Autonomous CaMKII Mediates Both LTP and LTD Using a Mechanism for Differential Substrate Site Selection
Open accessAbstract
Traditionally, hippocampal long-term potentiation (LTP) of synaptic strength requires Ca(2+)/calmodulin (CaM)-dependent protein kinase II (CaMKII) and other kinases, whereas long-term depression (LTD) requires phosphatases. Here, we found that LTD also requires CaMKII and its phospho-T286-induced "autonomous" (Ca(2+)-independent) activity. However, whereas LTP is known to induce phosphorylation of the AMPA-type glutamate receptor (AMPAR) subunit GluA1 at S831, LTD instead induced CaMKII-mediated phosphorylation at S567, a site known to reduce synaptic GluA1 localization. GluA1 S831 phosphorylation by "autonomous" CaMKII was further stimulated by Ca(2+)/CaM, as expected for traditional substrates. By contrast, GluA1 S567 represents a distinct substrate class that is unaffected by such stimulation. This differential regulation caused GluA1 S831 to be favored by LTP-type stimuli (strong but brief), whereas GluA1 S567 was favored by LTD-type stimuli (weak but prolonged). Thus, requirement of autonomous CaMKII in opposing forms of plasticity involves distinct substrate classes that are differentially regulated to enable stimulus-dependent substrate-site preference.
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During LTD-inducing conditions autonomous CaMKII selectively phosphorylates S567 on the GluA1 AMPAR subunit to reduce its synaptic localization.
“It has also been reported that during LTD-inducing conditions autonomous CaMKII selectively phosphorylates S567 on the GluA1 AMPAR subunit to reduce its synaptic localization (401).”
From Synaptic memory and CaMKII (2023) · cites this paper as [401]
NMDAR-dependent LTD also requires CaMKII and its autonomous (calcium-independent) activity.
“Interestingly, recent research indicates that NMDAR-dependent LTD also requires CaMKII and its autonomous (calcium-independent) activity.”
From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [69]
Autonomous CaMKII mediates opposing forms of plasticity through differential substrate site selection.
“This enables autonomous CaMKII to mediate opposing forms of plasticity through differential substrate site selection [69].”
From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [69]
LTD stimuli induce CaMKII-dependent phosphorylation of GluA1 at S567, a site that reduces synaptic localization and is unaffected by Ca2+/CaM stimulation, unlike the S831 site favored in LTP.
“In this context, LTD stimuli induce CaMKII-dependent phosphorylation of GluA1 at S567, a site that reduces synaptic localization and is unaffected by Ca2+/CaM stimulation, unlike the S831 site favored in LTP [69].”
From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [69]
CaMKII activity is required during LTD, where a prolonged weak stimulus favors phosphorylation of GluA1 S567 over S831, leading to removal of synaptic GluA1.
“CaMKII is well known to be required for LTP, but its activity is also required during LTD where a prolonged “weak” stimulus favors the phosphorylation of GluA1 S567 over S831, leading to removal of synaptic GluA1 (Coultrap et al., 2014).”
From The AMPA Receptor Code of Synaptic Plasticity (2018) · cites this paper as Coultrap et al., 2014
GluA1 S567 is phosphorylated by CaMKII and promotes removal of GluA1 from synapses.
“A phosphorylation site was identified in the first intracellular loop of GluA1 (S567) which is phosphorylated by CaMKII and promotes removal of GluA1 from synapses (Lu et al., 2010, Coultrap et al., 2014).”
From The AMPA Receptor Code of Synaptic Plasticity (2018) · cites this paper as Coultrap et al., 2014
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“It has also been reported that during LTD-inducing conditions autonomous CaMKII selectively phosphorylates S567 on the GluA1 AMPAR subunit to reduce its synaptic localization (401).”
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Molecular Physiology of the Neuronal Synapse
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“This enables autonomous CaMKII to mediate opposing forms of plasticity through differential substrate site selection [69].”
- Authors
- Coultrap, S. J., Freund, R. K., O’Leary, H., Sanderson, J. L., Roche, K. W., Dell’Acqua, M. L., & Bayer, K. U.
- Affiliations
- University of Colorado Anschutz (US)
- National Institutes of Health (US)
- Corresponding author
- Dell’Acqua, Mark L.
- Bayer, K. Ulrich
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2014-02
- Volume
- 6
- Issue
- 3
- Pages
- 431-437
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC3930569
- OpenAlex
- W2087436387
- Cited by
- 207
- References
- 7
- Citations by year
- 2026: 8 · 2025: 10 · 2024: 11 · 2023: 27 · 2022: 26 · 2021: 18 · 2020: 17 · 2019: 9 · 2018: 18 · 2017: 15 · 2016: 17 · 2015: 21 · 2014: 10
- FWCI
- 9.60
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institute of Mental Health (T32MH015442)
- National Institute of Neurological Disorders and Stroke (P30NS048154, NS080851, NS040701, R56NS040701, R01NS040701, NS048154, NS081248, R01NS080851, 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, long-term depression, GluR1, AMPA receptor phosphorylation, calcium/calmodulin-dependent protein kinase, hippocampus, synaptic plasticity
- MeSH terms
- Amino Acid Sequence, Animals, Hippocampus, Molecular Sequence Data, Phosphorylation, Phosphoserine, Substrate Specificity, Receptors, N-Methyl-D-Aspartate, Long-Term Potentiation, Receptors, AMPA, Long-Term Synaptic Depression, Mice, Calcium-Calmodulin-Dependent Protein Kinase Type 2
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