Interaction with the NMDA receptor locks CaMKII in an active conformation

K.-Ulrich Bayer (), Paul De Koninck, A. Soren Leonard, Johannes W. Hell and Howard Schulman ()
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K.-Ulrich Bayer: Stanford University School of Medicine
Paul De Koninck: Stanford University School of Medicine
A. Soren Leonard: University of Wisconsin
Johannes W. Hell: University of Wisconsin
Howard Schulman: Stanford University School of Medicine

Nature, 2001, vol. 411, issue 6839, 801-805

Abstract: 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.

Date: 2001
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DOI: 10.1038/35081080

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