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A Mechanism for Ca 2+ /Calmodulin-Dependent Protein Kinase II Clustering at Synaptic and Nonsynaptic Sites Based on Self-Association
Open accessAbstract
The activity of Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) plays an integral role in regulating synaptic development and plasticity. We designed a live-cell-imaging approach to monitor an activity-dependent clustering of green fluorescent protein (GFP)-CaMKII holoenzymes, termed self-association, a process that we hypothesize contributes to the translocation of CaMKII to synaptic and nonsynaptic sites in activated neurons. We show that GFP-CaMKII self-association in human embryonic kidney 293 (HEK293) cells requires a catalytic domain and multimeric structure, requires Ca 2+ stimulation and a functional Ca 2+ /CaM-binding domain, is regulated by cellular pH and Thr286 autophosphorylation, and has variable rates of dissociation depending on Ca 2+ levels. Furthermore, we show that the same rules that govern CaMKII self-association in HEK293 cells apply for extrasynaptic and postsynaptic translocation of GFP-CaMKII in hippocampal neurons. Our data support a novel mechanism for targeting CaMKII to postsynaptic sites after neuronal activation. As such, CaMKII may form a scaffold that, in combination with other synaptic proteins, recruits and localizes additional proteins to the postsynaptic density. We discuss the potential function of CaMKII self-association as a tag of synaptic activity.
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“Two aspects of kinase structure reduce clustering, one is the CaMKIIβ subunit and another is T286 phosphorylation, but these are countered by the high CaMKII concentration at the PSD (134, 135).”
From Synaptic memory and CaMKII (2023) · cites this paper as [134]
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“It is interesting to note that CaMKIIα, but not CaMKIIβ, can self-associate, at least at reduced pH or high concentration and this requires displacement of the autoinhibitory domain (133–135).”
From Synaptic memory and CaMKII (2023) · cites this paper as [134]
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“and is reversible (134).”
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“CaMKII in cellular clusters does contain T286P (134)”
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“Self-association occurring in transfected cells was used to show that the I205K mutant that blocks docking of GluN2B to the kinase also blocks clustering, suggesting that the regulatory segment and GluN2B have an overlapping docking site (134).”
From Synaptic memory and CaMKII (2023) · cites this paper as [134]
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Metadata
- Authors
- Hudmon, A., LeBel, E., Roy, H., Sik, A., Schulman, H., Waxham, M. N., & De Koninck, P.
- Affiliations
- Stanford University (US)
- Université Laval (CA)
- The University of Texas Health Science Center at Houston (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2005-07-27
- Volume
- 25
- Issue
- 30
- Pages
- 6971-6983
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6724830
- OpenAlex
- W2087706333
- Cited by
- 159
- References
- 64
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 5 · 2023: 6 · 2022: 3 · 2021: 3 · 2020: 5 · 2019: 2 · 2018: 4 · 2017: 5 · 2016: 7 · 2015: 10 · 2014: 10 · 2013: 12 · 2012: 13
- FWCI
- 4.33
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Burroughs Wellcome Fund
- National Institutes of Health
- Canadian Institutes of Health Research
- National Cancer Institute (R01CA094025)
- 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, self-association, protein clustering, synaptic localization, postsynaptic density, calmodulin, calcium signaling, pH control, hippocampal neurons, synaptic plasticity, live-cell imaging
- MeSH terms
- Animals, Calcium, Cell Membrane, Cells, Cultured, Hippocampus, Humans, Hydrogen-Ion Concentration, Kidney, Neurons, Phosphorylation, Synapses, Threonine, Transfection, Protein Structure, Tertiary, Receptors, Glutamate, Calcium-Calmodulin-Dependent Protein Kinases, Green Fluorescent Proteins, Rats, Calcium-Calmodulin-Dependent Protein Kinase Type 2
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