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Cited by 112Neuroscience and Neuropharmacology ResearchMemory and Neural MechanismsProtein Kinase Regulation and GTPase Signaling

LTP induction by structural rather than enzymatic functions of CaMKII

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Tullis, Jonathan E., Larsen, Matthew E., Rumian, Nicole L., Freund, Ronald K., Boxer, Emma E., Brown, Carolyn Nicole, Coultrap, Steven J., Schulman, Howard +3 more·2023·Nature
DOI 10.1038/s41586-023-06465-yPMC PMC10482691
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Abstract

Learning and memory are thought to require hippocampal long-term potentiation (LTP), and one of the few central dogmas of molecular neuroscience that has stood undisputed for more than three decades is that LTP induction requires enzymatic activity of the Ca 2+/calmodulin-dependent protein kinase II (CaMKII)1–3. However, as we delineate here, the experimental evidence is surprisingly far from conclusive. All previous interventions inhibiting enzymatic CaMKII activity and LTP 4–8 also interfere with structural CaMKII roles, in particular binding to the NMDA-type glutamate receptor subunit GluN2B 9–14. Thus, we here characterized and utilized complementary sets of new opto-/pharmaco-genetic tools to distinguish between enzymatic and structural CaMKII functions. Several independent lines of evidence demonstrated LTP induction by a structural function of CaMKII rather than by its enzymatic activity. The sole contribution of kinase activity was autoregulation of this structural role via T286 autophosphorylation, which explains why this distinction has been elusive for decades. Directly initiating the structural function in a manner that circumvented this T286 role was sufficient to elicit robust LTP, even when enzymatic CaMKII activity was blocked.

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Cited by

Sorted by citations

Authors
Tullis, J. E., Larsen, M. E., Rumian, N. L., Freund, R. K., Boxer, E. E., Brown, C. N., Coultrap, S. J., Schulman, H., Aoto, J., Dell’Acqua, M. L., & Bayer, K. U.
Affiliations
  • University of Colorado Anschutz (US)
  • Stanford Medicine (US)
Corresponding author
Bayer, K. Ulrich
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2023-08-30
Volume
621
Issue
7977
Pages
146-153
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/s41586-023-06465-y
PMC
PMC10482691
OpenAlex
W4386304522
Cited by
112
References
10
Citations by year
2026: 25 · 2025: 45 · 2024: 37 · 2023: 5
FWCI
13.70
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
Funders
  • Fondation Leducq
  • National Institutes of Health (NS040701)
  • Anschutz Medical Campus, University of Colorado
  • National Institute on Aging (F31AG062160, R01AG067713, F31AG069458, F31AG084197)
  • National Institute of Mental Health (F31MH125510, R01MH116901)
  • National Institute of General Medical Sciences (T32GM007635)
  • National Institute of Neurological Disorders and Stroke (R01NS040701, R01NS080851, F31NS129254, R01NS118786, R01NS110383, R01NS081248)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords
CaMKII, long-term potentiation, GluN2B, NMDA receptor, hippocampus, optogenetics, pharmacogenetics, autoregulation, learning and memory
MeSH terms
Hippocampus, Learning, Phosphorylation, Protein Binding, Receptors, N-Methyl-D-Aspartate, Long-Term Potentiation, Glutamic Acid, Calcium-Calmodulin-Dependent Protein Kinase Type 2, Optogenetics

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