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Scaffolding protein Homer1a protects against NMDA-induced neuronal injury

Excessive N-methyl-D-aspartate receptor (NMDAR) activation and the resulting activation of neuronal nitric oxide synthase (nNOS) cause neuronal injury. Homer1b/c facilitates NMDAR-PSD95-nNOS complex interactions, and Homer1a is a negative competitor of Homer1b/c. We report that Homer1a was both upre...

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Autores principales: Wang, Y, Rao, W, Zhang, C, Liu, M-d, Han, F, Yao, L-b, Han, H, Luo, P, Su, N, Fei, Z
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4558508/
https://www.ncbi.nlm.nih.gov/pubmed/26247728
http://dx.doi.org/10.1038/cddis.2015.216
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author Wang, Y
Rao, W
Zhang, C
Zhang, C
Liu, M-d
Han, F
Yao, L-b
Han, H
Luo, P
Su, N
Fei, Z
author_facet Wang, Y
Rao, W
Zhang, C
Zhang, C
Liu, M-d
Han, F
Yao, L-b
Han, H
Luo, P
Su, N
Fei, Z
author_sort Wang, Y
collection PubMed
description Excessive N-methyl-D-aspartate receptor (NMDAR) activation and the resulting activation of neuronal nitric oxide synthase (nNOS) cause neuronal injury. Homer1b/c facilitates NMDAR-PSD95-nNOS complex interactions, and Homer1a is a negative competitor of Homer1b/c. We report that Homer1a was both upregulated by and protected against NMDA-induced neuronal injury in vitro and in vivo. The neuroprotective activity of Homer1a was associated with NMDA-induced Ca(2+) influx, oxidative stress and the resultant downstream signaling activation. Additionally, we found that Homer1a functionally regulated NMDAR channel properties in neurons, but did not regulate recombinant NR1/NR2B receptors in HEK293 cells. Furthermore, we found that Homer1a detached the physical links among NR2B, PSD95 and nNOS and reduced the membrane distribution of NMDAR. NMDA-induced neuronal injury was more severe in Homer1a homozygous knockout mice (KO, Homer1a(−/−)) when compared with NMDA-induced neuronal injury in wild-type mice (WT, Homer1a(+/+)). Additionally, Homer1a overexpression in the cortex of Homer1a(−/−) mice alleviated NMDA-induced neuronal injury. These findings suggest that Homer1a may be a key neuroprotective endogenous molecule that protects against NMDA-induced neuronal injury by disassembling NR2B-PSD95-nNOS complexes and reducing the membrane distribution of NMDARs.
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spelling pubmed-45585082015-09-11 Scaffolding protein Homer1a protects against NMDA-induced neuronal injury Wang, Y Rao, W Zhang, C Zhang, C Liu, M-d Han, F Yao, L-b Han, H Luo, P Su, N Fei, Z Cell Death Dis Original Article Excessive N-methyl-D-aspartate receptor (NMDAR) activation and the resulting activation of neuronal nitric oxide synthase (nNOS) cause neuronal injury. Homer1b/c facilitates NMDAR-PSD95-nNOS complex interactions, and Homer1a is a negative competitor of Homer1b/c. We report that Homer1a was both upregulated by and protected against NMDA-induced neuronal injury in vitro and in vivo. The neuroprotective activity of Homer1a was associated with NMDA-induced Ca(2+) influx, oxidative stress and the resultant downstream signaling activation. Additionally, we found that Homer1a functionally regulated NMDAR channel properties in neurons, but did not regulate recombinant NR1/NR2B receptors in HEK293 cells. Furthermore, we found that Homer1a detached the physical links among NR2B, PSD95 and nNOS and reduced the membrane distribution of NMDAR. NMDA-induced neuronal injury was more severe in Homer1a homozygous knockout mice (KO, Homer1a(−/−)) when compared with NMDA-induced neuronal injury in wild-type mice (WT, Homer1a(+/+)). Additionally, Homer1a overexpression in the cortex of Homer1a(−/−) mice alleviated NMDA-induced neuronal injury. These findings suggest that Homer1a may be a key neuroprotective endogenous molecule that protects against NMDA-induced neuronal injury by disassembling NR2B-PSD95-nNOS complexes and reducing the membrane distribution of NMDARs. Nature Publishing Group 2015-08 2015-08-06 /pmc/articles/PMC4558508/ /pubmed/26247728 http://dx.doi.org/10.1038/cddis.2015.216 Text en Copyright © 2015 Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Original Article
Wang, Y
Rao, W
Zhang, C
Zhang, C
Liu, M-d
Han, F
Yao, L-b
Han, H
Luo, P
Su, N
Fei, Z
Scaffolding protein Homer1a protects against NMDA-induced neuronal injury
title Scaffolding protein Homer1a protects against NMDA-induced neuronal injury
title_full Scaffolding protein Homer1a protects against NMDA-induced neuronal injury
title_fullStr Scaffolding protein Homer1a protects against NMDA-induced neuronal injury
title_full_unstemmed Scaffolding protein Homer1a protects against NMDA-induced neuronal injury
title_short Scaffolding protein Homer1a protects against NMDA-induced neuronal injury
title_sort scaffolding protein homer1a protects against nmda-induced neuronal injury
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4558508/
https://www.ncbi.nlm.nih.gov/pubmed/26247728
http://dx.doi.org/10.1038/cddis.2015.216
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