ArticleThe Journal of biological chemistry2012
Cleavage of the NR2B subunit amino terminus of N-methyl-D-aspartate (NMDA) receptor by tissue plasminogen activator: identification of the cleavage site and characterization of ifenprodil and glycine affinities on truncated NMDA receptor.
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 24 citations in OpenAlex.
- Alterations of NMDAR Subunits in the Cerebrospinal Fluid Across Neurodegenerative and Immunological Disorders.Journal of neurochemistry · 2025Article
- Tissue-type plasminogen activator induces conditioned receptive field plasticity in the mouse auditory cortex.iScience · 2023Article
- NMDA Receptor and Its Emerging Role in Cancer.International journal of molecular sciences · 2023Review
- Low-density lipoprotein receptor-related protein-1 (LRP1) in the glial lineage modulates neuronal excitability.Frontiers in network physiology · 2023Review
- Plasminogen activator receptor assemblies in cell signaling, innate immunity, and inflammation.American journal of physiology. Cell physiology · 2021Review
- Low Density Receptor-Related Protein 1 Interactions With the Extracellular Matrix: More Than Meets the Eye.Frontiers in cell and developmental biology · 2019Review
- Differential regulation of ion channels function by proteolysis.Biochimica et biophysica acta. Molecular cell research · 2018Review
- Circadian rhythm and sleep-wake systems share the dynamic extracellular synaptic milieu.Neurobiology of sleep and circadian rhythms · 2018Review
- One-Compound-Multi-Target: Combination Prospect of Natural Compounds with Thrombolytic Therapy in Acute Ischemic Stroke.Current neuropharmacology · 2017Review
- Tissue-type plasminogen activator controls neuronal death by raising surface dynamics of extrasynaptic NMDA receptors.Cell death & disease · 2016Article
- Physiological and pathological roles of tissue plasminogen activator and its inhibitor neuroserpin in the nervous system.Frontiers in cellular neuroscience · 2015Review
- Tissue plasminogen activator inhibits NMDA-receptor-mediated increases in calcium levels in cultured hippocampal neurons.Frontiers in cellular neuroscience · 2015Article
- The Value of Serum NR2 Antibody in Prediction of Post-Cardiopulmonary Resuscitation Survival.Emergency (Tehran, Iran) · 2015Article
- Extracellular proteolysis in structural and functional plasticity of mossy fiber synapses in hippocampus.Frontiers in cellular neuroscience · 2015Review
- Impacts of tissue-type plasminogen activator (tPA) on neuronal survival.Frontiers in cellular neuroscience · 2015Review
- Tissue plasminogen activator regulates Purkinje neuron development and survival.Proceedings of the National Academy of Sciences of the United States of America · 2013Article
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Authors and funding
4 authors at 1 institution in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Thrombolysis using tissue plasminogen activator (tPA) has been the key treatment for patients with acute ischemic stroke for the past decade. Recent studies, however, suggest that this clot-busting protease also plays various roles in brain physiological and pathophysiological glutamatergic-dependent processes, such as synaptic plasticity and neurodegeneration. In addition, increasing evidence implicates tPA as an important neuromodulator of the N-methyl-d-aspartate (NMDA) receptors. Here, we demonstrate that recombinant human tPA cleaves the NR2B subunit of NMDA receptor. Analysis of NR2B in rat brain lysates and cortical neurons treated with tPA revealed concentration- and time-dependent degradation of NR2B proteins. Peptide sequencing studies performed on the cleaved-off products obtained from the tPA treatment on a recombinant fusion protein of the amino-terminal domain of NR2B revealed that tPA-mediated cleavage occurred at arginine 67 (Arg(67)). This cleavage is tPA-specific, plasmin-independent, and removes a predicted ~4-kDa fragment (Arg(27)-Arg(67)) from the amino-terminal domain of the NR2B protein. Site-directed mutagenesis of putative cleavage site Arg(67) to Ala(67) impeded tPA-mediated degradation of recombinant protein. This analysis revealed that NR2B is a novel substrate of tPA and suggested that an Arg(27)-Arg(67)-truncated NR2B-containing NMDA receptor could be formed. Heterologous expression of NR2B with Gln(29)-Arg(67) deleted is functional but exhibits reduced ifenprodil inhibition and increased glycine EC(50) with no change in glutamate EC(50). Our results confirmed NR2B as a novel proteolytic substrate of tPA, where tPA may directly interact with NR2B subunits leading to a change in pharmacological properties of NR2B-containing NMDA receptors.
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