing SIRT3 activity (mtNOS1-SIRT3-SOD2 axis). Hsp90 inhibitor geldanamycin blocks NOS1 mitochondrial translocation and reverses apoptosis resistance. Subcellular fractionation, stable NOS1 overexpression, geldanamycin treatment, SIRT3 activity assay, mitochondrial superoxide measurement, flow cytometry apoptosis assay Biochemical and biophysical research communications Medium 31153640
2017 nNOS splice variant nNOS-α generates ~2.3-fold more superoxide than nNOS-µ in electron-uncoupling reactions (EPR measurement) and in HEK293 cells upon calcium ionophore stimulation; nNOS-α expressing cells produce more 8-nitroguanosine-cGMP (a NO/ROS second messenger) than nNOS-µ expressing cells. Electron paramagnetic resonance (EPR), HEK293 stable transfection, calcium ionophore stimulation, immunocytochemistry for 8-nitroguanosine-cGMP The Biochemical journal Medium 28126743
2022 NOS1 loss-of-function mutations cause congenital hypogonadotropic hypogonadism by disrupting GnRH neuron function; NOS1 is transiently expressed by GnRH neurons in the human and mouse nose, and Nos1-deficient mice show dose-dependent defects in sexual maturation, olfaction, hearing, and cognition. Inhaled NO treatment during minipuberty rescues reproductive and behavioral phenotypes in Nos1-deficient mice. Whole-exome sequencing, in vitro NOS1 mutant activity assay (nitrite/cGMP production), Nos1-KO mouse model, pharmacological NO inhibition with critical time-window experiment, inhaled NO rescue Science translational medicine High 36197968
2022 In male mice, preoptic nNOS neurons (co-expressing ERα but not AR) show a sharp increase in Ser1412 phosphorylation at postnatal day 23 (minipuberty onset) that occurs independent of gonads; pharmacological ERα blockade during the infantile period blunts nNOS Ser1412 phosphorylation, linking extragonadal estrogen signaling through ERα to nNOS activation during minipuberty. Gonadectomy, ERα-selective pharmacological blockade, immunohistochemistry for phospho-nNOS Ser1412 and ERα/AR, nNOS-deficient mice, hormonal profiling (RIA/ELISA) Free radical biology & medicine Medium 36470319
2019 nNOS and the denitrosylase GSNOR co-localize at the sarcolemma and co-immunoprecipitate in C2C12 myotubes and mouse myofibers; GSNOR expression decreases in mouse models of muscular dystrophy, aging, and ALS, suggesting that nNOS–GSNOR interaction regulates S-nitrosylation homeostasis in skeletal muscle. Co-immunoprecipitation, immunofluorescence co-localization, C2C12 differentiation time-course, disease model muscle tissue analysis Cell death & disease Medium 31043586
2015 After stroke (ischemia-reperfusion), nNOS activity increases with Ser1412 phosphorylation; GSNO treatment reduces nNOS Ser1412 phosphorylation and activity by inhibiting the upstream AMPK–LKB1 axis, thereby reducing peroxynitrite levels and providing neuroprotection. Rat cerebral IR model, GSNO treatment, nNOS activity assay, phospho-nNOS western blot, AMPK activator/inhibitor pharmacology BMC neuroscience Medium 26174015
2019 Novel long-range inhibitory nNOS-expressing hippocampal neurons (LINCs) project extrahippocampally (tenia tecta, diagonal band, retromammillary nucleus) and locally to CA1; selective optogenetic activation of LINCs strongly influences hippocampal oscillations and interregional coherence. Intersectional viral vector approach in mice, optogenetic activation, electrophysiology, anatomical tracing eLife Medium 31609204
2019 SST+/nNOS+ cortical neuron-specific nNOS knockout mice show impaired homeostatic slow-wave (delta) activity after sleep loss and deficits in cortex-dependent recognition memory, placing NOS1 in SST interneurons as required for SWA homeostasis and cortical memory processes. Cell-type-specific Cre-mediated nNOS KO (SST-Cre × NOS1-flox), EEG/sleep recording, recognition memory behavioral testing Sleep Medium 31328777
