ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2007
Biphasic coupling of neuronal nitric oxide synthase phosphorylation to the NMDA receptor regulates AMPA receptor trafficking and neuronal cell death.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 84 papers.
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Who cites it
84 citing papers in PubMed, 157 citations in OpenAlex.
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- Ischemic stroke and intervention strategies based on the timeline of stroke progression: Review and prospects.Acta pharmaceutica Sinica. B · 2025Review
- SOD2 genetics regulating mitochondrial management of oxidative stress is tied to chemical sensitivity in Gulf war veterans.Scientific reports · 2025Article
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- Nitrogen waste metabolism as a locus of nitrergic co-transmission in the brain.Frontiers in behavioral neuroscience · 2025Review
- Long-term tuina can inhibit the occurrence of gastroparesis by protecting gastrointestinal function in diabetic rats.Frontiers in endocrinology · 2025Article
- Assessing the Effects of Thiazole-Carboxamide Derivatives on the Biophysical Properties of AMPA Receptor Complexes as a Potential Neuroprotective Agent.Molecules (Basel, Switzerland) · 2024Article
- Hypothalamic Kisspeptin Neurons: Integral Elements of the GnRH System.Reproductive sciences (Thousand Oaks, Calif.) · 2023Review
- Could respiration-driven blood oxygen changes modulate neural activity?Pflugers Archiv : European journal of physiology · 2023Review
- Targeting neuronal nitric oxide synthase and the nitrergic system in post-traumatic stress disorder.Psychopharmacology · 2022Review
- Possible involvement of NO-cGMP signaling in the antidepressant like Effect of Amantadine in mice.Metabolic brain disease · 2022Article
- Estrogen dampens central cannabinoid receptor 1-mediated neuroexcitation and pressor response in conscious female rats.Biochemical pharmacology · 2022Article
- Molecular pathogenesis and treatment of cavernous nerve injury-induced erectile dysfunction: A narrative review.Frontiers in physiology · 2022Review
- Estrogen Receptor β Contributes to Both Hypertension and Hypothalamic Plasticity in a Mouse Model of Peri-Menopause.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2021Article
- Chronically altered NMDAR signaling in epilepsy mediates comorbid depression.Acta neuropathologica communications · 2021Article
- Role of Nitric Oxide in Neurodegeneration: Function, Regulation, and Inhibition.Current neuropharmacology · 2021Review
- Neuronal Nitric Oxide Synthase (nNOS) in Neutrophils: An Insight.Reviews of physiology, biochemistry and pharmacology · 2021Review
- Nitric oxide signalling in the brain and its control of bodily functions.British journal of pharmacology · 2020Review
- Protein kinase A facilitates relaxation of mouse ileum via phosphorylation of neuronal nitric oxide synthase.British journal of pharmacology · 2020Article
- Effect of neuronal nitric oxide synthase serine-1412 phosphorylation on hypothalamic-pituitary-ovarian function and leptin response.Biology of reproduction · 2020Article
24 more citing papers are in PubMed but not listed here.
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
Abstract
Postsynaptic nitric oxide (NO) production affects synaptic plasticity and neuronal cell death. Ca2+ fluxes through the NMDA receptor (NMDAR) stimulate the production of NO by neuronal nitric oxide synthase (nNOS). However, the mechanisms by which nNOS activity is regulated are poorly understood. We evaluated the effect of neuronal stimulation with glutamate on the phosphorylation of nNOS. We show that, in cortical neurons, a low glutamate concentration (30 microM) induces rapid and transient NMDAR-dependent phosphorylation of S1412 by Akt, followed by sustained phosphorylation of S847 by CaMKII (calcium-calmodulin-dependent kinase II). We demonstrate that phosphorylation of S1412 by Akt is necessary for activation of nNOS by the NMDAR. nNOS mutagenesis confirms that these phosphorylations respectively activate and inhibit nNOS and, thus, transiently activate NO production. A constitutively active (S1412D), but not a constitutively repressed (S847D) nNOS mutant elevated surface glutamate receptor 2 levels, demonstrating that these phosphorylations can control AMPA receptor trafficking via NO. Notably, an excitotoxic stimulus (150 microM glutamate) induced S1412, but not S847 phosphorylation, leading to deregulated nNOS activation. S1412D did not kill neurons; however, it enhanced the excitotoxicity of a concomitant glutamate stimulus. We propose a swinging domain model for the regulation of nNOS: S1412 phosphorylation facilitates electron flow within the reductase module of nNOS, increasing nNOS sensitivity to Ca2+-calmodulin. These findings suggest a critical role for a kinetically complex and novel series of regulatory nNOS phosphorylations induced by the NMDA receptor for the in vivo control of nNOS.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.