Intracellular Ca2+ release through ryanodine receptors contributes to AMPA receptor-mediated mitochondrial dysfunction and ER stress in oligodendrocytes

Overactivation of ionotropic glutamate receptors in oligodendrocytes induces cytosolic Ca2+ overload and excitotoxic death, a process that contributes to demyelination and multiple sclerosis. Excitotoxic insults cause well-characterized mitochondrial alterations and endoplasmic reticulum (ER) dysfun...

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Autores: Ruiz Núñez, Asier, Matute Almau, Carlos José, Alberdi Alfonso, Elena María
Tipo de recurso: artículo
Fecha de publicación:2010
País:España
Institución:Universidad del País Vasco
Repositorio:Addi. Archivo Digital para la Docencia y la Investigación
OAI Identifier:oai:addi.ehu.eus:10810/11886
Acceso en línea:http://hdl.handle.net/10810/11886
Access Level:acceso abierto
Palabra clave:endoplasmic reticulum stress
inositol 1,4,5-triphosphate receptors
calcium signal transmission
kainate receptors
amyloid beta
cell death
apoptosis
protects
neurons
excitotoxicity
Ca2+ release
caspase-12
CELL BIOLOGY
ONCOLOGY
MEDICINE
IMMUNOLOGY AND MICROBIOLOGY
CELLULAR AND MOLECULAR NEUROSCIENCE
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spelling Intracellular Ca2+ release through ryanodine receptors contributes to AMPA receptor-mediated mitochondrial dysfunction and ER stress in oligodendrocytesRuiz Núñez, AsierMatute Almau, Carlos JoséAlberdi Alfonso, Elena Maríaendoplasmic reticulum stressinositol 1,4,5-triphosphate receptorscalcium signal transmissionkainate receptorsamyloid betacell deathapoptosisprotectsneuronsexcitotoxicityCa2+ releaseapoptosisexcitotoxicitycaspase-12CELL BIOLOGYONCOLOGYMEDICINEIMMUNOLOGY AND MICROBIOLOGYCELLULAR AND MOLECULAR NEUROSCIENCEOveractivation of ionotropic glutamate receptors in oligodendrocytes induces cytosolic Ca2+ overload and excitotoxic death, a process that contributes to demyelination and multiple sclerosis. Excitotoxic insults cause well-characterized mitochondrial alterations and endoplasmic reticulum (ER) dysfunction, which is not fully understood. In this study, we analyzed the contribution of ER-Ca2+ release through ryanodine receptors (RyRs) and inositol triphosphate receptors (IP(3)Rs) to excitotoxicity in oligodendrocytes in vitro. First, we observed that oligodendrocytes express all previously characterized RyRs and IP(3)Rs. Blockade of Ca2+-induced Ca2+ release by TMB-8 following alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptor-mediated insults attenuated both oligodendrocyte death and cytosolic Ca2+ overload. In turn, RyR inhibition by ryanodine reduced as well the Ca2+ overload whereas IP3R inhibition was ineffective. Furthermore, AMPA-triggered mitochondrial membrane depolarization, oxidative stress and activation of caspase-3, which in all instances was diminished by RyR inhibition. In addition, we observed that AMPA induced an ER stress response as revealed by alpha subunit of the eukaryotic initiation factor 2 alpha phosphorylation, overexpression of GRP chaperones and RyR-dependent cleavage of caspase-12. Finally, attenuating ER stress with salubrinal protected oligodendrocytes from AMPA excitotoxicity. Together, these results show that Ca2+ release through RyRs contributes to cytosolic Ca2+ overload, mitochondrial dysfunction, ER stress and cell death following AMPA receptor-mediated excitotoxicity in oligodendrocytes. Cell Death and Disease (2010) 1, e54; doi:10.1038/cddis.2010.31; published online 15 July 2010Supported by CIBERNED, European Leukodystrophy Association, and from Ministerio de Educacion y Ciencia, Gobierno Vasco and Universidad del Pais Vasco. Technical and human support provided by SGIker (UPV/EHU, MICINN, GV/EJ, ESF)Nature Publishing Group201420142010info:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10810/11886reponame:Addi. Archivo Digital para la Docencia y la Investigacióninstname:Universidad del País VascoInglésinfo:eu-repo/grantAgreement/MICINN//http://www.nature.com/cddis/journal/v1/n7/full/cddis201031a.htmlinfo:eu-repo/semantics/openAccessCell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivative Works 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/oai:addi.ehu.eus:10810/118862026-06-18T09:23:17Z
dc.title.none.fl_str_mv Intracellular Ca2+ release through ryanodine receptors contributes to AMPA receptor-mediated mitochondrial dysfunction and ER stress in oligodendrocytes
title Intracellular Ca2+ release through ryanodine receptors contributes to AMPA receptor-mediated mitochondrial dysfunction and ER stress in oligodendrocytes
spellingShingle Intracellular Ca2+ release through ryanodine receptors contributes to AMPA receptor-mediated mitochondrial dysfunction and ER stress in oligodendrocytes
Ruiz Núñez, Asier
