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2014-10-17

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cc-by (c) Grau, Cristina et al., 2014
Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/113346

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

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Recurs relacionat

https://doi.org/10.3389/fncel.2014.00331

Resum

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.

Matèries

Aminoàcids, Sinapsi, Transport biològic, Neurobiologia del desenvolupament, Síndrome de Down, Rates (Animals de laboratori)

Matèries (anglès)

Amino acids, Synapses, Biological transport, Developmental neurobiology, Down syndrome, Rats as laboratory animals

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Col·leccions

Articles publicats en revistes (Patologia i Terapèutica Experimental)
Articles publicats en revistes (Fonaments Clínics)
Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer)
Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))

Citació

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. DYRK1A-mediated phosphorylation of GluN2A at Ser1048 regulates the surface expression and channel activity of GluN1/GluN2A receptors. _Frontiers in Cellular Neuroscience_. 2014. Vol. 8, núm. 1. [consulta: 21 de gener de 2026]. ISSN: 1662-5102. [Disponible a: https://hdl.handle.net/2445/113346]

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