The DOI matches its Crossref record; 73 of the 73 references it cites were found in a registry or an index.
CaMKII activation persistently segregates postsynaptic proteins via liquid phase separation
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Abstract
Transient information input to the brain leads to persistent changes in synaptic circuits, contributing to the formation of memory engrams. Pre- and postsynaptic structures undergo coordinated functional and structural changes during this process, but how such changes are achieved by their component molecules remains largely unknown. We found that activated CaMKII, a central player of synaptic plasticity, undergoes liquid-liquid phase separation with the NMDA-type glutamate receptor subunit GluN2B. Due to CaMKII autophosphorylation, the condensate stably persists even after Ca 2+ is removed. The selective binding of activated CaMKII with GluN2B cosegregates AMPA receptors and the synaptic adhesion molecule neuroligin into a phase-in-phase assembly. In this way, Ca 2+-induced liquid-liquid phase separation of CaMKII has the potential to act as an activity-dependent mechanism to crosslink postsynaptic proteins, which may serve as a platform for synaptic reorganization associated with synaptic plasticity.
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“However, in the LLPS study, even after long incubation the CaMKII-GluN2B CTD dissipated after removal of Ca2+ unless the kinase was allowed to autophosphorylate, albeit slowly.”
From Synaptic memory and CaMKII (2023) · cites this paper as [323]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“As long as Ca2+/CaM is present, binding and phase separation are maintained even with a phosphonull mutant of T286 (T286A) (78, 169, 323, 377) or with a kinase-dead mutant of CaMKII (169, 323, 378, 379), although the binding of CaMKII to GluN2B is modestly enhanced by T286 phosphorylation (378).”
From Synaptic memory and CaMKII (2023) · cites this paper as [323]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Such a CaMKII-GluN2B hub may be the driver of increased AMPAR/TARPs that is the basis for LTP expression.”
From Synaptic memory and CaMKII (2023) · cites this paper as [323]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“For CaMKII co-condensation with GluN2B, our findings in HEK cells confirm prior results with cell-free assays20,21 indicating that Ca2+/CaM stimulation is sufficient for the induction of condensation but that pT286 is required for its maintenance beyond the initial stimulus.”
From LTP expression mediated by autonomous activity of GluN2B-bound CaMKII (2024) · cites this paper as [20]
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In the citing paper
“Furthermore, when AMPAR/TARPs (represented by the CTD of the auxiliary TARP subunit Stargazin) and PSD-95 are added to the system, activation of CaMKII in the presence of ATP partitions AMPAR/TARPs and NMDARs into two different phases (FIGURE 8).”
From Synaptic memory and CaMKII (2023) · cites this paper as [323]
The cited source says what the claim attributes to it.
In the citing paper
“In the LLPS study, autophosphorylation is necessary for persistence of the condensate.”
From Synaptic memory and CaMKII (2023) · cites this paper as [323]
The cited source says what the claim attributes to it.
In the citing paper
“The authors show that a mixture of the GluN2B CTD and CaMKII undergoes liquid-liquid phase separation (LLPS) when Ca2+/CaM binds to CaMKII in either the absence or presence of ATP.”
From Synaptic memory and CaMKII (2023) · cites this paper as [323]
The cited source says what the claim attributes to it.
In the citing paper
“Remarkably, when the CTD of neuroligin 1 is included, it partitions with the AMPAR/TARPs but not with the NMDARs, reminiscent of nanocolumns in the PSD (251–253)”
From Synaptic memory and CaMKII (2023) · cites this paper as [323]
The cited source says what the claim attributes to it.
In the citing paper
“In both cases addition of Ca2+/CaM in the absence of ATP or with the T286A mutant was sufficient for the LLPS or complex formation.”
From Synaptic memory and CaMKII (2023) · cites this paper as [323]
The cited source says what the claim attributes to it.
In the citing paper
“The phase separation resulting from GluN2B CTD and CaMKII mixed in the presence of Ca2+/CaM remains intact after the removal of Ca2+, but only if T286 is phosphorylated.”
From Synaptic memory and CaMKII (2023) · cites this paper as [323]
The cited source says what the claim attributes to it.
In the citing paper
“Importantly, although the maintenance of this segregation in the LLPS study required T286 autophosphorylation, it did not require the phosphorylation of any other component of the reconstituted system.”
From Synaptic memory and CaMKII (2023) · cites this paper as [323]
The cited source says what the claim attributes to it.
In the citing paper
“It is well established that the Ca2+/CaM-dependent binding and phase separation (LLPS) of CaMKII to GluN2B can occur in the absence of enzymatic activity (169, 323, 376).”
From Synaptic memory and CaMKII (2023) · cites this paper as [323]
The cited source says what the claim attributes to it.
In the citing paper
“T286 phosphorylation plays a role in the maintenance of liquid-liquid phase separation (LLPS) (323).”
From Synaptic memory and CaMKII (2023) · cites this paper as [323]
The cited source says what the claim attributes to it.
