Abstract
Interactions between NMDA receptors (NMDARs) and the PDZ [postsynaptic density-95 (PSD-95)/Discs large/zona occludens-1] domains of PSD-95/SAP90 (synapse-associated protein with a molecular weight of 90 kDa) family proteins play important roles in the synaptic targeting and signaling of NMDARs. However, little is known about the mechanisms that regulate these PDZ domain-mediated interactions. Here we show that casein kinase II (CK2) phosphorylates the serine residue (Ser1480) within the C-terminal PDZ ligand (IESDV) of the NR2B subunit of NMDAR in vitro and in vivo. Phosphorylation of Ser1480 disrupts the interaction of NR2B with the PDZ domains of PSD-95 and SAP102 and decreases surface NR2B expression in neurons. Interestingly, activity of the NMDAR and Ca2+/calmodulin-dependent protein kinase II regulates CK2 phosphorylation of Ser1480. Furthermore, CK2 colocalizes with NR1 and PSD-95 at synaptic sites. These results indicate that activity-dependent CK2 phosphorylation of the NR2B PDZ ligand regulates the interaction of NMDAR with PSD-95/SAP90 family proteins as well as surface NMDAR expression and may be a critical mechanism for modulating excitatory synaptic function and plasticity.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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2-Amino-5-phosphonovalerate / pharmacology
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Amino Acid Sequence
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Animals
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Calcium-Calmodulin-Dependent Protein Kinase Type 2
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Calcium-Calmodulin-Dependent Protein Kinases / physiology
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Casein Kinase II / physiology*
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Cell Line
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Colforsin / pharmacology
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Cyclic AMP-Dependent Protein Kinases / antagonists & inhibitors
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Cyclic AMP-Dependent Protein Kinases / metabolism
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Disks Large Homolog 4 Protein
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Enzyme Activation
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Hippocampus / cytology
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Hippocampus / metabolism
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Humans
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Intracellular Signaling Peptides and Proteins
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Ligands
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Membrane Proteins
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Molecular Sequence Data
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Mutagenesis, Site-Directed
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Nerve Tissue Proteins / metabolism*
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Neuronal Plasticity / physiology*
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Phosphorylation
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Phosphoserine / metabolism
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Protein Interaction Mapping
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Protein Kinase C / antagonists & inhibitors
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Protein Kinase C / metabolism
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Protein Processing, Post-Translational*
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Protein Structure, Tertiary
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Protein Subunits
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Protein Transport / physiology*
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Rats
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Receptors, N-Methyl-D-Aspartate / chemistry
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Receptors, N-Methyl-D-Aspartate / genetics
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Receptors, N-Methyl-D-Aspartate / metabolism*
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Recombinant Fusion Proteins / metabolism
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Structure-Activity Relationship
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Synapses / metabolism*
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Tetradecanoylphorbol Acetate / pharmacology
Substances
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DLG4 protein, human
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Disks Large Homolog 4 Protein
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Dlg4 protein, rat
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Intracellular Signaling Peptides and Proteins
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Ligands
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Membrane Proteins
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NR2B NMDA receptor
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Nerve Tissue Proteins
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Protein Subunits
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Receptors, N-Methyl-D-Aspartate
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Recombinant Fusion Proteins
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postsynaptic density proteins
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Phosphoserine
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Colforsin
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2-Amino-5-phosphonovalerate
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Casein Kinase II
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Cyclic AMP-Dependent Protein Kinases
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Protein Kinase C
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Calcium-Calmodulin-Dependent Protein Kinase Type 2
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Calcium-Calmodulin-Dependent Protein Kinases
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Tetradecanoylphorbol Acetate