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 potentiation1, CaMKII is activated by Ca2+ influx through NMDA (N-methyl-d-aspartate) receptors and then potentiates synaptic efficacy by inducing synaptic insertion2,3 and increased single-channel conductance4 of AMPA (α-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 activity5. CaMKII–NR2B interaction may be prototypical for direct activation of a kinase by its targeting protein.
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Acknowledgements
We thank A. Hudmon, S. Singla, M. Meffert, P. Nef and T. Bartfai for helpful discussions, and B. Barres, R. C. Malenka, T. Meyer and D. Mochly-Rosen for comments on the manuscript. Purified CaMKII and IAEDANS-CaM were provided by A. Hudmon and S. Singla. We also thank T. Meyer and colleagues for providing the α-CaMKII-GFP plasmid and help in designing the microporation technique. The research was supported by NIH grants (to H.S. and J.W.H.), a grant from Hoffmann-La Roche (H.S.), and an American Heart Award (J.W.H.). P.D.K. is a Career Awardee of the Burroughs Wellcome Fund and a Centennial Fellow of the Canadian Institutes of Health Research.
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Bayer, KU., De Koninck, P., Leonard, A. et al. Interaction with the NMDA receptor locks CaMKII in an active conformation. Nature 411, 801–805 (2001). https://doi.org/10.1038/35081080
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DOI: https://doi.org/10.1038/35081080
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