title: Scribble1/AP2 complex coordinates NMDA receptor endocytic recycling.
abstract: The appropriate trafficking of glutamate receptors to synapses is crucial for basic synaptic function and synaptic plasticity. It is now accepted that NMDA receptors (NMDARs) internalize and are recycled at the plasma membrane but also exchange between synaptic and extrasynaptic pools; these NMDAR properties are also key to governing synaptic plasticity. Scribble1 is a large PDZ protein required for synaptogenesis and synaptic plasticity. Herein, we show that the level of Scribble1 is regulated in an activity-dependent manner and that Scribble1 controls the number of NMDARs at the plasma membrane. Notably, Scribble1 prevents GluN2A subunits from undergoing lysosomal trafficking and degradation by increasing their recycling to the plasma membrane following NMDAR activation. Finally, we show that a specific YxxR motif on Scribble1 controls these mechanisms through a direct interaction with AP2. Altogether, our findings define a molecular mechanism to control the levels of synaptic NMDARs via Scribble1 complex signaling.
authors.affiliation: Physiopathologie de la Plasticité Neuronale, Neurocentre Magendie, INSERM, U862, 33000 Bordeaux, France; Neurocentre Magendie, University of Bordeaux, U862, 33000 Bordeaux, France.
authors.forename: Nicolas H
authors.initials: NH
authors.lastname: Piguel
authors.affiliation: Institut Interdisciplinaire de Neurosciences, University of Bordeaux, UMR 5297, 33000 Bordeaux, France; Institut Interdisciplinaire de Neurosciences, CNRS, UMR 5297, 33000 Bordeaux, France.
authors.forename: Sabine
authors.initials: S
authors.lastname: Fievre
authors.affiliation: Physiopathologie de la Plasticité Neuronale, Neurocentre Magendie, INSERM, U862, 33000 Bordeaux, France; Architecture et Fonction des Macromolecules Biologiques, UMR 7257, Campus de Luminy, CNRS/Aix-Marseille Universite, 13288 Marseille, France; BioXtal Structural Biology Unit, Campus de Luminy, 13288 Marseille, France.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Blanc
authors.affiliation: Institut Interdisciplinaire de Neurosciences, University of Bordeaux, UMR 5297, 33000 Bordeaux, France; Institut Interdisciplinaire de Neurosciences, CNRS, UMR 5297, 33000 Bordeaux, France.
authors.forename: Mario
authors.initials: M
authors.lastname: Carta
authors.affiliation: Physiopathologie de la Plasticité Neuronale, Neurocentre Magendie, INSERM, U862, 33000 Bordeaux, France; Neurocentre Magendie, University of Bordeaux, U862, 33000 Bordeaux, France.
authors.forename: Maïté M
authors.initials: MM
authors.lastname: Moreau
authors.affiliation: UMR-5203, Institut de Génomique Fonctionnelle, CNRS, 34000 Montpellier, France; INSERM, U661, 34000 Montpellier, France; Universités de Montpellier 1 and 2, UMR 5203, 34000 Montpellier, France.
authors.forename: Enora
authors.initials: E
authors.lastname: Moutin
authors.affiliation: Physiopathologie de la Plasticité Neuronale, Neurocentre Magendie, INSERM, U862, 33000 Bordeaux, France; Neurocentre Magendie, University of Bordeaux, U862, 33000 Bordeaux, France.
authors.forename: Vera L
authors.initials: VL
authors.lastname: Pinheiro
authors.affiliation: Physiopathologie de la Plasticité Neuronale, Neurocentre Magendie, INSERM, U862, 33000 Bordeaux, France; Neurocentre Magendie, University of Bordeaux, U862, 33000 Bordeaux, France.
authors.forename: Chantal
authors.initials: C
authors.lastname: Medina
authors.affiliation: Physiopathologie de la Plasticité Neuronale, Neurocentre Magendie, INSERM, U862, 33000 Bordeaux, France; Neurocentre Magendie, University of Bordeaux, U862, 33000 Bordeaux, France.
authors.forename: Jerome
authors.initials: J
authors.lastname: Ezan
authors.affiliation: Physiopathologie de la Plasticité Neuronale, Neurocentre Magendie, INSERM, U862, 33000 Bordeaux, France; Neurocentre Magendie, University of Bordeaux, U862, 33000 Bordeaux, France.
authors.forename: Léa
authors.initials: L
authors.lastname: Lasvaux
authors.affiliation: Physiopathologie de la Plasticité Neuronale, Neurocentre Magendie, INSERM, U862, 33000 Bordeaux, France; Neurocentre Magendie, University of Bordeaux, U862, 33000 Bordeaux, France.
authors.forename: François
authors.initials: F
authors.lastname: Loll
authors.affiliation: Physiopathologie de la Plasticité Neuronale, Neurocentre Magendie, INSERM, U862, 33000 Bordeaux, France; Neurocentre Magendie, University of Bordeaux, U862, 33000 Bordeaux, France.
authors.forename: Christelle M
authors.initials: CM
authors.lastname: Durand
authors.affiliation: Laboratory of Neurochemistry, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Chang
authors.affiliation: Laboratory of Neurochemistry, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD 20892, USA; Advanced Imaging Core of NIDCD, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Ronald S
authors.initials: RS
authors.lastname: Petralia
authors.affiliation: Laboratory of Neurochemistry, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Wenthold
authors.affiliation: University College London School of Pharmacy, London WC1N 1AX, UK.
authors.forename: F Anne
authors.initials: FA
authors.lastname: Stephenson
authors.affiliation: BioXtal Structural Biology Unit, Campus de Luminy, 13288 Marseille, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Vuillard
authors.affiliation: Architecture et Fonction des Macromolecules Biologiques, UMR 7257, Campus de Luminy, CNRS/Aix-Marseille Universite, 13288 Marseille, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Darbon
authors.affiliation: UMR-5203, Institut de Génomique Fonctionnelle, CNRS, 34000 Montpellier, France; INSERM, U661, 34000 Montpellier, France; Universités de Montpellier 1 and 2, UMR 5203, 34000 Montpellier, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Perroy
authors.affiliation: Institut Interdisciplinaire de Neurosciences, University of Bordeaux, UMR 5297, 33000 Bordeaux, France; Institut Interdisciplinaire de Neurosciences, CNRS, UMR 5297, 33000 Bordeaux, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Mulle
authors.affiliation: Physiopathologie de la Plasticité Neuronale, Neurocentre Magendie, INSERM, U862, 33000 Bordeaux, France; Neurocentre Magendie, University of Bordeaux, U862, 33000 Bordeaux, France.
authors.forename: Mireille
authors.initials: M
authors.lastname: Montcouquiol
authors.affiliation: Institute of Neuroscience, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
authors.forename: Claudia
authors.initials: C
authors.lastname: Racca
authors.affiliation: Physiopathologie de la Plasticité Neuronale, Neurocentre Magendie, INSERM, U862, 33000 Bordeaux, France; Neurocentre Magendie, University of Bordeaux, U862, 33000 Bordeaux, France. Electronic address: nathalie.sans@inserm.fr.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Sans
mesh_terms: D033962:Adaptor Protein Complex 2 / Q000378:metabolism*; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002478:Cells, Cultured; D011992:Endosomes / Q000378:metabolism*; D008969:Molecular Sequence Data; D009474:Neurons / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport; D059748:Proteolysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000378:metabolism*
chemical_list: D033962:Adaptor Protein Complex 2; D016194:Receptors, N-Methyl-D-Aspartate; D025521:Tumor Suppressor Proteins; C548802:scribble protein, rat