Differential roles of CaMKII isoforms in phase separation with NMDA receptors and in synaptic plasticity
Open accessAbstract
Calcium calmodulin-dependent kinase II (CaMKII) is critical for synaptic transmission and plasticity. Two major isoforms of CaMKII, CaMKIIα and CaMKIIβ, play distinct roles in synaptic transmission and long-term potentiation (LTP) with unknown mechanisms. Here, we show that the length of the unstructured linker between the kinase domain and the oligomerizing hub determines the ability of CaMKII to rescue the basal synaptic transmission and LTP defects caused by removal of both CaMKIIα and CaMKIIβ (double knockout [DKO]). Remarkably, although CaMKIIβ binds to GluN2B with a comparable affinity as CaMKIIα does, only CaMKIIα with the short linker forms robust dense clusters with GluN2B via phase separation. Lengthening the linker of CaMKIIα with unstructured "Gly-Gly-Ser" repeats impairs its phase separation with GluN2B, and the mutant enzyme cannot rescue the basal synaptic transmission and LTP defects of DKO mice. Our results suggest that the phase separation capacity of CaMKII with GluN2B is critical for its cellular functions in the brain.
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Binding of CaMKII to GluN2B is critical for the synaptic enhancement caused by CaMKII.
“This binding of CaMKII to GluN2B is critical for the synaptic enhancement caused by CaMKII (see sect. 6) (119–122).”
From Synaptic memory and CaMKII (2023) · cites this paper as [122]
Both isothermal titration calorimetry and glutathione S-transferase (GST) pulldowns indicate that the binding of both CaMKII isoforms to GluN2B is the same.
“both isothermal titration calorimetry and glutathione S-transferase (GST) pulldowns indicate that the binding of both isoforms is the same.”
From Synaptic memory and CaMKII (2023) · cites this paper as [122]
The failure of CaMKIIβ to phase separate could be rescued by swapping its long hub linker with the shorter linker from CaMKIIα, and this chimera fully rescued LTP.
“The failure of CaMKIIβ to phase separate could be rescued by swapping its long hub linker with the shorter linker from CaMKIIα, and this chimera fully rescued LTP.”
From Synaptic memory and CaMKII (2023) · cites this paper as [122]
Despite equal binding, CaMKIIβ, in contrast to CaMKIIα, failed to undergo liquid-liquid phase separation when combined with GluN2B CTD, Ca2+, and CaM.
“CaMKIIβ, in contrast to CaMKIIα, failed to undergo liquid-liquid phase separation when combined with GluN2B CTD, Ca2+, and CaM.”
From Synaptic memory and CaMKII (2023) · cites this paper as [122]
Cites
Interaction with the NMDA receptor locks CaMKII in an active conformation
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Functional Implications of the Subunit Composition of Neuronal CaM Kinase II
Brocke, L., Chiang, L. W., Wagner, P. D., & Schulman, H. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.32.22713 · Cited by 161 · see citing works
CaMKII activation persistently segregates postsynaptic proteins via liquid phase separation
Hosokawa, T., Liu, P.-W., Cai, Q., Ferreira, J. S., Levet, F., Butler, C., Sibarita, J.-B., Choquet, D., Groc, L., Hosy, E., et al. (2021) · Nature Neuroscience · doi:10.1038/s41593-021-00843-3 · Cited by 146 · see citing works
Self-citationKim, K., Lakhanpal, G., Lu, H. E., Khan, M., Suzuki, A., Kato Hayashi, M., Narayanan, R., Luyben, T. T., Matsuda, T., Nagai, T., et al. (2015) · Neuron · doi:10.1016/j.neuron.2015.07.023 · Cited by 145 · see citing works
Intersubunit capture of regulatory segments is a component of cooperative CaMKII activation
Chao, L. H., Pellicena, P., Deindl, S., Barclay, L. A., Schulman, H., & Kuriyan, J. (2010) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.1751 · Cited by 119 · see citing works
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Nicoll, R. A., & Schulman, H. (2023) · Physiological Reviews · doi:10.1152/physrev.00034.2022 · Cited by 126 · see citing works
Self-citation
- Authors
- Cai, Q., Chen, X., Zhu, S., Nicoll, R. A., & Zhang, M.
- Affiliations
- Xiamen University (CN)
- University of California, San Francisco (US)
- Hong Kong University of Science and Technology (HK)
- Corresponding author
- Nicoll, Roger A.
- Zhang, Mingjie
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2023-03
- Volume
- 42
- Issue
- 3
- Pages
- 112146
- ISSN
- 2211-1247 (ISSN-L)
- OpenAlex
- W4321523347
- Cited by
- 31
- References
- 7
- Citations by year
- 2026: 8 · 2025: 15 · 2024: 3 · 2023: 5
- FWCI
- 3.76
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
- Funders
- HFSP (RGP0020/2019)
- National Natural Science Foundation of China (82188101)
- MOST (2019YFA0508402)
- Research Grants Council, University Grants Committee (16101419, 16104518, AoE-M09-12)
- Horowitz Foundation for Social Policy
- NIH (R01MH117139)
- 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, CaMKIIα, CaMKIIβ, isoform-specific function, phase separation, NMDA receptor, GluN2B, synaptic transmission, long-term potentiation, synaptic plasticity, linker length, protein aggregation
- MeSH terms
- Animals, Neuronal Plasticity, Receptors, N-Methyl-D-Aspartate, Long-Term Potentiation, Protein Isoforms, Mice, Calcium-Calmodulin-Dependent Protein Kinase Type 2
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