DYRK1A-mediated phosphorylation of GluN2A at Ser1048 regulates the surface expression and channel activity of GluN1/GluN2A receptors

N-methyl-D-aspartate glutamate receptors (NMDARs) play a pivotal role in neural development and synaptic plasticity, as well as in neurological disease. Since NMDARs exert their function at the cell surface, their density in the plasma membrane is finely tuned by a plethora of molecules that regulat...

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Autores: Grau, Cristina, Arató, Krisztina, Fernández-Fernández, José Manuel, Valderrama, Aitana, Sindreu Balet, Carlos, Fillat i Fonts, Cristina, Ferrer, Isidro (Ferrer Abizanda), Luna, Susana de la, Altafaj, Xavier
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2014
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/113346
Acceso en línea:https://hdl.handle.net/2445/113346
Access Level:acceso abierto
Palabra clave:Aminoàcids
Sinapsi
Transport biològic
Neurobiologia del desenvolupament
Síndrome de Down
Rates (Animals de laboratori)
Amino acids
Synapses
Biological transport
Developmental neurobiology
Down syndrome
Rats as laboratory animals
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oai_identifier_str oai:diposit.ub.edu:2445/113346
network_acronym_str ES
network_name_str España
repository_id_str
spelling DYRK1A-mediated phosphorylation of GluN2A at Ser1048 regulates the surface expression and channel activity of GluN1/GluN2A receptorsGrau, CristinaArató, KrisztinaFernández-Fernández, José ManuelValderrama, AitanaSindreu Balet, CarlosFillat i Fonts, CristinaFerrer, Isidro (Ferrer Abizanda)Luna, Susana de laAltafaj, XavierAminoàcidsSinapsiTransport biològicNeurobiologia del desenvolupamentSíndrome de DownRates (Animals de laboratori)Amino acidsSynapsesBiological transportDevelopmental neurobiologyDown syndromeRats as laboratory animalsN-methyl-D-aspartate glutamate receptors (NMDARs) play a pivotal role in neural development and synaptic plasticity, as well as in neurological disease. Since NMDARs exert their function at the cell surface, their density in the plasma membrane is finely tuned by a plethora of molecules that regulate their production, trafficking, docking and internalization in response to external stimuli. In addition to transcriptional regulation, the density of NMDARs is also influenced by post-translational mechanisms like phosphorylation, a modification that also affects their biophysical properties. We previously described the increased surface expression of GluN1/GluN2A receptors in transgenic mice overexpressing the Dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A), suggesting that DYRK1A regulates NMDARs. Here we have further investigated whether the density and activity of NMDARs were modulated by DYRK1A phosphorylation. Accordingly, we show that endogenous DYRK1A is recruited to GluN2A-containing NMDARs in the adult mouse brain, and we identify a DYRK1A phosphorylation site at Ser(1048) of GluN2A, within its intracellular C-terminal domain. Mechanistically, the DYRK1A-dependent phosphorylation of GluN2A at Ser(1048) hinders the internalization of GluN1/GluN2A, causing an increase of surface GluN1/GluN2A in heterologous systems, as well as in primary cortical neurons. Furthermore, GluN2A phosphorylation at Ser(1048) increases the current density and potentiates the gating of GluN1/GluN2A receptors. We conclude that DYRK1A is a direct regulator of NMDA receptors and we propose a novel mechanism for the control of NMDAR activity in neurons.Frontiers Media2014info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/113346Articles publicats en revistes (Patologia i Terapèutica Experimental)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.3389/fncel.2014.00331Frontiers in Cellular Neuroscience, 2014, vol. 8, p. 1https://doi.org/10.3389/fncel.2014.00331cc-by (c) Grau, Cristina et al., 2014http://creativecommons.org/licenses/by/3.0/esinfo:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1133462026-05-27T06:46:51Z
dc.title.none.fl_str_mv DYRK1A-mediated phosphorylation of GluN2A at Ser1048 regulates the surface expression and channel activity of GluN1/GluN2A receptors
title DYRK1A-mediated phosphorylation of GluN2A at Ser1048 regulates the surface expression and channel activity of GluN1/GluN2A receptors
spellingShingle DYRK1A-mediated phosphorylation of GluN2A at Ser1048 regulates the surface expression and channel activity of GluN1/GluN2A receptors
Grau, Cristina
Aminoàcids
Sinapsi
Transport biològic
Neurobiologia del desenvolupament
Síndrome de Down
Rates (Animals de laboratori)
