title: Dock3 interaction with a glutamate-receptor NR2D subunit protects neurons from excitotoxicity.
abstract: 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.
authors: Laboratory of Molecular Neuroscience, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
authors: Ning
authors: N
authors: Bai
authors: Hideki
authors: H
authors: Hayashi
authors: Tomomi
authors: T
authors: Aida
authors: Kazuhiko
authors: K
authors: Namekata
authors: Takayuki
authors: T
authors: Harada
authors: Masayoshi
authors: M
authors: Mishina
authors: Kohichi
authors: K
authors: Tanaka
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D019610:Cytoprotection / Q000187:drug effects*; D027341:Excitatory Amino Acid Transporter 1 / Q000172:deficiency / Q000378:metabolism; D005971:Glutamates / Q000633:toxicity; D020662:Guanine Nucleotide Exchange Factors; D057809:HEK293 Cells; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D016202:N-Methylaspartate / Q000633:toxicity; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D009498:Neurotoxins / Q000633:toxicity*; D011485:Protein Binding / Q000187:drug effects; D021122:Protein Subunits / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D012160:Retina / Q000187:drug effects / Q000378:metabolism; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
chemical_list: D002352:Carrier Proteins; C410623:Dock3 protein, mouse; D027341:Excitatory Amino Acid Transporter 1; D005971:Glutamates; D020662:Guanine Nucleotide Exchange Factors; C464436:NR2D NMDA receptor; D009419:Nerve Tissue Proteins; D009498:Neurotoxins; D021122:Protein Subunits; D016194:Receptors, N-Methyl-D-Aspartate; C493393:Slc1a3 protein, mouse; D016202:N-Methylaspartate; D002118:Calcium
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