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Phosphoinositide 3-kinase couples NMDA receptors to superoxide release in excitotoxic neuronal death
Sustained activation of neuronal N-methly D-aspartate (NMDA)-type glutamate receptors leads to excitotoxic cell death in stroke, trauma, and neurodegenerative disorders. Excitotoxic neuronal death results in part from superoxide produced by neuronal NADPH oxidase (NOX2), but how NMDA receptors are c...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3641334/ https://www.ncbi.nlm.nih.gov/pubmed/23559014 http://dx.doi.org/10.1038/cddis.2013.111 |
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author | Brennan-Minnella, A M Shen, Y Swanson, R A |
author_facet | Brennan-Minnella, A M Shen, Y Swanson, R A |
author_sort | Brennan-Minnella, A M |
collection | PubMed |
description | Sustained activation of neuronal N-methly D-aspartate (NMDA)-type glutamate receptors leads to excitotoxic cell death in stroke, trauma, and neurodegenerative disorders. Excitotoxic neuronal death results in part from superoxide produced by neuronal NADPH oxidase (NOX2), but how NMDA receptors are coupled to neuronal NOX2 activation is not well understood. Here, we identify a signaling pathway coupling NMDA receptor activation to NOX2 activation in primary neuron cultures. Calcium influx through the NR2B subunit of NMDA receptors leads to the activation of phosphoinositide 3-kinase (PI3K). Formation of phosphatidylinositol (3,4,5)-triphosphate (PI(3,4,5)P3) by PI3K activates the atypical protein kinase C, PKC zeta (PKCζ), which in turn phosphorylates the p47(phox) organizing subunit of neuronal NOX2. Calcium influx through NR2B-containing NMDA receptors triggered mitochondrial depolarization, NOX2 activation, superoxide formation, and cell death. However, equivalent magnitude calcium elevations induced by ionomycin did not induce NOX2 activation or neuronal death, despite causing mitochondrial depolarization. The PI3K inhibitor wortmannin prevented NMDA-induced NOX2 activation and cell death, without preventing cell swelling, calcium elevation, or mitochondrial depolarization. The effects of wortmannin were circumvented by exogenous supply of the PI3K product, PI(3,4,5)P3, and by transfection with protein kinase M, a constitutively active form of PKCζ. These findings demonstrate that superoxide formation and excitotoxic neuronal death can be dissociated from mitochondrial depolarization, and identify a novel role for PI3K in this cell death pathway. Perturbations in this pathway may either increase or decrease superoxide production in response to NMDA receptor activation, and may thereby impact neurological disorders, in which excitotoxicity is a contributing factor. |
format | Online Article Text |
id | pubmed-3641334 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-36413342013-05-02 Phosphoinositide 3-kinase couples NMDA receptors to superoxide release in excitotoxic neuronal death Brennan-Minnella, A M Shen, Y Swanson, R A Cell Death Dis Original Article Sustained activation of neuronal N-methly D-aspartate (NMDA)-type glutamate receptors leads to excitotoxic cell death in stroke, trauma, and neurodegenerative disorders. Excitotoxic neuronal death results in part from superoxide produced by neuronal NADPH oxidase (NOX2), but how NMDA receptors are coupled to neuronal NOX2 activation is not well understood. Here, we identify a signaling pathway coupling NMDA receptor activation to NOX2 activation in primary neuron cultures. Calcium influx through the NR2B subunit of NMDA receptors leads to the activation of phosphoinositide 3-kinase (PI3K). Formation of phosphatidylinositol (3,4,5)-triphosphate (PI(3,4,5)P3) by PI3K activates the atypical protein kinase C, PKC zeta (PKCζ), which in turn phosphorylates the p47(phox) organizing subunit of neuronal NOX2. Calcium influx through NR2B-containing NMDA receptors triggered mitochondrial depolarization, NOX2 activation, superoxide formation, and cell death. However, equivalent magnitude calcium elevations induced by ionomycin did not induce NOX2 activation or neuronal death, despite causing mitochondrial depolarization. The PI3K inhibitor wortmannin prevented NMDA-induced NOX2 activation and cell death, without preventing cell swelling, calcium elevation, or mitochondrial depolarization. The effects of wortmannin were circumvented by exogenous supply of the PI3K product, PI(3,4,5)P3, and by transfection with protein kinase M, a constitutively active form of PKCζ. These findings demonstrate that superoxide formation and excitotoxic neuronal death can be dissociated from mitochondrial depolarization, and identify a novel role for PI3K in this cell death pathway. Perturbations in this pathway may either increase or decrease superoxide production in response to NMDA receptor activation, and may thereby impact neurological disorders, in which excitotoxicity is a contributing factor. Nature Publishing Group 2013-04 2013-04-04 /pmc/articles/PMC3641334/ /pubmed/23559014 http://dx.doi.org/10.1038/cddis.2013.111 Text en Copyright © 2013 Macmillan Publishers Limited http://creativecommons.org/licenses/by-nc-nd/3.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/ |
spellingShingle | Original Article Brennan-Minnella, A M Shen, Y Swanson, R A Phosphoinositide 3-kinase couples NMDA receptors to superoxide release in excitotoxic neuronal death |
title | Phosphoinositide 3-kinase couples NMDA receptors to superoxide release in excitotoxic neuronal death |
title_full | Phosphoinositide 3-kinase couples NMDA receptors to superoxide release in excitotoxic neuronal death |
title_fullStr | Phosphoinositide 3-kinase couples NMDA receptors to superoxide release in excitotoxic neuronal death |
title_full_unstemmed | Phosphoinositide 3-kinase couples NMDA receptors to superoxide release in excitotoxic neuronal death |
title_short | Phosphoinositide 3-kinase couples NMDA receptors to superoxide release in excitotoxic neuronal death |
title_sort | phosphoinositide 3-kinase couples nmda receptors to superoxide release in excitotoxic neuronal death |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3641334/ https://www.ncbi.nlm.nih.gov/pubmed/23559014 http://dx.doi.org/10.1038/cddis.2013.111 |
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