ArticleCell death & disease2016
Tissue-type plasminogen activator controls neuronal death by raising surface dynamics of extrasynaptic NMDA receptors.
Article in Cell death & disease, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 52 citations in OpenAlex.
- Ischemic stroke: molecular mechanisms of blood-brain barrier dysfunction and opportunities for drug development.Fluids and barriers of the CNS · 2026Review
- Inhibition of tPA-NMDAR interaction prevents neurovascular and functional deficits induced by organophosphorus nerve agents.Cell death and differentiation · 2026Article
- Purine Metabolism-Related Pathogenic Genes in Trigeminal Neuralgia: A Multiomics Mendelian Randomization Study.Pain research & management · 2026Article
- The Role of Blood-Brain Barrier Disruption in Epilepsy: Mechanisms and Consequences.Neurology international · 2025Review
- Neuronal conversion of single-chain tissue-type plasminogen activator into its two-chain form: implications in neurodevelopment, learning, and memory.Cell death & disease · 2025Article
- Restoring brain barriers: an innovative approach for treating neurological disorders.Fluids and barriers of the CNS · 2025Review
- The interaction of tPA with NMDAR1 drives neuroinflammation and neurodegeneration in α-synuclein-mediated neurotoxicity.Journal of neuroinflammation · 2025Article
- A sweet deal: blocking NMDAR for safer t-PA in diabetes.Blood advances · 2024Article
- Improving stroke outcomes in hyperglycemic mice by modulating tPA/NMDAR signaling to reduce inflammation and hemorrhages.Blood advances · 2024Article
- Tissue-type plasminogen activator induces conditioned receptive field plasticity in the mouse auditory cortex.iScience · 2023Article
- Low-density lipoprotein receptor-related protein-1 (LRP1) in the glial lineage modulates neuronal excitability.Frontiers in network physiology · 2023Review
- tPA-NMDAR Signaling Blockade Reduces the Incidence of Intracerebral Aneurysms.Translational stroke research · 2022Article
- NMDA Receptor C-Terminal Domain Signalling in Development, Maturity, and Disease.International journal of molecular sciences · 2022Review
- Targeting NMDA Receptors at the Neurovascular Unit: Past and Future Treatments for Central Nervous System Diseases.International journal of molecular sciences · 2022Review
- Ion flux-independent NMDA receptor signaling.Neuropharmacology · 2022Review
- A Soluble PrPJournal of immunology (Baltimore, Md. : 1950) · 2022Article
- Two-Chains Tissue Plasminogen Activator Unifies Met and NMDA Receptor Signalling to Control Neuronal Survival.International journal of molecular sciences · 2021Article
- Plasminogen activator receptor assemblies in cell signaling, innate immunity, and inflammation.American journal of physiology. Cell physiology · 2021Review
- New Approaches in Nanomedicine for Ischemic Stroke.Pharmaceutics · 2021Review
- Tissue plasminogen activator worsens experimental autoimmune encephalomyelitis by complementary actions on lymphoid and myeloid cell responses.Journal of neuroinflammation · 2021Article
Corrections and comments
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Authors and funding
17 authors at 8 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
N-methyl-d-aspartate receptors (NMDARs) are ion channels whose synaptic versus extrasynaptic localization critically influences their functions. This distribution of NMDARs is highly dependent on their lateral diffusion at the cell membrane. Each obligatory subunit of NMDARs (GluN1 and GluN2) contains two extracellular clamshell-like domains with an agonist-binding domain and a distal N-terminal domain (NTD). To date, the roles and dynamics of the NTD of the GluN1 subunit in NMDAR allosteric signaling remain poorly understood. Using single nanoparticle tracking in mouse neurons, we demonstrate that the extracellular neuronal protease tissue-type plasminogen activator (tPA), well known to have a role in the synaptic plasticity and neuronal survival, leads to a selective increase of the surface dynamics and subsequent diffusion of extrasynaptic NMDARs. This process explains the previously reported ability of tPA to promote NMDAR-mediated calcium influx. In parallel, we developed a monoclonal antibody capable of specifically blocking the interaction of tPA with the NTD of the GluN1 subunit of NMDAR. Using this original approach, we demonstrate that the tPA binds the NTD of the GluN1 subunit at a lysine in position 178. Accordingly, when applied to mouse neurons, our selected antibody (named Glunomab) leads to a selective reduction of the tPA-mediated surface dynamics of extrasynaptic NMDARs, subsequent signaling and neurotoxicity, both in vitro and in vivo. Altogether, we demonstrate that the tPA is a ligand of the NTD of the obligatory GluN1 subunit of NMDAR acting as a modulator of their dynamic distribution at the neuronal surface and subsequent signaling.
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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.