ArticleNeuron2022
Functional coupling of TRPM2 and extrasynaptic NMDARs exacerbates excitotoxicity in ischemic brain injury.
Article in Neuron, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 59 papers, 1 of them a synthesis that pooled it.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
59 citing papers in PubMed, 1 synthesis or guideline pooled it, 95 citations in OpenAlex.
- Pooled it
- Candidate Mechanisms of Cerebral Ischemia/Hypoxia Tolerance: Insights from Hibernating Rodents.Neurochemical research · 2026Review
- Inhibiting the transient receptor potential melastatin 2 channel in microglia: current evidence and therapeutic potential in neurological disorders.Acta pharmacologica Sinica · 2026Review
- Restricting Synaptotagmin-3 Internalization Mitigates Cerebral Ischemia/Reperfusion Injury by Curtailed Neuronal Apoptosis and Microglial Re-Programming.CNS neuroscience & therapeutics · 2026Article
- Pathophysiological significance of the TRPM2 ion channel as a potential target in cancer, neurological disorders, and ischemia/reperfusion injury.Pharmacological research · 2026Review
- Molecular Mechanisms and Targeted Intervention Strategies of Calcium Overload in Ischemic Stroke.International journal of molecular sciences · 2026Review
- CD13 activation assembles phosphoinositide (PI) signaling complexes to regulate the actin cytoskeleton.Scientific reports · 2026Article
- From venom peptides to neurotherapeutics: BmK defensins and short-chain peptides as modulators of ion channels.Frontiers in pharmacology · 2026Review
- Neuroimmune Regulation by TRPM2 Channels.Cells · 2026Review
- Harnessing extracellular vesicles for ischemic stroke management.Regenerative biomaterials · 2026Review
- The neurobiological regulatory mechanism of brain edema.Frontiers in cellular neuroscience · 2026Review
- Biomimetic dynamic nanomedicine SrHCF: Lattice self-reconstruction based on FeBioactive materials · 2026Article
- Anti-inflammatory and neuroprotective effect of bryodulcosigenin against cerebral ischemia/reperfusion injury via modulation of inflammatory signaling pathways.Inflammopharmacology · 2026Article
- Causality of blood metabolites and narcolepsy type 1: A Mendelian randomization study.Medicine · 2025Article
- Role and Relationship Between Homocysteine and HMolecular neurobiology · 2025Review
- Exploring NMDAR pathways in ischemic stroke: implications for neurotoxic and neuroprotective mechanisms and therapeutic strategies.Naunyn-Schmiedeberg's archives of pharmacology · 2025Review
- Physiological functions and pharmacological targeting of transient receptor potential channels.Pharmacological reviews · 2025Review
- Article
- Emerging Therapeutic Strategies in Intracerebral Hemorrhage: Enhancing Neurogenesis and Functional Recovery.MedComm · 2025Review
- A Bivalent Protease-Activated Receptor-Derived Peptide Mimics Neuronal Anti-Apoptotic Activity of Activated Protein C.Bioengineering (Basel, Switzerland) · 2025Article
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Authors and funding
14 authors at 4 institutions in 2 countries.
Funding
Abstract
Excitotoxicity induced by NMDA receptor (NMDAR) activation is a major cause of neuronal death in ischemic stroke. However, past efforts of directly targeting NMDARs have unfortunately failed in clinical trials. Here, we reveal an unexpected mechanism underlying NMDAR-mediated neurotoxicity, which leads to the identification of a novel target and development of an effective therapeutic peptide for ischemic stroke. We show that NMDAR-induced excitotoxicity is enhanced by physical and functional coupling of NMDAR to an ion channel TRPM2 upon ischemic insults. TRPM2-NMDAR association promotes the surface expression of extrasynaptic NMDARs, leading to enhanced NMDAR activity and increased neuronal death. We identified a specific NMDAR-interacting motif on TRPM2 and designed a membrane-permeable peptide to uncouple the TRPM2-NMDAR interaction. This disrupting peptide protects neurons against ischemic injury in vitro and protects mice against ischemic stroke in vivo. These findings provide an unconventional strategy to mitigate excitotoxic neuronal death without directly targeting NMDARs.
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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.