Presenilin-1/γ-secretase controls glutamate release, tyrosine phosphorylation, and surface expression of N-methyl-D-aspartate receptor (NMDAR) subunit GluN2B
Journal of Biological Chemistry. 2013-10-01; 288(42): 30495-30501
DOI: 10.1074/jbc.m113.499004
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Xuan Z(1), Barthet G(1), Shioi J(1), Xu J(1), Georgakopoulos A(1), Bruban J(1), Robakis NK(2).
Author information:
(1)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.
(2)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: .
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.