Dock3 interaction with a glutamate-receptor NR2D subunit protects neurons from excitotoxicity

Ning Bai,Kohichi Tanaka,Takayuki Harada,Masayoshi Mishina,Tomomi Aida,Kazuhiko Namekata,Hideki Hayashi

doi:10.1186/1756-6606-6-22

Abstract

BackgroundN-methyl-D-aspartate receptors (NMDARs) are critical for neuronal development and synaptic plasticity. Dysregulation of NMDARs is implicated in neuropsychiatric disorders. Native NMDARs are heteromultimeric protein complexes consisting of NR1 and NR2 subunits. NR2 subunits (NR2A–D) are the major determinants of the functional properties of NMDARs. Most research has focused on NR2A- and/or NR2B-containing receptors. A recent study demonstrated that NR2C- and/or NR2D-containing NMDARs are the primary targets of memantine, a drug that is widely prescribed to treat Alzheimer’s disease. Our laboratory demonstrated that memantine prevents the loss of retinal ganglion cells (RGCs) in GLAST glutamate transporter knockout mice, a model of normal tension glaucoma (NTG), suggesting that NR2D-containing receptors may be involved in RGC loss in NTG.ResultsHere we demonstrate that NR2D deficiency attenuates RGC loss in GLAST-deficient mice. Furthermore, Dock3, a guanine nucleotide exchange factor, binds to the NR2D C-terminal domain and reduces the surface expression of NR2D, thereby protecting RGCs from excitotoxicity.ConclusionsThese results suggest that NR2D is involved in the degeneration of RGCs induced by excitotoxicity, and that the interaction between NR2D and Dock3 may have a neuroprotective effect. These findings raise the possibility that NR2D and Dock3 might be potential therapeutic targets for treating neurodegenerative diseases such as Alzheimer’s disease and NTG.

Highlights

N-methyl-D-aspartate receptors (NMDARs) are critical for neuronal development and synaptic plasticity
NR2D deficiency prevents Retinal ganglion cell (RGC) death in glutamate aspartate transporter (GLAST)-deficient mice To determine whether NR2D is involved in RGC degeneration in GLAST-deficient mice, we examined the histopathology of retinas from GLAST−/− and NR2D−/− mice
In GLAST−/− NR2D−/− double-knockout mice, the number of ganglion cell layer (GCL) cells was significantly higher (401 ± 10) than that in GLAST−/− mice, it was still lower than that in WT and NR2D−/− mice. These results suggest that NR2D deficiency protects against the loss of RGCs in GLAST-deficient mice

Summary

Introduction

N-methyl-D-aspartate receptors (NMDARs) are critical for neuronal development and synaptic plasticity. Native NMDARs are heteromultimeric protein complexes consisting of NR1 and NR2 subunits. NR2 subunits (NR2A–D) are the major determinants of the functional properties of NMDARs. Most research has focused on NR2A- and/or NR2B-containing receptors. A recent study demonstrated that NR2C- and/or NR2D-containing NMDARs are the primary targets of memantine, a drug that is widely prescribed to treat Alzheimer’s disease. Native NMDARs are heteromultimeric protein complexes composed of NR1 and NR2 subunits, and in some cases NR3 subunits. NR2 subunits are major determinants of the functional properties of NMDARs, including characteristics such as agonist affinity, deactivation kinetics, single-channel conductance, Ca2+ permeability, and sensitivity to Mg2+. Since NR2A- and NR2B-containing receptors are highly expressed in the cortex, and NR2C- and NR2D-containing receptors have low opening probabilities and low single-channel conductances, most previous research has focused on NR2A- and/or NR2B-containing receptors [8,9,10]

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