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Cited by 52Neuroscience and Neuropharmacology ResearchProtein Kinase Regulation and GTPase SignalingSignaling Pathways in Disease

Autonomous CaMKII requires further stimulation by Ca 2+ /calmodulin for enhancing synaptic strength

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Barcomb, Kelsey, Buard, Isabelle, Coultrap, Steven J., Kulbe, Jacqueline R., O'Leary, Heather, Benke, Timothy A., Bayer, K. Ulrich·2014·The FASEB Journal
DOI 10.1096/fj.14-250407PMC PMC4101658
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Abstract

A hallmark feature of Ca 2+ /calmodulin (CaM)‐dependent protein kinase II (CaMKII) is generation of autonomous (Ca 2+ ‐independent) activity by T286 autophosphorylation. Biochemical studies have shown that “autonomous” CaMKII is ~5‐fold further stimulated by Ca 2+ /CaM, but demonstration of a physiological function for such regulation within cells has remained elusive. In this study, CaMKII‐induced enhancement of synaptic strength in rat hippocampal neurons required both autonomous activity and further stimulation. Synaptic strength was decreased by CaMKIIα knockdown and rescued by reexpression, but not by mutants impaired for autonomy (T286A) or binding to NMDA‐type glutamate receptor subunit 2B (GluN2B; formerly NR2B; I205K). Full rescue was seen with constitutively autonomous mutants (T286D), but only if they could be further stimulated (additional T305/306A mutation), and not with two other mutations that additionally impair Ca 2+ /CaM binding. Compared to rescue with wild‐type CaMKII, the CaM‐binding‐impaired mutants even had reduced synaptic strength. One of these mutants (T305/306D) mimicked an inhibitory autophosphorylation of CaMKII, whereas the other one (Δstim) abolished CaM binding without introducing charged residues. Inhibitory T305/306 autophosphorylation also reduced GluN2B binding, but this effect was independent of reduced Ca 2+ /CaM binding and was not mimicked by T305/306D mutation. Thus, even autonomous CaMKII activity must be further stimulated by Ca 2+ /CaM for enhancement of synaptic strength.—Barcomb, K., Buard, I., Coultrap, S. J., Kulbe, J. R., O'Leary, H., Benke, T. A., Bayer, K. U. Autonomous CaMKII requires further stimulation by Ca 2+ /calmodulin for enhancing synaptic strength. FASEB J. 28, 3810–3819 (2014). www.fasebj.org

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  • Using a T286D mutation alone is problematic because it generates a constitutively active kinase that then results in phosphorylation of T305/T306, which can counteract T286D and alter resident time at the synapse.

    “Just using a T286D mutation would be problematic because it generates a constitutively active kinase that then results in the phosphorylation of T305/T306, which can counteract T286D and alter resident time at the synapse (88, 210, 211).”

    From Synaptic memory and CaMKII (2023) · cites this paper as [211]

    The Results and Discussion (pages unavailable) describe T286D as constitutively autonomous and report that T305/306 phosphorylation is expected to follow its activity and can inhibit further Ca²⁺/calmodulin stimulation and reduce GluN2B binding. They also report a possible further reduction in synaptic localization, significant by t test but not ANOVA. The paper does not measure synaptic residence time, so that specific effect is not established. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • CaMKII contributes to baseline synaptic transmission, as shown by peptide inhibitors, RNAi, and CRISPR.

    “The first evidence that CaMKII contributes to synaptic transmission came from expression of peptide inhibitors (150, 154).”

    From Synaptic memory and CaMKII (2023) · cites this paper as [211]

    The Results (page unavailable) show that knocking down CaMKIIα in cultured hippocampal neurons decreased mEPSC amplitude, supporting a contribution to synaptic strength. The Materials and Methods identify shRNA as the knockdown method. Our copy does not establish that the first evidence came from expressed peptide inhibitors, or show a CRISPR experiment. (LLM, conf=0.88)

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Authors
Barcomb, K., Buard, I., Coultrap, S. J., Kulbe, J. R., O'Leary, H., Benke, T. A., & Bayer, K. U.
Affiliations
  • University of Colorado Anschutz (US)
  • Department of Pharmacology University of Colorado School of Medicine, Anschutz Medical Campus Aurora Colorado USA
Corresponding author
Bayer, K. Ulrich
ORCID
Venue
The FASEB Journal
Publisher
Wiley
Published
2014-05-19
Volume
28
Issue
8
Pages
3810-3819
ISSN
  • 0892-6638 (ISSN-L)
  • 1530-6860
DOI
10.1096/fj.14-250407
PMC
PMC4101658
OpenAlex
W2159738284
Cited by
52
References
4
Citations by year
2026: 2 · 2025: 4 · 2024: 5 · 2023: 4 · 2022: 7 · 2021: 3 · 2020: 3 · 2019: 3 · 2018: 3 · 2017: 7 · 2016: 4 · 2015: 7
FWCI
2.74
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • The FASEB Journal (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Institutes of Health (R01NS081248, R01NS076577, T32GM007635, P30NS04154)
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 › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
Keywords
CaMKII, synaptic efficacy, hippocampal neurons, GluN2B, NMDA receptor, synaptic plasticity
MeSH terms
Action Potentials, Animals, Calcium, Calmodulin, Enzyme Activation, Hippocampus, Neurons, Phosphorylation, Protein Binding, Protein Processing, Post-Translational, Synapses, Receptors, N-Methyl-D-Aspartate, Point Mutation, Genes, Reporter, Excitatory Postsynaptic Potentials, Mutation, Missense, RNA Interference, RNA, Small Interfering, Green Fluorescent Proteins, Rats, Calcium-Calmodulin-Dependent Protein Kinase Type 2, Miniature Postsynaptic Potentials

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