Tissue-type plasminogen activator controls neuronal death by raising surface dynamics of extrasynaptic NMDA receptors
Autor: | Arnaud Chevilley, Eric Maubert, Julie Jézéquel, Richard Macrez, Flavie Lesept, Laurent Lebouvier, Pascale Galea, Sophie Lenoir, Karl-Uwe Petersen, Laurent Groc, Laurent Ladépêche, Margaux Aimable, Denis Vivien, Laetitia Rubrecht, Carine Ali, Yannick Hommet, T Bertrand |
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Rok vydání: | 2016 |
Předmět: |
Male
0301 basic medicine Cancer Research Protein subunit Neurotoxins Immunology Allosteric regulation Receptors N-Methyl-D-Aspartate Diffusion Rats Sprague-Dawley 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine Protein Domains Animals Humans Fibrinolysin Receptor Ion channel Neurons Mice Inbred BALB C Cell Death Chemistry Lysine Cell Membrane HEK 293 cells Antibodies Monoclonal Cell Biology Cell biology HEK293 Cells 030104 developmental biology nervous system Tissue Plasminogen Activator Synapses Synaptic plasticity NMDA receptor Original Article Calcium Plasminogen activator 030217 neurology & neurosurgery Signal Transduction |
Zdroj: | Cell Death & Disease |
ISSN: | 2041-4889 |
Popis: | 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. |
Databáze: | OpenAIRE |
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