Zinc (Zn2+) is believed to play a relevant role in the physiology and pathophysiology of the brain. Hence, Zn2+ homeostasis is critical and involves different classes of molecules, including Zn2+ transporters. The ubiquitous Zn2+ transporter-1 (ZNT-1) is a transmembrane protein that pumps cytosolic Zn2+ 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.
Zinc transporter-1: a novel NMDA receptor-binding protein at the postsynaptic density / M. Mellone, S. Pelucchi, L. Alberti, A. Genazzani, M. Di Luca, F. Gardoni. - In: JOURNAL OF NEUROCHEMISTRY. - ISSN 0022-3042. - 132:2(2015), pp. 159-168.
|Titolo:||Zinc transporter-1: a novel NMDA receptor-binding protein at the postsynaptic density|
MELLONE, MANUELA (Primo)
PELUCCHI, SILVIA CECILIA (Secondo)
GARDONI, FABRIZIO (Corresponding)
|Parole Chiave:||dendritic spine; NMDA receptor; postsynaptic density; protein-protein interaction; ZNT-1|
|Settore Scientifico Disciplinare:||Settore BIO/14 - Farmacologia|
|Progetto:||Discinesia indotta dalla L-DOPA nella malattia di Parkinson: nuovi meccanismi e targets molecolari.|
|Data di pubblicazione:||2015|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1111/jnc.12968|
|Appare nelle tipologie:||01 - Articolo su periodico|