Abstract
The N-methyl-d-aspartate (NMDA) receptor subunits NR2 possess extended intracellular C-terminal domains by which they can directly interact with a large number of postsynaptic density (PSD) proteins involved in synaptic clustering and signaling. We have previously shown that PSD-associated alpha-calmodulin kinase II (alphaCaMKII) binds with high affinity to the C-terminal domain of the NR2A subunit. Here, we show that residues 1412-1419 of the cytosolic tail of NR2A are critical for alphaCaMKII binding, and we identify, by site directed mutagenesis, PKC-dependent phosphorylation of NR2A(Ser(1416)) as a key mechanism in inhibiting alphaCaMKII-binding and promoting dissociation of alphaCaMKII.NR2A complex. In addition, we show that stimulation of PKC activity in hippocampal slices either with phorbol esters or with the mGluRs specific agonist trans-1-amino-1,3- cyclopentanedicarboxylic acid (t-ACPD) decreases alphaCaMKII binding to NMDA receptor complex. Thus, our data provide clues on understanding the molecular basis of a direct cross-talk between alphaCaMKII and PKC pathways in the postsynaptic compartment.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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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 / chemistry*
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Calcium-Calmodulin-Dependent Protein Kinases / genetics
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
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Cloning, Molecular
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Cycloleucine / analogs & derivatives
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Cycloleucine / pharmacology
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Cytosol / metabolism
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Enzyme Activation
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Glutathione Transferase / metabolism
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Hippocampus / metabolism
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Mutagenesis, Site-Directed
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Neuroprotective Agents / pharmacology
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Phosphorylation
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Plasmids / metabolism
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Point Mutation
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Precipitin Tests
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Protein Binding
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Protein Kinase C / chemistry
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Protein Kinase C / metabolism*
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Protein Structure, Tertiary
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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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Signal Transduction
Substances
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NR2A NMDA receptor
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Neuroprotective Agents
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Receptors, N-Methyl-D-Aspartate
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Recombinant Fusion Proteins
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Cycloleucine
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1-amino-1,3-dicarboxycyclopentane
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Glutathione Transferase
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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