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Zinc transporter‐1: a novel NMDA receptor‐binding protein at the postsynaptic density
Author(s) -
Mellone Manuela,
Pelucchi Silvia,
Alberti Lorenzo,
Genazzani Armando A.,
Di Luca Monica,
Gardoni Fabrizio
Publication year - 2015
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.12968
Subject(s) - nmda receptor , postsynaptic potential , glutamatergic , synaptic plasticity , excitatory postsynaptic potential , postsynaptic density , microbiology and biotechnology , glutamate receptor , synaptic cleft , synapse , biology , hippocampal formation , neuroscience , chemistry , excitatory synapse , receptor , biochemistry
Abstract Zinc (Zn 2+ ) is believed to play a relevant role in the physiology and pathophysiology of the brain. Hence, Zn 2+ homeostasis is critical and involves different classes of molecules, including Zn 2+ transporters. The ubiquitous Zn 2+ transporter‐1 ( ZNT ‐1) is a transmembrane protein that pumps cytosolic Zn 2+ to the extracellular space, but its function in the central nervous system is not fully understood. Here, we show that ZNT ‐1 interacts with GluN2A‐containing NMDA receptors, suggesting a role for this transporter at the excitatory glutamatergic synapse. First, we found that ZNT ‐1 is highly expressed at the hippocampal postsynaptic density (PSD) where NMDA receptors are enriched. Two‐hybrid screening, coimmunoprecipitation experiments and clustering assay in COS ‐7 cells demonstrated that ZNT ‐1 specifically binds the GluN2A subunit of the NMDA receptor. GluN2A deletion mutants and pull‐down assays indicated GluN2A(1390–1464) domain as necessary for the binding to ZNT ‐1. Most importantly, ZNT ‐1/GluN2A complex was proved to be dynamic, since it was regulated by induction of synaptic plasticity. Finally, modulation of ZNT ‐1 expression in hippocampal neurons determined a significant change in dendritic spine morphology, PSD ‐95 clusters and GluN2A surface levels, supporting the involvement of ZNT ‐1 in the dynamics of excitatory PSD.Zn 2+ transporter‐1 (ZNT‐1) pumps cytosolic Zn 2+ to the extracellular space, but its function in the central nervous system is not fully understood. We show that ZNT‐1 interacts with GluN2A‐containing NMDA receptors at the glutamatergic synapse. Most importantly, ZNT‐1/GluN2A complex is regulated by induction of synaptic plasticity. Modulation of ZNT‐1 expression in hippocampal neurons determined a shrinkage of dendritic spines and a reduction of GluN2A surface levels supporting the involvement of ZNT‐1 in the dynamics of the excitatory synapse.