endoplasmic reticulum stress
inositol 1,4,5-triphosphate receptors
calcium signal transmission
kainate receptors
amyloid beta
cell death
apoptosis
protects
neurons
excitotoxicity
Ca2+ release
apoptosis
excitotoxicity
caspase-12
CELL BIOLOGY
ONCOLOGY
MEDICINE
IMMUNOLOGY AND MICROBIOLOGY
CELLULAR AND MOLECULAR NEUROSCIENCE
title_short Intracellular Ca2+ release through ryanodine receptors contributes to AMPA receptor-mediated mitochondrial dysfunction and ER stress in oligodendrocytes
title_full Intracellular Ca2+ release through ryanodine receptors contributes to AMPA receptor-mediated mitochondrial dysfunction and ER stress in oligodendrocytes
title_fullStr Intracellular Ca2+ release through ryanodine receptors contributes to AMPA receptor-mediated mitochondrial dysfunction and ER stress in oligodendrocytes
title_full_unstemmed Intracellular Ca2+ release through ryanodine receptors contributes to AMPA receptor-mediated mitochondrial dysfunction and ER stress in oligodendrocytes
title_sort Intracellular Ca2+ release through ryanodine receptors contributes to AMPA receptor-mediated mitochondrial dysfunction and ER stress in oligodendrocytes
dc.creator.none.fl_str_mv Ruiz Núñez, Asier
Matute Almau, Carlos José
Alberdi Alfonso, Elena María
author Ruiz Núñez, Asier
author_facet Ruiz Núñez, Asier
Matute Almau, Carlos José
Alberdi Alfonso, Elena María
author_role author
author2 Matute Almau, Carlos José
Alberdi Alfonso, Elena María
author2_role author
author
dc.subject.none.fl_str_mv endoplasmic reticulum stress
inositol 1,4,5-triphosphate receptors
calcium signal transmission
kainate receptors
amyloid beta
cell death
apoptosis
protects
neurons
excitotoxicity
Ca2+ release
apoptosis
excitotoxicity
caspase-12
CELL BIOLOGY
ONCOLOGY
MEDICINE
IMMUNOLOGY AND MICROBIOLOGY
CELLULAR AND MOLECULAR NEUROSCIENCE
topic endoplasmic reticulum stress
inositol 1,4,5-triphosphate receptors
calcium signal transmission
kainate receptors
amyloid beta
cell death
apoptosis
protects
neurons
excitotoxicity
Ca2+ release
apoptosis
excitotoxicity
caspase-12
CELL BIOLOGY
ONCOLOGY
MEDICINE
IMMUNOLOGY AND MICROBIOLOGY
CELLULAR AND MOLECULAR NEUROSCIENCE
description Overactivation of ionotropic glutamate receptors in oligodendrocytes induces cytosolic Ca2+ overload and excitotoxic death, a process that contributes to demyelination and multiple sclerosis. Excitotoxic insults cause well-characterized mitochondrial alterations and endoplasmic reticulum (ER) dysfunction, which is not fully understood. In this study, we analyzed the contribution of ER-Ca2+ release through ryanodine receptors (RyRs) and inositol triphosphate receptors (IP(3)Rs) to excitotoxicity in oligodendrocytes in vitro. First, we observed that oligodendrocytes express all previously characterized RyRs and IP(3)Rs. Blockade of Ca2+-induced Ca2+ release by TMB-8 following alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptor-mediated insults attenuated both oligodendrocyte death and cytosolic Ca2+ overload. In turn, RyR inhibition by ryanodine reduced as well the Ca2+ overload whereas IP3R inhibition was ineffective. Furthermore, AMPA-triggered mitochondrial membrane depolarization, oxidative stress and activation of caspase-3, which in all instances was diminished by RyR inhibition. In addition, we observed that AMPA induced an ER stress response as revealed by alpha subunit of the eukaryotic initiation factor 2 alpha phosphorylation, overexpression of GRP chaperones and RyR-dependent cleavage of caspase-12. Finally, attenuating ER stress with salubrinal protected oligodendrocytes from AMPA excitotoxicity. Together, these results show that Ca2+ release through RyRs contributes to cytosolic Ca2+ overload, mitochondrial dysfunction, ER stress and cell death following AMPA receptor-mediated excitotoxicity in oligodendrocytes. Cell Death and Disease (2010) 1, e54; doi:10.1038/cddis.2010.31; published online 15 July 2010
publishDate 2010
dc.date.none.fl_str_mv 2010
2014
2014
dc.type.none.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/10810/11886
url http://hdl.handle.net/10810/11886
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv info:eu-repo/grantAgreement/MICINN//
http://www.nature.com/cddis/journal/v1/n7/full/cddis201031a.html
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Nature Publishing Group
publisher.none.fl_str_mv Nature Publishing Group
dc.source.none.fl_str_mv reponame:Addi. Archivo Digital para la Docencia y la Investigación
instname:Universidad del País Vasco
instname_str Universidad del País Vasco
reponame_str Addi. Archivo Digital para la Docencia y la Investigación
collection Addi. Archivo Digital para la Docencia y la Investigación
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.301603

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