title: DYRK1A-mediated phosphorylation of GluN2A at Ser(1048) regulates the surface expression and channel activity of GluN1/GluN2A receptors.
abstract: 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.
authors.affiliation: Institute of Neuropathology, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat Barcelona, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Grau
authors.affiliation: Gene Regulation, Stem Cell and Cancer Programme, UPF and Center for Genomic Regulation (CRG) Barcelona, Spain ; CIBER de Enfermedades Raras (CIBERER) Barcelona, Spain.
authors.forename: Krisztina
authors.initials: K
authors.lastname: Arató
authors.affiliation: Laboratory of Molecular Physiology and Channelopathies, Department of Experimental and Health Sciences, Pompeu Fabra University Barcelona, Spain.
authors.forename: José M
authors.initials: JM
authors.lastname: Fernández-Fernández
authors.affiliation: Institute of Neuropathology, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat Barcelona, Spain.
authors.forename: Aitana
authors.initials: A
authors.lastname: Valderrama
authors.affiliation: Department of Anatomical Pathology, Pharmacology and Microbiology, University of Barcelona Barcelona, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Sindreu
authors.affiliation: CIBER de Enfermedades Raras (CIBERER) Barcelona, Spain ; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) Barcelona, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Fillat
authors.affiliation: Institute of Neuropathology, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat Barcelona, Spain.
authors.forename: Isidre
authors.initials: I
authors.lastname: Ferrer
authors.affiliation: Gene Regulation, Stem Cell and Cancer Programme, UPF and Center for Genomic Regulation (CRG) Barcelona, Spain ; CIBER de Enfermedades Raras (CIBERER) Barcelona, Spain ; Institució Catalana de Recerca i Estudis Avançats (ICREA) Barcelona, Spain.
authors.forename: Susana
authors.initials: S
authors.lastname: de la Luna
authors.affiliation: Institute of Neuropathology, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat Barcelona, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Altafaj
keywords: DYRK1A; Down syndrome; GluN2A; NMDA receptor; phosphorylation; trafficking