Regulation of Phosphorylated State of NMDA Receptor by STEP<sub>61</sub> 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...
| Main Authors: | , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-10-01
|
| Series: | Antioxidants |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2076-3921/10/10/1575 |
| _version_ | 1797515400828682240 |
|---|---|
| author | Francisco J. Carvajal Waldo Cerpa |
| author_facet | Francisco J. Carvajal Waldo Cerpa |
| author_sort | Francisco J. Carvajal |
| collection | DOAJ |
| 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<sub>61</sub> (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<sup>+/−</sup> mice such a model. We performed TBI protocol using a controlled frontal impact device using C57BL/6 mice and SOD2<sup>+/−</sup> 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<sub>61</sub> activity. These changes are reduced partially with the STEP<sub>61</sub>-inhibitor TC-2153 treatment in mice subjected to TBI protocol. This study contributes with evidence about the role of STEP<sub>61</sub> in the neuropathological progression after TBI and also the alteration in their activity, such as an early biomarker of synaptic damage in traumatic lesions. |
| first_indexed | 2024-03-10T06:44:58Z |
| format | Article |
| id | doaj.art-0addc3198f694c5a9e2a6491d13f21ff |
| institution | Directory Open Access Journal |
| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-03-10T06:44:58Z |
| publishDate | 2021-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antioxidants |
| spelling | doaj.art-0addc3198f694c5a9e2a6491d13f21ff2023-11-22T17:16:06ZengMDPI AGAntioxidants2076-39212021-10-011010157510.3390/antiox10101575Regulation of Phosphorylated State of NMDA Receptor by STEP<sub>61</sub> Phosphatase after Mild-Traumatic Brain Injury: Role of Oxidative StressFrancisco J. Carvajal0Waldo Cerpa1Laboratorio de Función y Patología Neuronal, Centro de Envejecimiento y Regeneración (CARE), Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 8331150, ChileLaboratorio de Función y Patología Neuronal, Centro de Envejecimiento y Regeneración (CARE), Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 8331150, ChileTraumatic 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<sub>61</sub> (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<sup>+/−</sup> mice such a model. We performed TBI protocol using a controlled frontal impact device using C57BL/6 mice and SOD2<sup>+/−</sup> 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<sub>61</sub> activity. These changes are reduced partially with the STEP<sub>61</sub>-inhibitor TC-2153 treatment in mice subjected to TBI protocol. This study contributes with evidence about the role of STEP<sub>61</sub> in the neuropathological progression after TBI and also the alteration in their activity, such as an early biomarker of synaptic damage in traumatic lesions.https://www.mdpi.com/2076-3921/10/10/1575mild traumatic brain injurySTEP<sub>61</sub>SOD2<sup>+/−</sup> miceoxidative stresssynaptic transmissionhippocampus |
| spellingShingle | Francisco J. Carvajal Waldo Cerpa Regulation of Phosphorylated State of NMDA Receptor by STEP<sub>61</sub> Phosphatase after Mild-Traumatic Brain Injury: Role of Oxidative Stress Antioxidants mild traumatic brain injury STEP<sub>61</sub> SOD2<sup>+/−</sup> mice oxidative stress synaptic transmission hippocampus |
| title | Regulation of Phosphorylated State of NMDA Receptor by STEP<sub>61</sub> Phosphatase after Mild-Traumatic Brain Injury: Role of Oxidative Stress |
| title_full | Regulation of Phosphorylated State of NMDA Receptor by STEP<sub>61</sub> Phosphatase after Mild-Traumatic Brain Injury: Role of Oxidative Stress |
| title_fullStr | Regulation of Phosphorylated State of NMDA Receptor by STEP<sub>61</sub> Phosphatase after Mild-Traumatic Brain Injury: Role of Oxidative Stress |
| title_full_unstemmed | Regulation of Phosphorylated State of NMDA Receptor by STEP<sub>61</sub> Phosphatase after Mild-Traumatic Brain Injury: Role of Oxidative Stress |
| title_short | Regulation of Phosphorylated State of NMDA Receptor by STEP<sub>61</sub> Phosphatase after Mild-Traumatic Brain Injury: Role of Oxidative Stress |
| title_sort | regulation of phosphorylated state of nmda receptor by step sub 61 sub phosphatase after mild traumatic brain injury role of oxidative stress |
| topic | mild traumatic brain injury STEP<sub>61</sub> SOD2<sup>+/−</sup> mice oxidative stress synaptic transmission hippocampus |
| url | https://www.mdpi.com/2076-3921/10/10/1575 |
| work_keys_str_mv | AT franciscojcarvajal regulationofphosphorylatedstateofnmdareceptorbystepsub61subphosphataseaftermildtraumaticbraininjuryroleofoxidativestress AT waldocerpa regulationofphosphorylatedstateofnmdareceptorbystepsub61subphosphataseaftermildtraumaticbraininjuryroleofoxidativestress |