Interaction with the NMDA receptor locks CaMKII in an active conformation.

TitleInteraction with the NMDA receptor locks CaMKII in an active conformation.
Publication TypeJournal Article
Year of Publication2001
AuthorsBayer K U, De Koninck P, Leonard AS, Hell JW, Schulman H
JournalNature
Volume411
Issue6839
Pagination801-5
Date Published2001 Jun 14
ISSN0028-0836
KeywordsAnimals, Calcium, Calcium-Calmodulin-Dependent Protein Kinase Type 2, Calcium-Calmodulin-Dependent Protein Kinases, Calmodulin, Cell Line, Enzyme Activation, Hippocampus, Neurons, Phosphorylation, Protein Binding, Protein Conformation, Rats, Receptors, N-Methyl-D-Aspartate, Recombinant Fusion Proteins
Abstract

Calcium- and calmodulin-dependent protein kinase II (CaMKII) and glutamate receptors are integrally involved in forms of synaptic plasticity that may underlie learning and memory. In the simplest model for long-term potentiation, CaMKII is activated by Ca2+ influx through NMDA (N-methyl-D-aspartate) receptors and then potentiates synaptic efficacy by inducing synaptic insertion and increased single-channel conductance of AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors. Here we show that regulated CaMKII interaction with two sites on the NMDA receptor subunit NR2B provides a mechanism for the glutamate-induced translocation of the kinase to the synapse in hippocampal neurons. This interaction can lead to additional forms of potentiation by: facilitated CaMKII response to synaptic Ca2+; suppression of inhibitory autophosphorylation of CaMKII; and, most notably, direct generation of sustained Ca2+/calmodulin (CaM)-independent (autonomous) kinase activity by a mechanism that is independent of the phosphorylation state. Furthermore, the interaction leads to trapping of CaM that may reduce down-regulation of NMDA receptor activity. CaMKII-NR2B interaction may be prototypical for direct activation of a kinase by its targeting protein.

DOI10.1038/35081080
Alternate JournalNature
PubMed ID11459059

Funding

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Canadian Institutes of Health Research - Instituts de recherche en santé du Canada Fonds de recherche du Québec – Nature et technologies (FRQNT)Fonds de la recherche en santé du Québec NARSAD Natural Sciences and Engineering Research Council of Canada (NSERC) - Conseil de recherche en sciences naturelles et en génie du Canada (CRSNG)innovation.caHuman Frontier Science Program