Mechanisms of CaMKII action in long-term potentiation
Open accessAbstract
Long-term potentiation (LTP) of synaptic strength occurs during learning and can last for long periods, making it a probable mechanism for memory storage. LTP induction results in calcium entry, which activates calcium/calmodulin-dependent protein kinase II (CaMKII). CaMKII subsequently translocates to the synapse, where it binds to NMDA-type glutamate receptors and produces potentiation by phosphorylating principal and auxiliary subunits of AMPA-type glutamate receptors. These processes are all localized to stimulated spines and account for the synapse-specificity of LTP. In the later stages of LTP, CaMKII has a structural role in enlarging and strengthening the synapse.
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CaMKII also plays a role in the later stages of LTP by contributing to structural changes in the synapse, including the remodeling of the actin cytoskeleton within dendritic spines.
“Beyond these functional changes, CaMKII also plays a role in the later stages of LTP by contributing to structural changes in the synapse, including the remodeling of the actin cytoskeleton within dendritic spines [52].”
From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [52]
The Abstract and Maintenance of long-term potentiation section describe a possible structural role for CaMKII in later LTP and report persistent spine enlargement. The Translocation and binding to the NMDA receptor section links spine enlargement to increased F-actin and CaMKII binding, but describes the F-actin increase as contributing to CaMKII localization—not CaMKII as driving actin remodeling. That specific mechanism is not established by the cited paper. (LLM, conf=0.84)
Experimental — accuracy not yet measuredThe CaMKII complex maintains the on-state of synaptic memory through physical interactions within the PSD, effectively functioning as a structural switch that resists protein turnover.
“This complex maintains the ‘on-state’ of synaptic memory through physical interactions within the PSD, effectively functioning as a structural switch that resists protein turnover [51,52,63,64].”
From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [52]
The Maintenance of long-term potentiation section describes a possible persistent, structural role for CaMKII–NMDAR complexes at the PSD. Conclusions and perspectives discusses a model for preserving phosphorylated CaMKII during protein turnover, but treats how synaptic information survives turnover as unresolved. The claim therefore presents a proposed structural mechanism as an established switch that resists turnover. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThe interaction of CaMKII with GluN2B is crucial for LTP induction and is thought to initiate structural rearrangements within the PSD.
“This interaction is crucial for LTP induction and is thought to initiate structural rearrangements within the PSD [52].”
From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [52]
In 'Translocation and binding to the NMDA receptor' (page not provided), the review says CaMKII binding to NR2B is necessary for LTP, supporting the first part of the claim. It does not establish that this interaction initiates structural rearrangements within the PSD; 'Maintenance of long-term potentiation' (page not provided) says the mechanisms triggering structural changes and CaMKII’s role in them are unknown. (LLM, conf=0.87)
Experimental — accuracy not yet measuredUpon activation, CaMKII acts as a persistent structural seed or molecular tag that captures proteins, such as densin and delta-catenin, required for spine growth and synaptic stabilization.
“Upon activation, CaMKII acts as a persistent structural ‘seed’ or molecular tag that captures proteins, such as densin and delta-catenin, required for spine growth and synaptic stabilization.”
From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [52]
In “Translocation and binding to the NMDA receptor” (page unavailable), the paper says activated CaMKII moves to synapses and can remain bound there; it names densin-180 as a binding partner that may hold CaMKII in the postsynaptic density. “Maintenance of long-term potentiation” links active CaMKII to increased spine volume but says the structural process is uncertain. These passages do not establish that CaMKII acts as a persistent seed or tag that captures densin or delta-catenin for spine growth and stabilization; delta-catenin was not found in the searched passages. (LLM, conf=0.88)
Experimental — accuracy not yet measuredCaMKII is critically involved in NMDAR-dependent LTP.
“CaMKII, a highly abundant protein enriched in the PSD, is critically involved in NMDAR-dependent LTP [51,52].”
From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [52]
Activated CaMKII translocates to the PSD, where it binds to the cytoplasmic C-tail of the GluN2B subunit of NMDARs.
“Activated CaMKII then translocates to the PSD, where it binds to the cytoplasmic C-tail of the GluN2B subunit of NMDARs.”
From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [52]
Upon activation, CaMKII undergoes autophosphorylation at Thr-286, which renders it constitutively active even after calcium levels return to baseline.
“Upon activation, CaMKII undergoes autophosphorylation at Thr-286, which renders it constitutively active even after calcium levels return to baseline.”
From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [52]
CaMKII is highly abundant in the postsynaptic density and is rapidly activated by calcium/calmodulin binding following NMDAR activation.
“CaMKII is highly abundant in the postsynaptic density (PSD) and is rapidly activated by calcium/calmodulin binding following NMDAR activation [52].”
From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [52]
Interneurons lack Ca2+/calmodulin-dependent kinase IIa, which is an essential component of the NMDAR-dependent cascade that underlies LTP at glutamatergic synapses onto principal cells, suggesting that alternative mechanisms must exist for LTP/LTD onto interneurons.
“Although NMDAR-dependent plasticity has been observed at synapses onto interneurons (see below for further discussion), interneurons lack Ca2+/calmodulin-dependent kinase IIa (686, 1012), which is an essential component of the NMDAR-dependent cascade that underlies LTP at glutamatergic synapses onto principal cells (682), suggesting that alternative mechanisms must exist for LTP/LTD onto interneur”
From Hippocampal GABAergic Inhibitory Interneurons (2017) · cites this paper as [682]
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- Authors
- Lisman, J., Yasuda, R., & Raghavachari, S.
- Affiliations
- Brandeis University (US)
- Duke University (US)
- Corresponding author
- Lisman, John
- Venue
- Nature Reviews Neuroscience
- Published
- 2012-02-15
- Volume
- 13
- Issue
- 3
- Pages
- 169-182
- ISSN
- 1471-003X (ISSN-L)
- 1471-0048
- PMC
- PMC4050655
- OpenAlex
- W2013115334
- Cited by
- 1,134
- References
- 154
- Citations by year
- 2026: 74 · 2025: 80 · 2024: 66 · 2023: 79 · 2022: 82 · 2021: 78 · 2020: 76 · 2019: 88 · 2018: 81 · 2017: 74 · 2016: 65 · 2015: 85 · 2014: 84 · 2013: 82 · 2012: 39
- FWCI
- 9.81
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature reviews. Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute on Drug Abuse (R01DA027807)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Keywords
- CaMKII, long-term potentiation, synaptic plasticity, NMDA receptor, AMPA receptor phosphorylation, calcium/calmodulin-dependent protein kinase II, postsynaptic mechanisms, synapse specificity, dendritic spines, learning and memory, calcium influx
- MeSH terms
- Animals, Hippocampus, Phosphorylation, Synapses, Receptors, N-Methyl-D-Aspartate, Long-Term Potentiation, Receptors, AMPA, Calcium-Calmodulin-Dependent Protein Kinase Type 2
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