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Interaction with the NMDA receptor locks CaMKII in an active conformation

Author

Listed:
  • K.-Ulrich Bayer

    (Stanford University School of Medicine)

  • Paul De Koninck

    (Stanford University School of Medicine
    Centre de Recherche Université Laval Robert-Giffard)

  • A. Soren Leonard

    (University of Wisconsin
    University of Iowa)

  • Johannes W. Hell

    (University of Wisconsin
    University of Iowa)

  • Howard Schulman

    (Stanford University School of Medicine)

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.

Suggested Citation

  • K.-Ulrich Bayer & Paul De Koninck & A. Soren Leonard & Johannes W. Hell & Howard Schulman, 2001. "Interaction with the NMDA receptor locks CaMKII in an active conformation," Nature, Nature, vol. 411(6839), pages 801-805, June.
    • Handle: RePEc:nat:nature:v:411:y:2001:i:6839:d:10.1038_35081080
    DOI: 10.1038/35081080
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    Cited by:

    1. Tuan A. Nguyen & Henry L. Puhl & Kirk Hines & Daniel J. Liput & Steven S. Vogel, 2022. "Binary-FRET reveals transient excited-state structure associated with activity-dependent CaMKII - NR2B binding and adaptation," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    2. Paul Miller & Anatol M Zhabotinsky & John E Lisman & Xiao-Jing Wang, 2005. "The Stability of a Stochastic CaMKII Switch: Dependence on the Number of Enzyme Molecules and Protein Turnover," PLOS Biology, Public Library of Science, vol. 3(4), pages 1-1, March.

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