Selective regulation of NR2B by protein phosphatase-1 for the control of the NMDA receptor in neuroprotection.
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 Ca(2+) signaling, the underlying mechanisms remain undefined. We identified the protein...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2012-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3316588?pdf=render |
| _version_ | 1819037911017848832 |
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| author | Mélissa Farinelli Fabrice D Heitz Benjamin F Grewe Shiva K Tyagarajan Fritjof Helmchen Isabelle M Mansuy |
| author_facet | Mélissa Farinelli Fabrice D Heitz Benjamin F Grewe Shiva K Tyagarajan Fritjof Helmchen Isabelle M Mansuy |
| author_sort | Mélissa Farinelli |
| collection | DOAJ |
| description | 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 Ca(2+) 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 Ca(2+) overload during an excitotoxic event, while PP1 inhibition favors Ca(2+) 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. |
| first_indexed | 2024-12-21T08:28:56Z |
| format | Article |
| id | doaj.art-b1cf6a2140a14f388931394cd7d4dd31 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-21T08:28:56Z |
| publishDate | 2012-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-b1cf6a2140a14f388931394cd7d4dd312022-12-21T19:10:15ZengPublic Library of Science (PLoS)PLoS ONE1932-62032012-01-0173e3404710.1371/journal.pone.0034047Selective regulation of NR2B by protein phosphatase-1 for the control of the NMDA receptor in neuroprotection.Mélissa FarinelliFabrice D HeitzBenjamin F GreweShiva K TyagarajanFritjof HelmchenIsabelle M MansuyAn 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 Ca(2+) 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 Ca(2+) overload during an excitotoxic event, while PP1 inhibition favors Ca(2+) 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.http://europepmc.org/articles/PMC3316588?pdf=render |
| spellingShingle | Mélissa Farinelli Fabrice D Heitz Benjamin F Grewe Shiva K Tyagarajan Fritjof Helmchen Isabelle M Mansuy Selective regulation of NR2B by protein phosphatase-1 for the control of the NMDA receptor in neuroprotection. PLoS ONE |
| title | Selective regulation of NR2B by protein phosphatase-1 for the control of the NMDA receptor in neuroprotection. |
| title_full | Selective regulation of NR2B by protein phosphatase-1 for the control of the NMDA receptor in neuroprotection. |
| title_fullStr | Selective regulation of NR2B by protein phosphatase-1 for the control of the NMDA receptor in neuroprotection. |
| title_full_unstemmed | Selective regulation of NR2B by protein phosphatase-1 for the control of the NMDA receptor in neuroprotection. |
| title_short | Selective regulation of NR2B by protein phosphatase-1 for the control of the NMDA receptor in neuroprotection. |
| title_sort | selective regulation of nr2b by protein phosphatase 1 for the control of the nmda receptor in neuroprotection |
| url | http://europepmc.org/articles/PMC3316588?pdf=render |
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