2021 nNOS-derived NO promotes OxLDL uptake and proinflammatory cytokine expression by macrophages; NOS1 inhibition (L-NAME) suppresses OxLDL uptake and cytokine release, implicating NOS1 in foam cell formation and atherosclerosis progression. Pharmacological NOS1 inhibition, OxLDL uptake assay, cytokine ELISA, macrophage culture Cell biology international Low 33501735
1997 nNOS (localized at the plasma membrane of pancreatic acinar and submandibular salivary gland cells) mediates agonist-activated Ca2+ influx through generation of cGMP; nNOS inhibitor 7-NI selectively blocked bombesin-evoked but not CCK-JMV-180-evoked Ca2+ oscillations and Ca2+ influx. Pharmacological NOS inhibition (7-NI, NOS pathway inhibitors), cGMP assay, [Ca2+]i fluorimetry, western blot and immunolocalization of NOS isoforms Cell calcium Medium 9330792
2021 nNOS-derived NO promotes C/EBPα-dependent neutrophil differentiation through the G-CSFR–STAT3 axis; in vivo nNOS inhibition abrogates granulopoiesis (decreased BM mature and progenitor neutrophils). NOSIP (NOS inhibitory protein) expression decreases during the final stage of differentiation, correlating with augmented NO release and differentiation completion. nNOS overexpression in K562 cells, nNOS inhibitor in vivo (mice) and in vitro (human CD34+ HSPCs), surface marker/transcription factor analysis, NOSIP expression profiling, CML patient neutrophils vs healthy controls Biochimica et biophysica acta. Molecular cell research Medium 33771575

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 Manganese superoxide dismutase protects nNOS neurons from NMDA and nitric oxide-mediated neurotoxicity. The Journal of neuroscience : the official journal of the Society for Neuroscience 210 9482791
2012 Species-dependent posttranscriptional regulation of NOS1 by FMRP in the developing cerebral cortex. Cell 111 22579290
2002 Allelic association of the neuronal nitric oxide synthase (NOS1) gene with schizophrenia. Molecular psychiatry 102 12140778
2015 Neuronal nitric oxide synthase (NOS1) and its adaptor, NOS1AP, as a genetic risk factors for psychiatric disorders. Genes, brain, and behavior 95 25612209
2007 Differences in inflammatory pain in nNOS-, iNOS- and eNOS-deficient mice. European journal of pain (London, England) 91 17395508
2014 CAPON-nNOS coupling can serve as a target for developing new anxiolytics. Nature medicine 88 25129479
2013 The nNOS-p38MAPK pathway is mediated by NOS1AP during neuronal death. The Journal of neuroscience : the official journal of the Society for Neuroscience 85 23658158
2019 Macula Densa SGLT1-NOS1-Tubuloglomerular Feedback Pathway, a New Mechanism for Glomerular Hyperfiltration during Hyperglycemia. Journal of the American Society of Nephrology : JASN 83 30867247
2017 Accumbens nNOS Interneurons Regulate Cocaine Relapse. The Journal of neuroscience : the official journal of the Society for Neuroscience 79 28123012
2013 Renal collecting duct NOS1 maintains fluid-electrolyte homeostasis and blood pressure. Hypertension (Dallas, Tex. : 1979) 74 23608660
2002 Loss of sarcolemma nNOS in sarcoglycan-deficient muscle. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 69 12409321
2008 Variants in the neuronal nitric oxide synthase (nNOS, NOS1) gene are associated with restless legs syndrome. Movement disorders : official journal of the Movement Disorder Society 66 18058820
2011 The PSD-95/nNOS complex: new drugs for depression? Pharmacology & therapeutics 65 22133842
1998 Genetic analysis of NOS isoforms using nNOS and eNOS knockout animals. Progress in brain research 62 9932431
2008 Inhibition of nNOS reduces ischemic cell death through down-regulating calpain and caspase-3 after experimental stroke. Neurochemistry international 60 19162106
2003 Roles of iNOS and nNOS in sepsis-induced pulmonary apoptosis. American journal of physiology. Lung cellular and molecular physiology 58 14660484
2012 Decreased NOS1 expression in the anterior cingulate cortex in depression. Cerebral cortex (New York, N.Y. : 1991) 56 22989585
2003 NMDA receptor regulation of nNOS phosphorylation and induction of neuron death. Neurobiology of aging 55 14643384
