Mechanism and regulation of calcium/calmodulin-dependent protein kinase II targeting to the NR2B subunit of the N-methyl-D-aspartate receptor

Stefan Strack; R Blair McNeill; Roger J Colbran

doi:10.1074/jbc.M001471200

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Mechanism and regulation of calcium/calmodulin-dependent protein kinase II targeting to the NR2B subunit of the N-methyl-D-aspartate receptor

Journal article

Open access

Peer reviewed

Mechanism and regulation of calcium/calmodulin-dependent protein kinase II targeting to the NR2B subunit of the N-methyl-D-aspartate receptor

Stefan Strack, R Blair McNeill and Roger J Colbran

The Journal of biological chemistry, Vol.275(31), pp.23798-23806

08/04/2000

DOI: 10.1074/jbc.M001471200

PMID: 10764765

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Abstract

Calcium influx through the N-methyl-d-aspartate (NMDA)-type glutamate receptor and activation of calcium/calmodulin-dependent kinase II (CaMKII) are critical events in certain forms of synaptic plasticity. We have previously shown that autophosphorylation of CaMKII induces high-affinity binding to the NR2B subunit of the NMDA receptor (Strack, S., and Colbran, R. J. (1998) J. Biol. Chem. 273, 20689-20692). Here, we show that residues 1290-1309 in the cytosolic tail of NR2B are critical for CaMKII binding and identify by site-directed mutagenesis several key residues (Lys(1292), Leu(1298), Arg(1299), Arg(1300), Gln(1301), and Ser(1303)). Phosphorylation of NR2B at Ser(1303) by CaMKII inhibits binding and promotes slow dissociation of preformed CaMKII.NR2B complexes. Peptide competition studies imply a role for the CaMKII catalytic domain, but not the substrate-binding pocket, in the association with NR2B. However, analysis of monomeric CaMKII mutants indicates that the holoenzyme structure may also be important for stable association with NR2B. Residues 1260-1316 of NR2B are sufficient to direct the subcellular localization of CaMKII in intact cells and to confer dynamic regulation by calcium influx. Furthermore, mutation of residues in the CaMKII-binding domain in full-length NR2B bidirectionally modulates colocalization with CaMKII after NMDA receptor activation, suggesting a dynamic model for the translocation of CaMKII to postsynaptic targets.

Phosphorylation

Binding, Competitive

Amino Acid Sequence

Peptide Fragments - metabolism

Intercellular Signaling Peptides and Proteins

Receptors, N-Methyl-D-Aspartate - metabolism

Molecular Sequence Data

Phosphoproteins - metabolism

Peptides - pharmacology

Cell Compartmentation

Receptors, N-Methyl-D-Aspartate - isolation & purification

Calcium-Calmodulin-Dependent Protein Kinases - isolation & purification

Animals

Holoenzymes - metabolism

Isoenzymes - metabolism

Protein Structure, Quaternary

Protein Binding

Mice

Binding Sites

Calcium-Calmodulin-Dependent Protein Kinase Type 2

Calcium-Calmodulin-Dependent Protein Kinases - metabolism

Synapses

Details

Title: Subtitle: Mechanism and regulation of calcium/calmodulin-dependent protein kinase II targeting to the NR2B subunit of the N-methyl-D-aspartate receptor
Creators: Stefan Strack - Department of Molecular Physiology and Biophysics and the Center for Molecular Neuroscience, Vanderbilt University Medical Center, Nashville, Tennessee 37232-0615, USA
R Blair McNeill
Roger J Colbran
Resource Type: Journal article
Publication Details: The Journal of biological chemistry, Vol.275(31), pp.23798-23806
DOI: 10.1074/jbc.M001471200
PMID: 10764765
NLM abbreviation: J Biol Chem
ISSN: 0021-9258
eISSN: 1083-351X
Publisher: United States
Grant note: NS37508 / NINDS NIH HHS DK20593 / NIDDK NIH HHS CA68485 / NCI NIH HHS
Language: English
Date published: 08/04/2000
Academic Unit: Pathology; Iowa Neuroscience Institute; Fraternal Order of Eagles Diabetes Research Center; Neuroscience and Pharmacology
Record Identifier: 9984040242702771

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