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 potentiation, CaMKII is activated by Ca2+ influx through NMDA (N-methyl-D-aspartate) receptors and then potentiates synaptic efficacy by inducing synaptic insertion and increased single-channel conductance of AMPA (alpha-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 activity. CaMKII-NR2B interaction may be prototypical for direct activation of a kinase by its targeting protein.
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CaMKII binding to GluN2B directly generates Ca2+-independent autonomous CaMKII activity.
“This binding directly generates Ca2+-independent autonomous CaMKII activity”
From LTP expression mediated by autonomous activity of GluN2B-bound CaMKII (2024) · cites this paper as [13]
Binding of the GluN2B subunit of the NMDAR to the CaMKII surface groove in place of the autoinhibitory domain allows autonomous activity without autophosphorylation.
“A second mechanism proposed for generating autonomy involves binding of the GluN2B subunit of the NMDAR to the kinase surface groove in place of the autoinhibitory domain that allows for autonomous activity without autophosphorylation (78).”
From Synaptic memory and CaMKII (2023) · cites this paper as [78]
The CTD peptide may act like a wedge between the kinase and its regulatory segment, propping the enzyme in an open active conformation that persists as long as the CTD peptide is bound, even after Ca2+/CaM dissociates.
“The CTD peptide may act like a wedge between the kinase and its regulatory segment, propping the enzyme in an open active conformation that persists as long as the CTD peptide is bound, even after Ca2+/CaM dissociates (FIGURE 2B6) (78).”
From Synaptic memory and CaMKII (2023) · cites this paper as [78]
The CaMKII-CTD complex is autonomously active after Ca2+/CaM removal.
“Ca2+/CaM was then removed and when the CaMKII-CTD complex was assayed with substrate and ATP it was found to be autonomously active (78).”
From Synaptic memory and CaMKII (2023) · cites this paper as [78]
The CTD peptide induces constitutive activity of the T286A phosphonull mutant without T286P.
“A similar finding was made with T286A, the phosphonull mutant, i.e., the CTD peptide induced constitutive activity without T286P.”
From Synaptic memory and CaMKII (2023) · cites this paper as [78]
The CaMKII I205K mutation prevents binding to GluN2B but is otherwise reported to function normally.
“A third approach takes advantage of a point mutation of CaMKII (I205K), which prevents binding to GluN2B but otherwise reported to function normally (78)”
From Synaptic memory and CaMKII (2023) · cites this paper as [78]
This translocation involves the binding of CaMKII to the NMDAR.
“This translocation involves the binding of CaMKII to the NMDAR (78, 125, 144, 221–224).”
From Synaptic memory and CaMKII (2023) · cites this paper as [78]
In the binding study, no autophosphorylation is necessary; the transient CaMKII-GluN2B complex transitions into a persistent form that remains constitutively active.
“In the binding study, no autophosphorylation is necessary; the transient CaMKII-GluN2B complex transitions into a persistent form that remains constitutively active.”
From Synaptic memory and CaMKII (2023) · cites this paper as [78]
In contrast, the CaMKII-GluN2B CTD interaction and constitutive activity appeared to transition to a stable interaction that was almost as persistent with T286A as with phosphorylated T286.
“In contrast, the CaMKII-GluN2B CTD interaction and constitutive activity appeared to transition to a stable interaction that was almost as persistent with T286A as with phosphorylated T286.”
From Synaptic memory and CaMKII (2023) · cites this paper as [78]
In both LLPS and biochemical complex formation, addition of Ca2+/CaM in the absence of ATP or with the T286A mutant was sufficient for LLPS or complex formation.
“In both cases addition of Ca2+/CaM in the absence of ATP or with the T286A mutant was sufficient for the LLPS or complex formation.”
From Synaptic memory and CaMKII (2023) · cites this paper as [78]
Ca2+/CaM peeling away the autoinhibitory segment results in the phosphorylation of T286 and also the binding of CaMKII to GluN2B even without prior autophosphorylation, both of which maintain CaMKII in an active state.
“The first step involves Ca2+/CaM peeling away the autoinhibitory segment from the kinase domain. This results in the phosphorylation of T286 and also the binding of CaMKII to GluN2B even without prior autophosphorylation, both of which maintain CaMKII in an active state (64, 78, 119–121, 221).”
From Synaptic memory and CaMKII (2023) · cites this paper as [78]
As long as Ca2+/CaM is present, binding and phase separation are maintained even with a phosphonull mutant of T286 (T286A) or with a kinase-dead mutant of CaMKII, although the binding of CaMKII to GluN2B is modestly enhanced by T286 phosphorylation.
“As long as Ca2+/CaM is present, binding and phase separation are maintained even with a phosphonull mutant of T286 (T286A) (78, 169, 323, 377) or with a kinase-dead mutant of CaMKII (169, 323, 378, 379), although the binding of CaMKII to GluN2B is modestly enhanced by T286 phosphorylation (378).”
From Synaptic memory and CaMKII (2023) · cites this paper as [78]
In the absence of added ATP, and with sufficient time, the binding of CaMKII to GluN2B persists after the removal of Ca2+/CaM.
“First, a biochemical study demonstrated that in the absence of added ATP, and with sufficient time, the binding of CaMKII to GluN2B persists after the removal of Ca2+/CaM (78).”
From Synaptic memory and CaMKII (2023) · cites this paper as [78]
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“One of the major interacting partners for CaMKII is the GluN2B subunit of NMDARs (Bayer et al., 2001; Leonard, Lim, Hemsworth, Horne, & Hell, 1999; Leonard et al., 2002; Strack & Colbran, 1998).”
Background
- Authors
- Bayer, K.-U., De Koninck, P., Leonard, A. S., Hell, J. W., & Schulman, H.
- Affiliations
- Stanford Medicine (US)
- University of Iowa (US)
- Corresponding author
- Bayer, K.-Ulrich
- Venue
- Nature
- Published
- 2001-06
- Volume
- 411
- Issue
- 6839
- Pages
- 801-805
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2007393704
- Cited by
- 732
- References
- 30
- Citations by year
- 2026: 12 · 2025: 23 · 2024: 28 · 2023: 23 · 2022: 28 · 2021: 28 · 2020: 30 · 2019: 21 · 2018: 26 · 2017: 27 · 2016: 18 · 2015: 23 · 2014: 42 · 2013: 25 · 2012: 37
- FWCI
- 12.97
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Keywords
- CaMKII, NMDA receptor, NR2B subunit, kinase activation, synaptic plasticity, long-term potentiation, autophosphorylation, hippocampal neurons, glutamate signaling
- MeSH terms
- Animals, Calcium, Calmodulin, Cell Line, Enzyme Activation, Hippocampus, Neurons, Phosphorylation, Protein Binding, Protein Conformation, Recombinant Fusion Proteins, Receptors, N-Methyl-D-Aspartate, Calcium-Calmodulin-Dependent Protein Kinases, Rats, Calcium-Calmodulin-Dependent Protein Kinase Type 2
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