Calcium/Calmodulin Dependent Protein Kinase II Bound to NMDA Receptor 2B Subunit Exhibits Increased ATP Affinity and Attenuated Dephosphorylation

Cheriyan, John; Kumar, P. Rajesh; Mayadevi, Madhavan; Surolia, Avadhesha; Omkumar, Ramakrishnapillai V.

doi:10.1371/journal.pone.0016495

Cited by 28 publications

(30 citation statements)

References 28 publications

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“…Consistent with these findings, CaMKII binding to GluN2B does, vice versa, enhance nucleotide binding to the kinase (53). The present study shows that the positive effect of nucleotide binding on CaMKII/GluN2B interaction is important in order to overcome the negative effect caused by GluN2B S1303 phosphorylation.…”

Section: Discussionsupporting

confidence: 90%

Nucleotides and Phosphorylation Bi-directionally Modulate Ca2+/Calmodulin-dependent Protein Kinase II (CaMKII) Binding to the N-Methyl-d-aspartate (NMDA) Receptor Subunit GluN2B

O’Leary

Liu

Rorabaugh

et al. 2011

Journal of Biological Chemistry

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The Ca 2؉ /calmodulin (CaM)-dependent protein kinase II (CaMKII) and the NMDA-type glutamate receptor are key regulators of synaptic plasticity underlying learning and memory. Direct binding of CaMKII to the NMDA receptor subunit GluN2B (formerly known as NR2B) (i) is induced by Ca 2؉ /CaM but outlasts this initial Ca 2؉ -stimulus, (ii) mediates CaMKII translocation to synapses, and (iii) regulates synaptic strength. CaMKII binds to GluN2B around S1303, the major CaMKII phosphorylation site on GluN2B. We show here that a phosphomimetic S1303D mutation inhibited CaM-induced CaMKII binding to GluN2B in vitro, presenting a conundrum how binding can occur within cells, where high ATP concentration should promote S1303 phosphorylation. Surprisingly, addition of ATP actually enhanced the binding. Mutational analysis revealed that this positive net effect was caused by four modulatory effects of ATP, two positive (direct nucleotide binding and CaMKII T286 autophosphorylation) and two negative (GluN2B S1303 phosphorylation and CaMKII T305/6 autophosphorylation). Imaging showed positive regulation by nucleotide binding also within transfected HEK cells and neurons. In fact, nucleotide binding was a requirement for efficient CaMKII interaction with GluN2B in cells, while T286 autophosphorylation was not. Kinetic considerations support a model in which positive regulation by nucleotide binding and T286 autophosphorylation occurs faster than negative modulation by GluN2B S1303 and CaMKII T305/6 phosphorylation, allowing efficient CaMKII binding to GluN2B despite the inhibitory effects of the two slower reactions.The Ca 2ϩ

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Section: Discussionsupporting

confidence: 90%

Nucleotides and Phosphorylation Bi-directionally Modulate Ca2+/Calmodulin-dependent Protein Kinase II (CaMKII) Binding to the N-Methyl-d-aspartate (NMDA) Receptor Subunit GluN2B

O’Leary

Liu

Rorabaugh

et al. 2011

Journal of Biological Chemistry

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“…This work shows that although protein phosphatase-1 at the PSD dephosphorylates some sites on CaMKII, it cannot dephosphorylate T286 139 . Recent work shows that T286 sites cannot be dephosphorylated because the NMDAR itself shields these sites 140 . On the other hand, there are also hints that long-term memory storage may not depend on autophosphorylation of T286.…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of CaMKII action in long-term potentiation

2012

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Long-term potentiation (LTP) of synaptic strength occurs during learning and can last for long periods, making it a probable mechanism for memory storage. LTP induction results in calcium entry, which activates calcium–calmodulin-dependent protein kinase II (CaMKII). CaMKII subsequently translocates to the synapse, where it binds to the NMDA-type glutamate receptors and produces potentiation by phosphorylating principal and auxiliary subunits of AMPA-type glutamate receptors. These processes all are localized to stimulated spines and account for the synapse specificity of LTP. In the later stages of LTP, CaMKII has a structural role in enlarging and strengthening the synapse.

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“…Thus, the T286 sites were somehow protected from phosphatase. (Cheriyan et al, 2011) obtained evidence that the binding of the NR2B to CaMKII somehow provides such protection. As shown in Fig.4, in experiments with purified CaMKII and PP1, the addition of NR2B peptide inhibited pT286 dephosphorylation.…”

Section: Principle 2: In the On State Dephosphorylation Of T286 Becomentioning

confidence: 99%

“…Data normalized to level of CaMKII phosphorylation in absence of PP1. From Fig.4B of (Cheriyan et al, 2011). …”

Section: Highlightsmentioning

confidence: 99%

Biochemical principles underlying the stable maintenance of LTP by the CaMKII/NMDAR complex

Lisman¹,

Raghavachari²

2015

Brain Research

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Memory involves the storage of information at synapses by an LTP-like process. This information storage is synapse specific and can endure for years despite the turnover of all synaptic proteins. There must, therefore, be special principles that underlie the stability of LTP. Recent experimental results suggest that LTP is maintained by the complex of CaMKII with the NMDAR. Here we consider the specifics of the CaMKII/NMDAR molecular switch, with the goal of understanding the biochemical principles that underlie stable information storage by synapses. Consideration of a variety of experimental results suggests that multiple principles are involved. One switch requirement is to prevent spontaneous transitions from the off to the on state. The highly cooperative nature of CaMKII autophosphorylation by Ca2+ (Hill coefficient of 8) and the fact that formation of the CaMKII/NMDAR complex requires release of CaMKII from actin are mechanisms that stabilize the off state. The stability of the on state depends critically on intersubunit autophosphorylation, a process that restores any loss of pT286 due to phosphatase activity. Intersubunit autophosphorylation is also important in explaining why on state stability is not compromised by protein turnover. Recent evidence suggests that turnover occurs by subunit exchange. Thus, stability could be achieved if a newly inserted unphosphorylated subunit was autophosphorylated by a neighboring subunit. Based on other recent work, we posit a novel mechanism that enhances the stability of the on state by protection of pT286 from phosphatases. We posit that the binding of the NMNDAR to CaMKII forces pT286 into the catalytic site of a neighboring subunit, thereby protecting pT286 from phosphatases. A final principle concerns the role of structural changes. The binding of CaMKII to the NMDAR may act as a tag to organize the binding of further proteins that produce the synapse enlargement that underlies late LTP. We argue that these structural changes not only enhance transmission, but also enhance the stability of the CaMKII/NMDAR complex. Together, these principles provide a mechanistic framework for understanding how individual synapses produce stable information storage.

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Calcium/Calmodulin Dependent Protein Kinase II Bound to NMDA Receptor 2B Subunit Exhibits Increased ATP Affinity and Attenuated Dephosphorylation

Cited by 28 publications

References 28 publications

Nucleotides and Phosphorylation Bi-directionally Modulate Ca2+/Calmodulin-dependent Protein Kinase II (CaMKII) Binding to the N-Methyl-d-aspartate (NMDA) Receptor Subunit GluN2B

Nucleotides and Phosphorylation Bi-directionally Modulate Ca2+/Calmodulin-dependent Protein Kinase II (CaMKII) Binding to the N-Methyl-d-aspartate (NMDA) Receptor Subunit GluN2B

Mechanisms of CaMKII action in long-term potentiation

Biochemical principles underlying the stable maintenance of LTP by the CaMKII/NMDAR complex

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