Selective Regulation of NR2B by Protein Phosphatase-1 for the Control of the NMDA Receptor in Neuroprotection
Heitz, Fabrice D.
Grewe, Benjamin F.
Tyagarajan, Shiva K.
Mansuy, Isabelle M.
- Journal Article
Rights / licenseCreative Commons Attribution 3.0 Unported
An imbalance between pro-survival and pro-death pathways in brain cells can lead to neuronal cell death and neurodegeneration. While such imbalance is known to be associated with alterations in glutamatergic and Ca2+ signaling, the underlying mechanisms remain undefined. We identified the protein Ser/Thr phosphatase protein phosphatase-1 (PP1), an enzyme associated with glutamate receptors, as a key trigger of survival pathways that can prevent neuronal death and neurodegeneration in the adult hippocampus. We show that PP1α overexpression in hippocampal neurons limits NMDA receptor overactivation and Ca2+ overload during an excitotoxic event, while PP1 inhibition favors Ca2+ overload and cell death. The protective effect of PP1 is associated with a selective dephosphorylation on a residue phosphorylated by CaMKIIα on the NMDA receptor subunit NR2B, which promotes pro-survival pathways and associated transcriptional programs. These results reveal a novel contributor to the mechanisms of neuroprotection and underscore the importance of PP1-dependent dephosphorylation in these mechanisms. They provide a new target for the development of potential therapeutic treatment of neurodegeneration. Show more
Journal / seriesPLoS ONE
Pages / Article No.
PublisherPublic Library of Science
Organisational unit03518 - Mansuy, Isabelle / Mansuy, Isabelle
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