2005 Expression of neuronal nitric oxide synthase (nNOS) and nitric-oxide-induced changes in cGMP in the urothelial layer of the guinea pig bladder. Cell and tissue research 52 15965654
2014 The role of nNOS and PGC-1α in skeletal muscle cells. Journal of cell science 51 25217629
2014 Mechanisms of NOS1AP action on NMDA receptor-nNOS signaling. Frontiers in cellular neuroscience 51 25221472
2006 Biglycan regulates the expression and sarcolemmal localization of dystrobrevin, syntrophin, and nNOS. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 51 16807372
2019 NOS1 inhibits the interferon response of cancer cells by S-nitrosylation of HDAC2. Journal of experimental & clinical cancer research : CR 49 31805977
1997 nNOS and Ca2+ influx in rat pancreatic acinar and submandibular salivary gland cells. Cell calcium 49 9330792
2017 Phenotyping of nNOS neurons in the postnatal and adult female mouse hypothalamus. The Journal of comparative neurology 46 28577305
2011 nNOS regulation of skeletal muscle fatigue and exercise performance. Biophysical reviews 44 28510048
2009 Influence of NOS1 on verbal intelligence and working memory in both patients with schizophrenia and healthy control subjects. Archives of general psychiatry 44 19805695
2017 Nitric oxide pathway genes (NOS1AP and NOS1) are involved in PTSD severity, depression, anxiety, stress and resilience. Gene 42 28465168
2014 Melanoma NOS1 expression promotes dysfunctional IFN signaling. The Journal of clinical investigation 42 24691438
2011 Distinct regulation of nNOS and iNOS by CB2 receptor in remote delayed neurodegeneration. Journal of molecular medicine (Berlin, Germany) 40 22198001
2017 NOS1 S-nitrosylates PTEN and inhibits autophagy in nasopharyngeal carcinoma cells. Cell death discovery 39 28243469
1999 Neuronal NO synthase (NOS1) is a major candidate gene for asthma. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology 39 10641565
2023 nNOS and Neurological, Neuropsychiatric Disorders: A 20-Year Story. Neuroscience bulletin 38 37074530
2020 Disrupting nNOS-PSD95 Interaction Improves Neurological and Cognitive Recoveries after Traumatic Brain Injury. Cerebral cortex (New York, N.Y. : 1991) 38 31989159
2001 Upregulation of juxtaglomerular NOS1 and COX-2 precedes glomerulosclerosis in fawn-hooded hypertensive rats. American journal of physiology. Renal physiology 38 11249862
2012 Cardiomyocyte GTP cyclohydrolase 1 and tetrahydrobiopterin increase NOS1 activity and accelerate myocardial relaxation. Circulation research 37 22798524
2018 nNOS-CAPON interaction mediates amyloid-β-induced neurotoxicity, especially in the early stages. Aging cell 35 29577585
2022 Requirement of hippocampal DG nNOS-CAPON dissociation for the anxiolytic and antidepressant effects of fluoxetine. Theranostics 34 35664081
2018 Sarcolemmal loss of active nNOS (Nos1) is an oxidative stress-dependent, early event driving disuse atrophy. The Journal of pathology 34 30066461
2018 PSD-95-nNOS Coupling Regulates Contextual Fear Extinction in the Dorsal CA3. Scientific reports 34 30143658
2016 The TLR4-NOS1-AP1 signaling axis regulates macrophage polarization. Inflammation research : official journal of the European Histamine Research Society ... [et al.] 33 28013342
2010 A putative cis-acting polymorphism in the NOS1 gene is associated with schizophrenia and NOS1 immunoreactivity in the postmortem brain. Schizophrenia research 33 20605417
2015 Blocking a vicious cycle nNOS/peroxynitrite/AMPK by S-nitrosoglutathione: implication for stroke therapy. BMC neuroscience 32 26174015
2005 Suppression of stress-induced nNOS expression in the rat hypothalamus by biting. Journal of dental research 32 15972590
2022 The expanding roles of neuronal nitric oxide synthase (NOS1). PeerJ 31 35821897
2022 NOS1 mutations cause hypogonadotropic hypogonadism with sensory and cognitive deficits that can be reversed in infantile mice. Science translational medicine 31 36197968
2020 Berberine attenuates Aβ-induced neuronal damage through regulating miR-188/NOS1 in Alzheimer's disease. Molecular and cellular biochemistry 31 32779043
