Abstract
NMDA receptor (NMDAR) composition and synaptic retention represent pivotal features in the physiology and pathology of excitatory synapses. Here, we identify Rabphilin 3A (Rph3A) as a new GluN2A subunit-binding partner. Rph3A is known as a synaptic vesicle-associated protein involved in the regulation of exo- and endocytosis processes at presynaptic sites. We find that Rph3A is enriched at dendritic spines. Protein-protein interaction assays reveals that Rph3A N-terminal domain interacts with GluN2A(1349-1389) as well as with PSD-95(PDZ3) domains, creating a ternary complex. Rph3A silencing in neurons reduces the surface localization of synaptic GluN2A and NMDAR currents. Moreover, perturbing GluN2A/Rph3A interaction with interfering peptides in organotypic slices or in vivo induces a decrease of the amplitude of NMDAR-mediated currents and GluN2A density at dendritic spines. In conclusion, Rph3A interacts with GluN2A and PSD-95 forming a complex that regulates NMDARs stabilization at postsynaptic membranes.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / metabolism*
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Animals
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CA1 Region, Hippocampal / metabolism*
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COS Cells
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Chlorocebus aethiops
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Computer Simulation
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Dendritic Spines / metabolism*
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Disks Large Homolog 4 Protein
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Endocytosis
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Guanylate Kinases / metabolism*
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Hippocampus / metabolism
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Immunohistochemistry
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Immunoprecipitation
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Intracellular Signaling Peptides and Proteins / metabolism*
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Membrane Proteins / metabolism*
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Mice
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Microscopy, Confocal
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Nerve Tissue Proteins / metabolism*
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Neurons / metabolism*
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PDZ Domains
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Patch-Clamp Techniques
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Rabphilin-3A
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Rats
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Receptors, N-Methyl-D-Aspartate / metabolism*
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Synapses / metabolism
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Synaptic Membranes / metabolism*
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Vesicular Transport Proteins / metabolism*
Substances
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Adaptor Proteins, Signal Transducing
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Disks Large Homolog 4 Protein
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Dlg4 protein, mouse
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Dlg4 protein, rat
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Intracellular Signaling Peptides and Proteins
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Membrane Proteins
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Nerve Tissue Proteins
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Receptors, N-Methyl-D-Aspartate
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Vesicular Transport Proteins
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Guanylate Kinases
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N-methyl D-aspartate receptor subtype 2A