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Cited by 160Neuroscience and Neuropharmacology ResearchProtein Kinase Regulation and GTPase SignalingMemory and Neural Mechanisms

A Mechanism for Ca 2+ /Calmodulin-Dependent Protein Kinase II Clustering at Synaptic and Nonsynaptic Sites Based on Self-Association

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Hudmon, Andy, LeBel, Eric, Roy, Hugo, Sik, Attila, Schulman, Howard, Waxham, M. Neal, De Koninck, Paul·2005·The Journal of Neuroscience
DOI 10.1523/jneurosci.4698-04.2005PMC PMC6724830
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Abstract

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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Crossref · 10.1523/jneurosci.4698-04.2005

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  • Two aspects of kinase structure reduce clustering, the CaMKIIβ subunit and T286 phosphorylation, but these are countered by the high CaMKII concentration at the PSD.

    “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]

    The section “Role of Thr286 autophosphorylation in CaMKII self-association” (page unavailable) reports that a phosphorylation-mimicking Thr286 mutation strongly reduced self-association, supporting the T286 part of the claim. The passages examined do not show that the CaMKIIβ subunit reduces clustering or that a high CaMKII concentration at the PSD counteracts either effect; the Discussion describes a concentrating effect of self-association, not that counteraction. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • CaMKIIα, but not CaMKIIβ, can self-associate at least at reduced pH or high concentration, and this requires displacement of the autoinhibitory domain.

    “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]

    The section on pH-dependent clustering reports that αCaMKII forms clusters at reduced pH in the presence of elevated Ca²⁺, and the Discussion proposes release of the autoregulatory domain as a step in self-association. Our copy does not establish that CaMKIIβ cannot self-associate or that high concentration alone permits CaMKIIα self-association; it presents the domain-displacement mechanism as a model rather than a demonstrated requirement. Page numbers are unavailable in our copy. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Self-association is reversible.

    “and is reversible (134).”

    From Synaptic memory and CaMKII (2023) · cites this paper as [134]

  • CaMKII in cellular clusters contains T286P.

    “CaMKII in cellular clusters does contain T286P (134)”

    From Synaptic memory and CaMKII (2023) · cites this paper as [134]

  • 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.

    “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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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)
ORCID
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
DOI
10.1523/jneurosci.4698-04.2005
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
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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