2019 Novel long-range inhibitory nNOS-expressing hippocampal cells. eLife 28 31609204
2008 Evidence for association between the 5' flank of the NOS1 gene and schizophrenia in the Chinese population. The international journal of neuropsychopharmacology 28 18544180
2015 Polybacterial Periodontal Pathogens Alter Vascular and Gut BH4/nNOS/NRF2-Phase II Enzyme Expression. PloS one 27 26111153
2014 Evidence for the contribution of NOS1 gene polymorphism (rs3782206) to prefrontal function in schizophrenia patients and healthy controls. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 27 25490993
2018 Disrupting interaction of PSD-95 with nNOS attenuates hemorrhage-induced thalamic pain. Neuropharmacology 26 30193808
2007 Increased longevity of hematopoiesis in continuous bone marrow cultures derived from NOS1 (nNOS, mtNOS) homozygous recombinant negative mice correlates with radioresistance of hematopoietic and marrow stromal cells. Experimental hematology 26 17198882
2006 Inhibition of nNOS and COX-2 expression by lutein in acute retinal ischemia. Nutrition (Burbank, Los Angeles County, Calif.) 26 16631350
2001 Expression and distribution of NOS1 and NOS3 in the myocardium of angiotensin II-infused rats. Hypertension (Dallas, Tex. : 1979) 26 11408389
2021 NOS1AP polymorphisms reduce NOS1 activity and interact with prolonged repolarization in arrhythmogenesis. Cardiovascular research 25 32061134
2020 Macrophage neuronal nitric oxide synthase (NOS1) controls the inflammatory response and foam cell formation in atherosclerosis. International immunopharmacology 25 32193098
2019 Somatostatin+/nNOS+ neurons are involved in delta electroencephalogram activity and cortical-dependent recognition memory. Sleep 25 31328777
2018 Disruption of nNOS-NOS1AP protein-protein interactions suppresses neuropathic pain in mice. Pain 25 29319606
2018 Role of neuronal nitric oxide synthase (nNOS) in Duchenne and Becker muscular dystrophies - Still a possible treatment modality? Neuromuscular disorders : NMD 25 30352768
2012 Amitriptyline attenuates astrocyte activation and morphine tolerance in rats: role of the PSD-95/NR1/nNOS/PKCγ signaling pathway. Behavioural brain research 25 22309983
2020 Leptin Contributes to Neuropathic Pain via Extrasynaptic NMDAR-nNOS Activation. Molecular neurobiology 24 33099751
2016 Role of ERK1/2 activation and nNOS uncoupling on endothelial dysfunction induced by lysophosphatidylcholine. Atherosclerosis 24 28235709
2005 Targeted nNOS gene transfer into the cardiac vagus rapidly increases parasympathetic function in the pig. Journal of molecular and cellular cardiology 24 15893765
2020 NOS1 expression promotes proliferation and invasion and enhances chemoresistance in ovarian cancer. Oncology letters 23 32218855
2014 NOS1 methylation and carotid artery intima-media thickness in children. Circulation. Cardiovascular genetics 23 24622112
2007 Endothelin(A) (ET(A)) and ET(B) receptor-mediated regulation of nitric oxide synthase 1 (NOS1) and NOS3 isoforms in the renal inner medulla. Acta physiologica (Oxford, England) 23 17892518
2004 Differential response of nNOS knockout mice to MDMA ("ecstasy")- and methamphetamine-induced psychomotor sensitization and neurotoxicity. Annals of the New York Academy of Sciences 23 15542708
2020 Effects of selective inhibition of nNOS and iNOS on neuropathic pain in rats. Molecular and cellular neurosciences 22 32353527
2020 An autophagic deficit in the uterine vessel microenvironment provokes hyperpermeability through deregulated VEGFA, NOS1, and CTNNB1. Autophagy 22 32579471
2021 BH4 Increases nNOS Activity and Preserves Left Ventricular Function in Diabetes. Circulation research 21 33494625
2019 Mitochondrial NOS1 suppresses apoptosis in colon cancer cells through increasing SIRT3 activity. Biochemical and biophysical research communications 21 31153640
2014 Hippocampal nNOS inhibition induces an antidepressant-like effect: involvement of 5HT1A receptors. Behavioural pharmacology 21 24710314
