Journal Article

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

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

2013

Overview

Background N-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. Results Here 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. Conclusions These 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.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V
• Subject: Alzheimer's disease / Analysis / Animals / Apoptosis / Aspartate / Biomedical and Life Sciences / Biomedicine / Brain - drug effects / Brain - metabolism / Brain research / Calcium - metabolism / Carrier Proteins - metabolism / Cell adhesion & migration / Cell Death - drug effects / Cell Membrane - drug effects / Cell Membrane - metabolism / Cytoprotection - drug effects / Excitatory Amino Acid Transporter 1 - deficiency / Excitatory Amino Acid Transporter 1 - metabolism / Experiments / Glaucoma / Glutamate / Glutamates - toxicity / HEK293 Cells / Humans / Intracellular Space - drug effects / Intracellular Space - metabolism / Mice / N-Methylaspartate - toxicity / Nerve Tissue Proteins - metabolism / Nervous system diseases / Neurology / Neurons / Neurons - drug effects / Neurons - metabolism / Neurons - pathology / Neurosciences / Neurotoxins - toxicity / Protein Binding - drug effects / Protein Subunits - metabolism / Protein Transport - drug effects / Proteins / Psychopharmacology / Ratios / Receptors, N-Methyl-D-Aspartate - metabolism / Retina - drug effects / Retina - metabolism / Retinal Ganglion Cells - drug effects / Retinal Ganglion Cells - metabolism / Retinal Ganglion Cells - pathology / Rodents / Schizophrenia / Science / Software / Studies