Rabphilin 3A retains NMDA receptors at synaptic sites through interaction with GluN2A/PSD-95 complex

Jennifer Stanic, Mario Carta, Ivano Eberini, Silvia Pelucchi, Elena Marcello, Armando A. Genazzani, Claudia Racca, Christophe Mulle, Monica Di Luca () and Fabrizio Gardoni
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Jennifer Stanic: DiSFeB, Università degli Studi di Milano, Via Balzaretti 9
Mario Carta: Institut Interdisciplinaire de Neurosciences, University of Bordeaux
Ivano Eberini: DiSFeB, Università degli Studi di Milano, Via Balzaretti 9
Silvia Pelucchi: DiSFeB, Università degli Studi di Milano, Via Balzaretti 9
Elena Marcello: DiSFeB, Università degli Studi di Milano, Via Balzaretti 9
Armando A. Genazzani: Università degli Studi del Piemonte Orientale ‘Amedeo Avogadro’
Claudia Racca: Institute of Neuroscience, Newcastle University
Christophe Mulle: Institut Interdisciplinaire de Neurosciences, University of Bordeaux
Monica Di Luca: DiSFeB, Università degli Studi di Milano, Via Balzaretti 9
Fabrizio Gardoni: DiSFeB, Università degli Studi di Milano, Via Balzaretti 9

Nature Communications, 2015, vol. 6, issue 1, 1-16

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms10181

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