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Molecular Pharmacology

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Research ArticleArticle

Enzymatic Activity of CaMKII Is Not Required for Its Interaction with the Glutamate Receptor Subunit GluN2B

Kelsey Barcomb, Steven J. Coultrap and K. Ulrich Bayer
Molecular Pharmacology December 2013, 84 (6) 834-843; DOI: https://doi.org/10.1124/mol.113.089045
Kelsey Barcomb
Department of Pharmacology, University of Colorado Denver, Aurora, Colorado
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Steven J. Coultrap
Department of Pharmacology, University of Colorado Denver, Aurora, Colorado
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K. Ulrich Bayer
Department of Pharmacology, University of Colorado Denver, Aurora, Colorado
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Abstract

Binding of the Ca2+/calmodulin (CaM)-dependent protein kinase II (CaMKII) to the NMDA-type glutamate receptor subunit GluN2B is an important control mechanism for the regulation of synaptic strength. CaMKII binding to GluN2B and CaMKII translocation to synapses are induced by an initial Ca2+/CaM stimulus, which also activates the kinase. Indeed, several mechanistically different CaMKII inhibitors [tatCN21 and KN-93 (N-[2-[[[3-(4-chlorophenyl)-2-propen​yl]methylamino]methyl]phenyl]-N-(2-hydroxyethyl)-4​-methoxybenzenesulphonamide)] and inactivating mutations (K42M, A302R, and T305/T306D) impair this interaction, suggesting that it requires CaMKII enzymatic activity. However, this study shows that two general kinase inhibitors, H7 [1-(5-isoquinolinylsulfonyl)-2-methylpiperazine] and staurosporine (Sta), which inhibit CaMKII activity by yet another mechanism, did not interfere with GluN2B binding in vitro or within cells. In contrast to a previous report, we found that Sta, like H7, inhibited CaMKII in an ATP-competitive manner. Nucleotide binding significantly enhances CaMKII/GluN2B binding in vitro, but the nucleotide competition by H7 or Sta did not prevent this effect and instead even mimicked it. H7 (700 µM) and Sta (2 µM) efficiently blocked enzymatic activity of CaMKII, both in vitro and within cells. However, neither H7 nor Sta prevented Ca2+-induced translocation of CaMKII to GluN2B in heterologous cells or to synapses in hippocampal neurons. Thus, activity of CaMKII (or of any other kinase inhibited by H7 or Sta) is not required for stimulation-induced GluN2B-binding or synaptic translocation of CaMKII, despite previous indication to the contrary. This shows that results with inhibitors and inhibiting mutants can be caused by structural effects independent from catalytic activity, and that detailed understanding of the mechanisms is required for their interpretation.

Footnotes

    • Received August 7, 2013.
    • Accepted September 20, 2013.
  • This work was supported by the National Institutes of Health National Institute of Neurological Disorders and Stroke [Grants R01NS081248 and P30NS048154]; the National Institutes of Health National Institute on Drug Abuse [Grant R21DA36300]; and the National Institutes of Health National Institute of General Medical Sciences [Grant T32GM007635].

  • This work is part of the PhD thesis for K.B. and was previously presented as follows: Barcomb K, Buard I, Coultrap SJ, and Bayer KU (2013) CaMKII activity and GluN2B binding in regulation of synaptic strength. Gordon Research Conference on Excitatory Synapses & Brain Function; 2013 Jun 9–14; Les Diablerets, Switzerland (poster and lecture); and Barcomb K, Coultrap S, and Bayer KU (2012) CaMKII activity is not required for GluN2B binding. Rocky Mountain Regional Neuroscience Group Annual Meeting; 2012 May 10; Aurora, CO; and Barcomb K, Buard I, Coultrap SJ, and Bayer KU (2013) CaMKII activity and GluN2B binding in the regulation of synaptic strength. Rocky Mountain Regional Neuroscience Group Annual Meeting; 2013 May 16; Aurora, CO.

  • dx.doi.org/10.1124/mol.113.089045.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 84 (6)
Molecular Pharmacology
Vol. 84, Issue 6
1 Dec 2013
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Research ArticleArticle

Activity Independence of CaMKII/GluN2B Binding

Kelsey Barcomb, Steven J. Coultrap and K. Ulrich Bayer
Molecular Pharmacology December 1, 2013, 84 (6) 834-843; DOI: https://doi.org/10.1124/mol.113.089045

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Research ArticleArticle

Activity Independence of CaMKII/GluN2B Binding

Kelsey Barcomb, Steven J. Coultrap and K. Ulrich Bayer
Molecular Pharmacology December 1, 2013, 84 (6) 834-843; DOI: https://doi.org/10.1124/mol.113.089045
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