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, Fabrizio Gardoni
Nat Commun. 2015-12-01; 6(1):
DOI: 10.1038/ncomms10181

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Stanic J(1), Carta M(2), Eberini I(1), Pelucchi S(1), Marcello E(1), Genazzani AA(3), Racca C(4), Mulle C(2), Di Luca M(1), Gardoni F(1).

Author information:
(1)DiSFeB, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Via Balzaretti 9, Milano 20133, Italy.
(2)Institut Interdisciplinaire de Neurosciences, University of Bordeaux, CNRS UMR 5297, Bordeaux 33000, France.
(3)Dipartimento di Scienze del Farmaco, Università degli Studi del Piemonte Orientale ‘Amedeo Avogadro’, Novara 28100, Italy.
(4)Institute of Neuroscience, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.

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


Auteurs Bordeaux Neurocampus