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Cited by 40Neuroscience and Neuropharmacology ResearchRedox biology and oxidative stressNitric Oxide and Endothelin Effects

Superoxide and Non-ionotropic Signaling in Neuronal Excitotoxicity

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Wang, Jiejie, Swanson, Raymond A.·2020·Frontiers in Neuroscience
DOI 10.3389/fnins.2020.00861PMC PMC7497801
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Abstract

Excitotoxicity is classically attributed to Ca2+ influx through NMDA receptors (NMDAr), leading to production of nitric oxide and mitochondrial superoxide, which together generate the cytotoxic peroxynitrite radical. More recent observations warrant revision of the classic view and help to explain some otherwise puzzling aspects of excitotoxic cell injury. Studies using pharmacological and genetic approaches show that superoxide production induced by NMDAr activation originates primarily from NADPH oxidase rather than from mitochondria. NADPH oxidase is localized to the plasma membrane, and release of superoxide to the extracellular space thereby provides a mechanism for the cell-to-cell “spread” of excitotoxic injury observed in vitro and in vivo. The signaling pathway linking NMDAr to NADPH oxidase involves Ca2+ influx, phosphoinostitol-3-kinase, and protein kinase Cζ, and interventions at any of these steps prevents superoxide production and excitotoxic injury. Ca2+ influx specifically through NMDAr is normally required to induce excitotoxicity, through a mechanism presumed to involve privileged Ca2+ access to local signaling domains. However, experiments using selective blockade of the NMDAr ion channel and artificial reconstitution of Ca2+ by other routes indicate that these special effects of NMDAr - mediated Ca2+ influx are attributable instead to the concurrent action of non-ionotropic NMDAr signaling during agonist binding to NMDAr. The non-ionotropic signaling is mediated by the C-terminal domain of GluN2B receptor subunits, and is associated with phosphoinostitol-3-kinase binding to GluN2B. These more recently identified aspects of excitotoxicity expand our appreciation of the complexity of excitotoxic processes and suggest novel approaches for limiting neuronal injury.

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  • Under physiological conditions, NMDA receptor activity is tightly regulated; Mg2+ acts as voltage-dependent blockers of the NMDA channel, preventing excessive ion entry at resting membrane potentials.

    “Under physiological conditions, NMDA receptor activity is tightly regulated. Magnesium ions (Mg2+) act as voltage-dependent blockers of the NMDA channel, preventing excessive ion entry at resting membrane potentials [116].”

    From Toward a Unified Framework in Molecular Neurobiology of Alzheimer’s Disease: Revisiting the Pathophysiological Hypotheses (2026) · cites this paper as [116]

    The Non-Ionotropic NMDAr Signaling in Excitotoxicity section discusses calcium influx and experimental NMDA-receptor channel blockers, but not magnesium blockade under physiological conditions. Searches for Mg2+, magnesium, and voltage-dependent blockade at resting membrane potentials found no passage addressing the claim. (LLM, conf=0.74)

    Experimental — accuracy not yet measured

  • Glutamate-induced excitotoxicity potentiates tau phosphorylation and enhances Aβ neurotoxicity, both of which further destabilize synaptic networks.

    “Furthermore, glutamate-induced excitotoxicity potentiates tau phosphorylation and enhances Aβ neurotoxicity, both of which further destabilize synaptic networks [116].”

    From Toward a Unified Framework in Molecular Neurobiology of Alzheimer’s Disease: Revisiting the Pathophysiological Hypotheses (2026) · cites this paper as [116]

    The Non-Ionotropic NMDAr Signaling in Excitotoxicity section discusses excitotoxicity, synaptic depression and dendritic spine shrinkage, but does not say that glutamate-induced excitotoxicity increases tau phosphorylation or Aβ neurotoxicity. The References list mentions amyloid-beta-induced synaptic depression, which does not establish the claimed direction of effect. Searches for tau, amyloid and Aβ neurotoxicity found no passage supporting those links or their claimed effect on synaptic networks; page numbers were unavailable in our copy. (LLM, conf=0.75)

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Authors
Wang, J., & Swanson, R. A.
Affiliations
University of California, San Francisco (US)
Corresponding author
Swanson, Raymond A.
ORCID
Venue
Frontiers in Neuroscience
Publisher
Frontiers Media SA
Published
2020-09-03
Volume
4
Pages
861-861
ISSN
1662-453X (ISSN-L)
DOI
10.3389/fnins.2020.00861
PMC
PMC7497801
OpenAlex
W3083653831
Cited by
40
References
6
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0.67
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journal article
Language
en
Open access
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Locations
  • Frontiers in Neuroscience (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • U.S. Department of Veterans Affairs
  • National Institutes of Health
  • National Institute of Neurological Disorders and Stroke (R01NS081149, R01NS105774)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
  • Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
Keywords
excitotoxicity, superoxide, NMDA receptor, NADPH oxidase, phosphatidylinositol 3-kinase, protein kinase C, calcium influx, peroxynitrite, nitric oxide, mitochondrial superoxide, neuronal injury

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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