2014 Neuronal nitric oxide synthase (nNOS, NOS1) rs693534 and rs7977109 variants and risk for restless legs syndrome. Journal of neural transmission (Vienna, Austria : 1996) 21 25300364
2022 Inhibition of interferon-gamma-stimulated melanoma progression by targeting neuronal nitric oxide synthase (nNOS). Scientific reports 20 35105915
2020 nNOS-mediated protein-protein interactions: promising targets for treating neurological and neuropsychiatric disorders. Journal of biomedical research 20 33402546
2009 Genetic association analysis of functional polymorphisms in neuronal nitric oxide synthase 1 gene (NOS1) and mood disorders and fluvoxamine response in major depressive disorder in the Japanese population. Neuropsychobiology 20 20016223
2018 NOS1 mediates AP1 nuclear translocation and inflammatory response. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 19 29605772
2018 NOS1 upregulates ABCG2 expression contributing to DDP chemoresistance in ovarian cancer cells. Oncology letters 19 30675218
2011 NOS1 ex1f-VNTR polymorphism influences prefrontal brain oxygenation during a working memory task. NeuroImage 19 21620982
2023 nNOS-induced tyrosine nitration of TRKB impairs BDNF signaling and restrains neuronal plasticity. Progress in neurobiology 18 36682419
2018 Pathology of nNOS-Expressing GABAergic Neurons in Mouse Model of Alzheimer's Disease. Neuroscience 18 29782905
2017 Superoxide generation from nNOS splice variants and its potential involvement in redox signal regulation. The Biochemical journal 18 28126743
2016 Human Ischemic Cardiomyopathy Shows Cardiac Nos1 Translocation and its Increased Levels are Related to Left Ventricular Performance. Scientific reports 18 27041589
2007 Spatiotemporal expression of PSD-95 and nNOS after rat sciatic nerve injury. Neurochemical research 18 18095156
2009 No association between polymorphisms of neuronal oxide synthase 1 gene (NOS1) and schizophrenia in a Japanese population. Neuromolecular medicine 17 19513863
2021 NOS1-mediated macrophage and endothelial cell interaction in the progression of atherosclerosis. Cell biology international 16 33501735
2020 Changes of nNOS expression in the tuberal hypothalamic nuclei during ageing. Nitric oxide : biology and chemistry 16 32283261
2019 Dystrophin R16/17 protein therapy restores sarcolemmal nNOS in trans and improves muscle perfusion and function. Molecular medicine (Cambridge, Mass.) 16 31266455
2018 miR-708-5p and miR-34c-5p are involved in nNOS regulation in dystrophic context. Skeletal muscle 16 29703249
2015 On the role of NOS1 ex1f-VNTR in ADHD-allelic, subgroup, and meta-analysis. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 16 26086921
2013 Association analysis of nitric oxide synthases: NOS1, NOS2A and NOS3 genes, with multiple sclerosis. Annals of human biology 16 23826716
2013 Development of nNOS-positive neurons in the rat sensory and sympathetic ganglia. Neuroscience 16 24161722
2019 nNOS/GSNOR interaction contributes to skeletal muscle differentiation and homeostasis. Cell death & disease 15 31043586
2016 Activity and MeCP2-dependent regulation of nNOS levels in enteric neurons. Neurogastroenterology and motility 15 27254746
2015 The neuronal nitric oxide synthase (nNOS) gene and neuroprotection against alcohol toxicity. Cellular and molecular neurobiology 15 25672665
2015 Neuronal Nitric Oxide Synthase (nNOS, NOS1) rs693534 and rs7977109 Variants and Risk for Migraine. Headache 15 26283425
2023 Nos1+ and Nos1- excitatory neurons in the BLA regulate anxiety- and depression-related behaviors oppositely. Journal of affective disorders 14 37080493
2022 Male minipuberty involves the gonad-independent activation of preoptic nNOS neurons. Free radical biology & medicine 14 36470319
2021 nNOS induction and NOSIP interaction impact granulopoiesis and neutrophil differentiation by modulating nitric oxide generation. Biochimica et biophysica acta. Molecular cell research 14 33771575

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