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Interaction with the NMDA receptor locks CaMKII in an active conformation

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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Figure 1: Differential regulation of CaMKII binding to two regions on NR2B.
Figure 2: CaMKII translocation in HEK cells and in neurons.
Figure 3: An NR2B fragment sufficient to induce CaM trapping by CaMKII.
Figure 4: Interaction of CaMKII with NR2B-C generates autonomous kinase activity by a mechanism that does not require autophosphorylation or CaM trapping.
Figure 5: Phosphorylation within CaMKII–NR2B complexes.

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References

  1. Malenka, R. C. & Nicoll, R. A. Long-term potentiation - a decade of progress? Science 285, 1870–1874 (1999).

    Article  CAS  Google Scholar 

  2. Rongo, C. & Kaplan, J. M. CaMKII regulates the density of central glutamatergic synapses in vivo. Nature 402, 195–199 (1999).

    Article  ADS  CAS  Google Scholar 

  3. Hayashi, Y. et al. Driving AMPA receptors into synapses by LTP and CaMKII: requirement for GluR1 and PDZ domain interaction. Science 287, 2262–2267 (2000).

    Article  ADS  CAS  Google Scholar 

  4. Derkach, V., Barria, A. & Soderling, T. R. Ca2+/calmodulin-kinase II enhances channel conductance of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate type glutamate receptors. Proc. Natl Acad. Sci. USA 96, 3269–3274 (1999).

    Article  ADS  CAS  Google Scholar 

  5. Ehlers, M. D., Zhang, S., Bernhadt, J. P. & Huganir, R. L. Inactivation of NMDA receptors by direct interaction of calmodulin with the NR1 subunit. Cell 84, 745–755 (1996).

    Article  CAS  Google Scholar 

  6. Lisman, J., Malenka, R. C., Nicoll, R. A. & Malinow, R. Learning mechanisms: the case for CaM-KII. Science 276, 2001–2002 (1997).

    Article  CAS  Google Scholar 

  7. Schulman, H. & Brown, A. in Calcium as Cellular Regulator (eds. Carafoli, E. & Klee, C.) 311–343 (Oxford Univ. Press, New York, 1999).

    Google Scholar 

  8. Hanson, P. I., Meyer, T., Stryer, L. & Schulman, H. Dual role of calmodulin in autophosphorylation of multifunctional CaM kinase may underlie decoding of calcium signals. Neuron 12, 943–956 (1994).

    Article  CAS  Google Scholar 

  9. Rich, R. C. & Schulman, H. Substrate-directed function of calmodulin in autophosphorylation of Ca2+/calmodulin-dependent protein kinase II. J. Biol. Chem. 273, 28424–28429 (1998).

    Article  CAS  Google Scholar 

  10. De Koninck, P. & Schulman, H. Sensitivity of CaM kinase II to the frequency of Ca2+ oscillations. Science 279, 227–230 (1998).

    Article  ADS  CAS  Google Scholar 

  11. Meyer, T., Hanson, P. I., Stryer, L. & Schulman, H. Calmodulin trapping by calcium-calmodulin-dependent protein kinase. Science 256, 1199–1201 (1992).

    Article  ADS  CAS  Google Scholar 

  12. Gardoni, F. et al. Calcium/calmodulin-dependent protein kinase II is associated with NR2A/B subunits of NMDA receptor in postsynaptic densities. J. Neurochem. 71, 1733–1741 (1998).

    Article  CAS  Google Scholar 

  13. Leonard, A. S., Lim, I. A., Hemsworth, D. E., Horne, M. C. & Hell, J. W. Calcium/calmodulin-dependent protein kinase II is associated with the N-methyl-d-aspartate receptor. Proc. Natl Acad. Sci. USA 96, 3239–3244 (1999).

    Article  ADS  CAS  Google Scholar 

  14. Strack, S., McNeill, R. B. & Colbran, R. J. Mechanism and regulation of calcium/calmodulin-dependent protein kinase II targeting to the NR2B subunit of the N-methyl-d-aspartate receptor. J. Biol. Chem. 275, 23798–23806 (2000).

    Article  CAS  Google Scholar 

  15. Shen, K. & Meyer, T. Dynamic control of CaMKII translocation and localization in hippocampal neurons by NMDA receptor stimulation. Science 284, 162–166 (1999).