Amino acids
Synapses
Biological transport
Developmental neurobiology
Down syndrome
Rats as laboratory animals
title_short DYRK1A-mediated phosphorylation of GluN2A at Ser1048 regulates the surface expression and channel activity of GluN1/GluN2A receptors
title_full DYRK1A-mediated phosphorylation of GluN2A at Ser1048 regulates the surface expression and channel activity of GluN1/GluN2A receptors
title_fullStr DYRK1A-mediated phosphorylation of GluN2A at Ser1048 regulates the surface expression and channel activity of GluN1/GluN2A receptors
title_full_unstemmed DYRK1A-mediated phosphorylation of GluN2A at Ser1048 regulates the surface expression and channel activity of GluN1/GluN2A receptors
title_sort DYRK1A-mediated phosphorylation of GluN2A at Ser1048 regulates the surface expression and channel activity of GluN1/GluN2A receptors
dc.creator.none.fl_str_mv Grau, Cristina
Arató, Krisztina
Fernández-Fernández, José Manuel
Valderrama, Aitana
Sindreu Balet, Carlos
Fillat i Fonts, Cristina
Ferrer, Isidro (Ferrer Abizanda)
Luna, Susana de la
Altafaj, Xavier
author Grau, Cristina
author_facet Grau, Cristina
Arató, Krisztina
Fernández-Fernández, José Manuel
Valderrama, Aitana
Sindreu Balet, Carlos
Fillat i Fonts, Cristina
Ferrer, Isidro (Ferrer Abizanda)
Luna, Susana de la
Altafaj, Xavier
author_role author
author2 Arató, Krisztina
Fernández-Fernández, José Manuel
Valderrama, Aitana
Sindreu Balet, Carlos
Fillat i Fonts, Cristina
Ferrer, Isidro (Ferrer Abizanda)
Luna, Susana de la
Altafaj, Xavier
author2_role author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Aminoàcids
Sinapsi
Transport biològic
Neurobiologia del desenvolupament
Síndrome de Down
Rates (Animals de laboratori)
Amino acids
Synapses
Biological transport
Developmental neurobiology
Down syndrome
Rats as laboratory animals
topic Aminoàcids
Sinapsi
Transport biològic
Neurobiologia del desenvolupament
Síndrome de Down
Rates (Animals de laboratori)
Amino acids
Synapses
Biological transport
Developmental neurobiology
Down syndrome
Rats as laboratory animals
description N-methyl-D-aspartate glutamate receptors (NMDARs) play a pivotal role in neural development and synaptic plasticity, as well as in neurological disease. Since NMDARs exert their function at the cell surface, their density in the plasma membrane is finely tuned by a plethora of molecules that regulate their production, trafficking, docking and internalization in response to external stimuli. In addition to transcriptional regulation, the density of NMDARs is also influenced by post-translational mechanisms like phosphorylation, a modification that also affects their biophysical properties. We previously described the increased surface expression of GluN1/GluN2A receptors in transgenic mice overexpressing the Dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A), suggesting that DYRK1A regulates NMDARs. Here we have further investigated whether the density and activity of NMDARs were modulated by DYRK1A phosphorylation. Accordingly, we show that endogenous DYRK1A is recruited to GluN2A-containing NMDARs in the adult mouse brain, and we identify a DYRK1A phosphorylation site at Ser(1048) of GluN2A, within its intracellular C-terminal domain. Mechanistically, the DYRK1A-dependent phosphorylation of GluN2A at Ser(1048) hinders the internalization of GluN1/GluN2A, causing an increase of surface GluN1/GluN2A in heterologous systems, as well as in primary cortical neurons. Furthermore, GluN2A phosphorylation at Ser(1048) increases the current density and potentiates the gating of GluN1/GluN2A receptors. We conclude that DYRK1A is a direct regulator of NMDA receptors and we propose a novel mechanism for the control of NMDAR activity in neurons.
publishDate 2014
dc.date.none.fl_str_mv 2014
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/113346
url https://hdl.handle.net/2445/113346
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.3389/fncel.2014.00331
Frontiers in Cellular Neuroscience, 2014, vol. 8, p. 1
https://doi.org/10.3389/fncel.2014.00331
dc.rights.none.fl_str_mv cc-by (c) Grau, Cristina et al., 2014
http://creativecommons.org/licenses/by/3.0/es
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by (c) Grau, Cristina et al., 2014
http://creativecommons.org/licenses/by/3.0/es
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Frontiers Media
publisher.none.fl_str_mv Frontiers Media
dc.source.none.fl_str_mv Articles publicats en revistes (Patologia i Terapèutica Experimental)
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,301629

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