ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2013
Distinct roles for μ-calpain and m-calpain in synaptic NMDAR-mediated neuroprotection and extrasynaptic NMDAR-mediated neurodegeneration.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 88 papers, 1 of them a synthesis that pooled it.
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Who cites it
88 citing papers in PubMed, 1 synthesis or guideline pooled it, 145 citations in OpenAlex.
- Calpain Inhibitors as Potential Therapeutic Modulators in Neurodegenerative Diseases.Neurochemical research · 2022Pooled it
- How muscle talks to brain: apelin protein mediates exercise-induced antidepressant effects.Molecular psychiatry · 2026Article
- Proteolytic cleavage of G3BP1 by calpain 1 couples NMDAR activation to mTOR-dependent local translation.EMBO reports · 2026Article
- Ceftriaxone alleviates mitochondrial damage through the inhibition of extrasynaptic NMDA receptor-mediated changes in intracellular calcium levels to improve cognitive deficits in APP/PS1 mice.Alzheimer's research & therapy · 2025Article
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- Exploration of autophagy-related molecular mechanisms underlying epilepsy using multiple datasets.The Journal of international medical research · 2025Article
- ENO1 Dysfunction-Mediated Glycolytic Attenuation Exacerbates Oxidative Stress-Induced Retinal Ganglion Cell Death via Altered ATP Synthesis Pathway.Investigative ophthalmology & visual science · 2025Article
- Contrasting patterns of extrasynaptic NMDAR-GluN2B expression in macaque subgenual cingulate and dorsolateral prefrontal cortices.Frontiers in neuroanatomy · 2025Article
- Brief and Diverse Excitotoxic Insults Increase the Neuronal Nuclear Membrane Permeability in the Neonatal Brain, Resulting in Neuronal Dysfunction and Cell Death.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2024Article
- Trauma in Neonatal Acute Brain Slices Alters Calcium and Network Dynamics and Causes Calpain-Mediated Cell Death.eNeuro · 2024Article
- Identification and neuroprotective properties of NA-184, a calpain-2 inhibitor.Pharmacology research & perspectives · 2024Article
- Revisiting the calpain hypothesis of learning and memory 40 years later.Frontiers in molecular neuroscience · 2024Review
- Calpain-2 Inhibitors as Therapy for Traumatic Brain Injury.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2023Review
- N-Terminomic Changes in Neurons During Excitotoxicity Reveal Proteolytic Events Associated With Synaptic Dysfunctions and Potential Targets for Neuroprotection.Molecular & cellular proteomics : MCP · 2023Article
- The regulatory role of Pin1 in neuronal death.Neural regeneration research · 2023Review
- Myelinating Co-Culture as a Model to Study Anti-NMDAR Neurotoxicity.International journal of molecular sciences · 2022Article
- Neuronal injuries in cerebral infarction and ischemic stroke: From mechanisms to treatment (Review).International journal of molecular medicine · 2022Review
- Revisiting Excitotoxicity in Traumatic Brain Injury: From Bench to Bedside.Pharmaceutics · 2022Review
- Identification of Genes Linking Natural Killer Cells to Apoptosis in Acute Myocardial Infarction and Ischemic Stroke.Frontiers in immunology · 2022Article
28 more citing papers are in PubMed but not listed here.
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
Prolonged calpain activation is widely recognized as a key component of neurodegeneration in a variety of pathological conditions. Numerous reports have also indicated that synaptic activation of NMDA receptors (NMDARs) provides neuroprotection against a variety of insults. Here, we report the paradoxical finding that such neuroprotection involves calpain activation. NMDAR activation in cultured rat cortical neurons was neuroprotective against starvation and oxidative stress-induced damage. It also resulted in the degradation of two splice variants of PH domain and Leucine-rich repeat Protein Phosphatase 1 (PHLPP1), PHLPP1α and PHLPP1β, which inhibit the Akt and ERK1/2 pathways. Synaptic NMDAR-induced neuroprotection and PHLPP1 degradation were blocked by calpain inhibition. Lentiviral knockdown of PHLPP1 mimicked the neuroprotective effects of synaptic NMDAR activation and occluded the effects of calpain inhibition on neuroprotection. In contrast to synaptic NMDAR activation, extrasynaptic NMDAR activation had no effect on PHLPP1 and the Akt and ERK1/2 pathways, but resulted in calpain-mediated degradation of striatal-enriched protein tyrosine phosphatase (STEP) and neuronal death. Using μ-calpain- and m-calpain-selective inhibitors and μ-calpain and m-calpain siRNAs, we found that μ-calpain-dependent PHLPP1 cleavage was involved in synaptic NMDAR-mediated neuroprotection, while m-calpain-mediated STEP degradation was associated with extrasynaptic NMDAR-induced neurotoxicity. Furthermore, m-calpain inhibition reduced while μ-calpain knockout exacerbated NMDA-induced neurotoxicity in acute mouse hippocampal slices. Thus, synaptic NMDAR-coupled μ-calpain activation is neuroprotective, while extrasynaptic NMDAR-coupled m-calpain activation is neurodegenerative. These results help to reconcile a number of contradictory results in the literature and have critical implications for the understanding and potential treatment of neurodegenerative diseases.
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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.