    Article  ADS  CAS  Google Scholar 

  16. Shen, K., Teruel, M. N., Connor, J. H., Shenolikar, S. & Meyer, T. Molecular memory by reversible translocation of calcium/calmodulin-dependent protein kinase II. Nature Neurosci. 3, 881–886 (2000).

    Article  CAS  Google Scholar 

  17. Yang, E. & Schulman, H. Structural examination of autoregulation of multifunctional calcium/calmodulin-dependent protein kinase II. J. .Biol. Chem. 274, 26199–26208 (1999).

    Article  CAS  Google Scholar 

  18. Putkey, J. A. & Waxham, M. N. A peptide model for calmodulin trapping by calcium/calmodulin-dependent protein kinase II. J. Biol. Chem. 271, 29619–29623 (1996).

    Article  CAS  Google Scholar 

  19. Smith, M. K., Colbran, R. J., Brickey, D. A. & Soderling, T. R. Functional determinants in the autoinhibitory domain of calcium/calmodulin-dependent protein kinase II. Role of His282 and multiple basic residues. J. Biol. Chem. 267, 1761–1768 (1992).

    CAS  PubMed  Google Scholar 

  20. Kolodziej, S. J., Hudmon, A., Waxham, M. N. & Stoops, J. K. Three-dimensional reconstructions of calcium/calmodulin-dependent (CaM) kinase IIα and truncated CaM kinase IIα reveal a unique organization for its structural core and functional domains. J Biol. Chem. 275, 14354–14359 (2000).

    Article  CAS  Google Scholar 

  21. Colbran, R. J. & Soderling, T. R. Calcium/calmodulin-independent autophosphorylation sites of calcium/calmodulin-dependent protein kinase II. Studies on the effect of phosphorylation of threonine 305/306 and serine 314 on calmodulin binding using synthetic peptides. J. Biol. Chem. 265, 11213–11219 (1990).

    CAS  PubMed  Google Scholar 

  22. Hanson, P. I. & Schulman, H. Inhibitory autophosphorylation of multifunctional Ca2+/calmodulin-dependent protein kinase analyzed by site-directed mutagenesis. J. Biol. Chem. 267, 17216–17224 (1992).

    CAS  PubMed  Google Scholar 

  23. Omkumar, R. V., Kiely, M. J., Rosenstein, A. J., Min, K. T. & Kennedy, M. B. Identification of a phosphorylation site for calcium/calmodulin-dependent protein kinase II in the NR2B subunit of the N-methyl-d-aspartate receptor. J. Biol. Chem. 271, 31670–31678 (1996).

    Article  CAS  Google Scholar 

  24. Lieberman, D. N. & Mody, I. Regulation of NMDA channel function by endogenous Ca2+-dependent phosphatase. Nature 369, 235–239 (1994).

    Article  ADS  CAS  Google Scholar 

  25. Hisatsune, C. et al. Phosphorylation-dependent regulation of N-methyl-d-aspartate receptors by calmodulin. J. Biol. Chem. 272, 20805–20810 (1997).

    Article  CAS  Google Scholar 

  26. Chen, H. J., Rojas-Soto, M., Oguni, A. & Kennedy, M. B. A synaptic Ras-GTPase activating protein (p135 SynGAP) inhibited by CaM kinase II. Neuron 20, 895–904 (1998).

    Article  CAS  Google Scholar 

  27. Bayer, K.-U., Löhler, J. & Harbers, K. An alternative, nonkinase product of the brain-specifically expressed Ca2+/calmodulin-dependent kinase II α isoform gene in skeletal muscle. Mol. Cell. Biol. 16, 29–36 (1996).

    Article  CAS  Google Scholar 

  28. Bayer, K.-U., Harbers, K. & Schulman, H. αKAP is an anchoring protein for a novel CaM kinase II isoform in skeletal muscle. EMBO J. 17, 5598–5605 (1998).

    Article  CAS  Google Scholar 

  29. Shen, K., Teruel, M. N., Subramanian, K. & Meyer, T. CaMKIIβ functions as an F-actin targeting module that localizes CaMKIIα/β heterooligomers to dendritic spines. Neuron 21, 593–606 (1998).

    Article  CAS  Google Scholar 

  30. Strack, S., Robison, A. J., Bass, M. A. & Colbran, R. J. Association of calcium/calmodulin-dependent kinase II with developmentally regulated splice variants of the postsynaptic density protein densin-180. J. Biol. Chem. 275, 25061–25064 (2000).

    Article  CAS  Google Scholar 

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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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Correspondence to K.-Ulrich Bayer.

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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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