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Regulation of Phosphorylated State of NMDA Receptor by STEP(61) Phosphatase after Mild-Traumatic Brain Injury: Role of Oxidative Stress

Traumatic Brain Injury (TBI) mediates neuronal death through several events involving many molecular pathways, including the glutamate-mediated excitotoxicity for excessive stimulation of N-methyl-D-aspartate receptors (NMDARs), producing activation of death signaling pathways. However, the contribu...

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Autores principales: Carvajal, Francisco J., Cerpa, Waldo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8533270/
https://www.ncbi.nlm.nih.gov/pubmed/34679709
http://dx.doi.org/10.3390/antiox10101575
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author Carvajal, Francisco J.
Cerpa, Waldo
author_facet Carvajal, Francisco J.
Cerpa, Waldo
author_sort Carvajal, Francisco J.
collection PubMed
description Traumatic Brain Injury (TBI) mediates neuronal death through several events involving many molecular pathways, including the glutamate-mediated excitotoxicity for excessive stimulation of N-methyl-D-aspartate receptors (NMDARs), producing activation of death signaling pathways. However, the contribution of NMDARs (distribution and signaling-associated to the distribution) remains incompletely understood. We propose a critical role of STEP(61) (Striatal-Enriched protein tyrosine phosphatase) in TBI; this phosphatase regulates the dephosphorylated state of the GluN2B subunit through two pathways: by direct dephosphorylation of tyrosine-1472 and indirectly via dephosphorylation and inactivation of Fyn kinase. We previously demonstrated oxidative stress’s contribution to NMDAR signaling and distribution using SOD2(+/−) mice such a model. We performed TBI protocol using a controlled frontal impact device using C57BL/6 mice and SOD2(+/−) animals. After TBI, we found alterations in cognitive performance, NMDAR-dependent synaptic function (decreased synaptic form of NMDARs and decreased synaptic current NMDAR-dependent), and increased STEP(61) activity. These changes are reduced partially with the STEP(61)-inhibitor TC-2153 treatment in mice subjected to TBI protocol. This study contributes with evidence about the role of STEP(61) in the neuropathological progression after TBI and also the alteration in their activity, such as an early biomarker of synaptic damage in traumatic lesions.
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spelling pubmed-85332702021-10-23 Regulation of Phosphorylated State of NMDA Receptor by STEP(61) Phosphatase after Mild-Traumatic Brain Injury: Role of Oxidative Stress Carvajal, Francisco J. Cerpa, Waldo Antioxidants (Basel) Article Traumatic Brain Injury (TBI) mediates neuronal death through several events involving many molecular pathways, including the glutamate-mediated excitotoxicity for excessive stimulation of N-methyl-D-aspartate receptors (NMDARs), producing activation of death signaling pathways. However, the contribution of NMDARs (distribution and signaling-associated to the distribution) remains incompletely understood. We propose a critical role of STEP(61) (Striatal-Enriched protein tyrosine phosphatase) in TBI; this phosphatase regulates the dephosphorylated state of the GluN2B subunit through two pathways: by direct dephosphorylation of tyrosine-1472 and indirectly via dephosphorylation and inactivation of Fyn kinase. We previously demonstrated oxidative stress’s contribution to NMDAR signaling and distribution using SOD2(+/−) mice such a model. We performed TBI protocol using a controlled frontal impact device using C57BL/6 mice and SOD2(+/−) animals. After TBI, we found alterations in cognitive performance, NMDAR-dependent synaptic function (decreased synaptic form of NMDARs and decreased synaptic current NMDAR-dependent), and increased STEP(61) activity. These changes are reduced partially with the STEP(61)-inhibitor TC-2153 treatment in mice subjected to TBI protocol. This study contributes with evidence about the role of STEP(61) in the neuropathological progression after TBI and also the alteration in their activity, such as an early biomarker of synaptic damage in traumatic lesions. MDPI 2021-10-05 /pmc/articles/PMC8533270/ /pubmed/34679709 http://dx.doi.org/10.3390/antiox10101575 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Carvajal, Francisco J.
Cerpa, Waldo
Regulation of Phosphorylated State of NMDA Receptor by STEP(61) Phosphatase after Mild-Traumatic Brain Injury: Role of Oxidative Stress
title Regulation of Phosphorylated State of NMDA Receptor by STEP(61) Phosphatase after Mild-Traumatic Brain Injury: Role of Oxidative Stress
title_full Regulation of Phosphorylated State of NMDA Receptor by STEP(61) Phosphatase after Mild-Traumatic Brain Injury: Role of Oxidative Stress
title_fullStr Regulation of Phosphorylated State of NMDA Receptor by STEP(61) Phosphatase after Mild-Traumatic Brain Injury: Role of Oxidative Stress
title_full_unstemmed Regulation of Phosphorylated State of NMDA Receptor by STEP(61) Phosphatase after Mild-Traumatic Brain Injury: Role of Oxidative Stress
title_short Regulation of Phosphorylated State of NMDA Receptor by STEP(61) Phosphatase after Mild-Traumatic Brain Injury: Role of Oxidative Stress
title_sort regulation of phosphorylated state of nmda receptor by step(61) phosphatase after mild-traumatic brain injury: role of oxidative stress
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8533270/
https://www.ncbi.nlm.nih.gov/pubmed/34679709
http://dx.doi.org/10.3390/antiox10101575
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