Scribble1/AP2 complex coordinates NMDA receptor endocytic recycling.

Nicolas H. Piguel, Sabine Fievre, Jean-Michel Blanc, Mario Carta, Maïté M. Moreau, Enora Moutin, Vera L. Pinheiro, Chantal Medina, Jerome Ezan, Léa Lasvaux, François Loll, Christelle M. Durand, Kai Chang, Ronald S. Petralia, Robert J. Wenthold, F. Anne Stephenson, Laurent Vuillard, Hervé Darbon, Julie Perroy, Christophe Mulle, Mireille Montcouquiol, Claudia Racca, Nathalie Sans
Cell Reports. 2014-10-01; 9(2): 712-727
DOI: 10.1016/j.celrep.2014.09.017

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Piguel NH(1), Fievre S(2), Blanc JM(3), Carta M(2), Moreau MM(1), Moutin E(4), Pinheiro VL(1), Medina C(1), Ezan J(1), Lasvaux L(1), Loll F(1), Durand CM(1), Chang K(5), Petralia RS(6), Wenthold RJ(5), Stephenson FA(7), Vuillard L(8), Darbon H(9), Perroy J(4), Mulle C(2), Montcouquiol M(1), Racca C(10), Sans N(11).

Author information:
(1)Physiopathologie de la Plasticité Neuronale, Neurocentre Magendie, INSERM, U862, 33000 Bordeaux, France; Neurocentre Magendie, University of Bordeaux, U862, 33000 Bordeaux, France.
(2)Institut Interdisciplinaire de Neurosciences, University of Bordeaux, UMR 5297, 33000 Bordeaux, France; Institut Interdisciplinaire de Neurosciences, CNRS, UMR 5297, 33000 Bordeaux, France.
(3)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.
(4)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.
(5)Laboratory of Neurochemistry, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD 20892, USA.
(6)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.
(7)University College London School of Pharmacy, London WC1N 1AX, UK.
(8)BioXtal Structural Biology Unit, Campus de Luminy, 13288 Marseille, France.
(9)Architecture et Fonction des Macromolecules Biologiques, UMR 7257, Campus de Luminy, CNRS/Aix-Marseille Universite, 13288 Marseille, France.
(10)Institute of Neuroscience, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
(11)Physiopathologie de la Plasticité Neuronale, Neurocentre Magendie, INSERM, U862, 33000 Bordeaux, France; Neurocentre Magendie, University of Bordeaux, U862, 33000 Bordeaux, France. Electronic address: .

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.

Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

 


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