title: Presenilin-1/γ-secretase controls glutamate release, tyrosine phosphorylation, and surface expression of N-methyl-D-aspartate receptor (NMDAR) subunit GluN2B.
abstract: Abnormally high concentrations of extracellular glutamate in the brain may cause neuronal damage via excitotoxicity. Thus, tight regulation of glutamate release is critical to neuronal function and survival. Excitotoxicity is caused mainly by overactivation of the extrasynaptic NMDA receptor (NMDAR) and results in specific cellular changes, including calcium-induced activation of calpain proteases. Here, we report that presenilin-1 (PS1) null mouse cortical neuronal cultures have increased amounts of calpain-dependent spectrin breakdown products (SBDPs) compared with WT cultures. NMDAR antagonists blocked accumulation of SBDPs, suggesting abnormal activation of this receptor in PS1 null cultures. Importantly, an increase in SBDPs was detected in cultures of at least 7 days in vitro but not in younger cultures. Conditioned medium from PS1 null neuronal cultures at 8 days in vitro contained higher levels of glutamate than medium from WT cultures and stimulated production of SBDPs when added to WT cultures. Use of glutamate reuptake inhibitors indicated that accumulation of this neurotransmitter in the media of PS1 null cultures was due to increased rates of release. PS1 null neurons showed decreased cell surface expression and phosphorylation of the GluN2B subunit of NMDAR, indicating decreased amounts of extrasynaptic NMDAR in the absence of PS1. Inhibition of γ-secretase activity in WT neurons caused changes similar to those observed in PS1 null neurons. Together, these data indicate that the PS1/γ-secretase system regulates release of glutamate, tyrosine phosphorylation, and surface expression of GluN2B-containing NMDARs.
authors.affiliation: From the Center for Molecular Biology and Genetics of Neurodegeneration, Departments of Psychiatry and Neuroscience, Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
authors.forename: Zhao
authors.initials: Z
authors.lastname: Xuan
authors.affiliation: From the Center for Molecular Biology and Genetics of Neurodegeneration, Departments of Psychiatry and Neuroscience, Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
authors.forename: Gael
authors.initials: G
authors.lastname: Barthet
authors.affiliation: From the Center for Molecular Biology and Genetics of Neurodegeneration, Departments of Psychiatry and Neuroscience, Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
authors.forename: Junichi
authors.initials: J
authors.lastname: Shioi
authors.affiliation: From the Center for Molecular Biology and Genetics of Neurodegeneration, Departments of Psychiatry and Neuroscience, Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
authors.forename: Jindong
authors.initials: J
authors.lastname: Xu
authors.affiliation: From the Center for Molecular Biology and Genetics of Neurodegeneration, Departments of Psychiatry and Neuroscience, Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
authors.forename: Anastasios
authors.initials: A
authors.lastname: Georgakopoulos
authors.affiliation: From the Center for Molecular Biology and Genetics of Neurodegeneration, Departments of Psychiatry and Neuroscience, Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
authors.forename: Julien
authors.initials: J
authors.lastname: Bruban
authors.affiliation: From the Center for Molecular Biology and Genetics of Neurodegeneration, Departments of Psychiatry and Neuroscience, Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029. Electronic address: nikos.robakis@mssm.edu.
authors.forename: Nikolaos K
authors.initials: NK
authors.lastname: Robakis
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000096:biosynthesis* / Q000235:genetics; D013049:Spectrin / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014443:Tyrosine / Q000235:genetics / Q000378:metabolism
chemical_list: C121001:NR2B NMDA receptor; D009419:Nerve Tissue Proteins; D053764:Presenilin-1; D016194:Receptors, N-Methyl-D-Aspartate; D013049:Spectrin; D014443:Tyrosine; D053829:Amyloid Precursor Protein Secretases
keywords: Calpain; Glutamate; Glutamate Receptor Ionotropic (AMPA, NMDA); Presenilin; Secretases
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