ArticleMolecular & cellular proteomics : MCP2023
N-Terminomic Changes in Neurons During Excitotoxicity Reveal Proteolytic Events Associated With Synaptic Dysfunctions and Potential Targets for Neuroprotection.
Article in Molecular & cellular proteomics : MCP, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 19 citations in OpenAlex.
- Caveolin-1 Attenuates Excitotoxic Signaling by Regulating NMDA, AMPA, and Kainate Receptor-Mediated Calcium Influx in Hippocampal Neuronal Cultures.International journal of molecular sciences · 2026Article
- ADAM10-Mediated Proteolytic Remodelling of Signalling and Adhesion Proteins on Brain Cell-Derived Small Extracellular Vesicles.Journal of extracellular biology · 2026Article
- Inflammation-centered neurovascular-immune-metabolic remodeling in ischemic stroke: stage-dependent mechanisms, regulated cell death, and therapeutic translation.Frontiers in immunology · 2026Review
- Stress and neurodegeneration: mechanistic insights and therapeutic opportunities for preserving brain resilience.Acta neurologica Belgica · 2025Review
- Effects of Troxerutin on Oxidative Stress, Inflammation and Galectin- 3 Expression in Intracerebroventricular Kainic Acid-Induced Neurotoxicity.Inflammation · 2025Article
- Evaluation of Nanoparticle-Based Plasma Enrichment on Individuals with Primary and Metastatic Pancreatic Cancer.Cancers · 2025Article
- Degradation of CaMKII is stimulated by its active conformation.The Journal of biological chemistry · 2025Article
- Ubiquitous calpastatin overexpression in brain-injured mice attenuates motor and cognitive behavioral deficits without overt neuroprotection.Molecular and cellular neurosciences · 2025Article
- Metabolic changes and biochemical degradation during dark anoxic incubation of Nannochloropsis: implications for low-energy microalgal cell rupture.Bioprocess and biosystems engineering · 2025Article
- The Identification of Proteolytic Substrates of Calpain-5 with N-Terminomics.International journal of molecular sciences · 2025Article
- Review
- Mitochondrial Dysfunction as the Major Basis of Brain Aging.Biomolecules · 2024Review
- The GHB analogue HOCPCA improves deficits in cognition and sensorimotor function after MCAO via CaMKIIα.Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism · 2023Article
- CaMKIIα as a Promising Drug Target for Ischemic Grey Matter.Brain sciences · 2022Review
Corrections and comments
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Authors and funding
27 authors at 12 institutions in 6 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Excitotoxicity, a neuronal death process in neurological disorders such as stroke, is initiated by the overstimulation of ionotropic glutamate receptors. Although dysregulation of proteolytic signaling networks is critical for excitotoxicity, the identity of affected proteins and mechanisms by which they induce neuronal cell death remain unclear. To address this, we used quantitative N-terminomics to identify proteins modified by proteolysis in neurons undergoing excitotoxic cell death. We found that most proteolytically processed proteins in excitotoxic neurons are likely substrates of calpains, including key synaptic regulatory proteins such as CRMP2, doublecortin-like kinase I, Src tyrosine kinase and calmodulin-dependent protein kinase IIβ (CaMKIIβ). Critically, calpain-catalyzed proteolytic processing of these proteins generates stable truncated fragments with altered activities that potentially contribute to neuronal death by perturbing synaptic organization and function. Blocking calpain-mediated proteolysis of one of these proteins, Src, protected against neuronal loss in a rat model of neurotoxicity. Extrapolation of our N-terminomic results led to the discovery that CaMKIIα, an isoform of CaMKIIβ, undergoes differential processing in mouse brains under physiological conditions and during ischemic stroke. In summary, by identifying the neuronal proteins undergoing proteolysis during excitotoxicity, our findings offer new insights into excitotoxic neuronal death mechanisms and reveal potential neuroprotective targets for neurological disorders.
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