In the citing paper
“The recent findings of Hosokawa et al. (323) show that the CaMKII-GluN2B undergoes LLPS.”
From Synaptic memory and CaMKII (2023) · cites this paper as [323]
The cited source says what the claim attributes to it.
In the citing paper
“Most intriguingly, this orchestrates a phase-in-phase condensation of AMPAR/TARPs, PSD-95, and neuroligin1, largely independent of phosphorylation, although T286 phosphorylation is required for the maintenance of the condensates.”
From Synaptic memory and CaMKII (2023) · cites this paper as [323]
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Citations
Cites
Liquid-Liquid Phase Separation in Biology
Hyman, A. A., Weber, C. A., & Jülicher, F. (2014) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev-cellbio-100913-013325 · Cited by 3,155
Peptide tag forming a rapid covalent bond to a protein, through engineering a bacterial adhesin
Zakeri, B., Fierer, J. O., Çelik, E., Chittock, E. C., Schwarz‐Linek, U., Moy, V. T., & Howarth, M. R. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1115485109 · Cited by 1,673
Hayashi, Y., Shi, S.-H., Esteban, J. A., Piccini, A., Poncer, J.-C., & Malinow, R. (2000) · Science · doi:10.1126/science.287.5461.2262 · Cited by 1,524
Self-citationNeuroligin Expressed in Nonneuronal Cells Triggers Presynaptic Development in Contacting Axons
Scheiffele, P., Fan, J., Choih, J., Fetter, R., & Serafini, T. (2000) · Cell · doi:10.1016/s0092-8674(00)80877-6 · Cited by 1,218
The Postsynaptic Architecture of Excitatory Synapses: A More Quantitative View
Sheng, M., & Hoogenraad, C. C. (2007) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.76.060805.160029 · Cited by 1,003
Okamoto, K.-I., Nagai, T., Miyawaki, A., & Hayashi, Y. (2004) · Nature Neuroscience · doi:10.1038/nn1311 · Cited by 854
Self-citationThe AMPA Receptor Code of Synaptic Plasticity
Diering, G. H., & Huganir, R. L. (2018) · Neuron · doi:10.1016/j.neuron.2018.10.018 · Cited by 844
Ambadipudi, S., Biernat, J., Riedel, D., Mandelkow, E., & Zweckstetter, M. (2017) · Nature Communications · doi:10.1038/s41467-017-00480-0 · Cited by 782
Interaction with the NMDA receptor locks CaMKII in an active conformation
Bayer, K.-U., De Koninck, P., Leonard, A. S., Hell, J. W., & Schulman, H. (2001) · Nature · doi:10.1038/35081080 · Cited by 732
Activation of CaMKII in single dendritic spines during long-term potentiation
Lee, S.-J. R., Escobedo-Lozoya, Y., Szatmari, E. M., & Yasuda, R. (2009) · Nature · doi:10.1038/nature07842 · Cited by 685
Cited by
Sorted by citations
CaMKII: a central molecular organizer of synaptic plasticity, learning and memory
Yasuda, R., Hayashi, Y., & Hell, J. W. (2022) · Nature Reviews Neuroscience · doi:10.1038/s41583-022-00624-2 · Cited by 431
Self-citationNMDA receptor functions in health and disease: Old actor, new dimensions
Dupuis, J. P., Nicole, O., & Groc, L. (2023) · Neuron · doi:10.1016/j.neuron.2023.05.002 · Cited by 175
Self-citationNicoll, R. A., & Schulman, H. (2023) · Physiological Reviews · doi:10.1152/physrev.00034.2022 · Cited by 126
“These studies can inform our investigation of possible LLPS involvement in signaling at the PSD. Condensates require proteins capable of multi-valent interactions to produce a mesh or network that concentrate proteins and drive phase separation.”
BackgroundInfluentialLTP induction by structural rather than enzymatic functions of CaMKII
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., et al. (2023) · Nature · doi:10.1038/s41586-023-06465-y · Cited by 112
Hayashi, Y. (2022) · Neuroscience Research · doi:10.1016/j.neures.2021.08.001 · Cited by 102
Self-citation
Metadata
- Authors
- Hosokawa, T., Liu, P.-W., Cai, Q., Ferreira, J. S., Levet, F., Butler, C., Sibarita, J.-B., Choquet, D., Groc, L., Hosy, E., Zhang, M., & Hayashi, Y.
- Affiliations
- Kyoto University (JP)
- Hong Kong University of Science and Technology (HK)
- Université de Bordeaux (FR)
- Corresponding author
- Zhang, Mingjie
- Hayashi, Yasunori
- ORCID
- Venue
- Nature Neuroscience
- Published
- 2021-04-29
- Volume
- 24
- Issue
- 6
- Pages
- 777-785
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- OpenAlex
- W3157311560
- Cited by
- 146
- References
- 73
- Citations by year
- 2026: 26 · 2025: 26 · 2024: 33 · 2023: 28 · 2022: 23 · 2021: 10
- FWCI
- 10.86
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Locations
- Nature Neuroscience (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
- Funders
- Simons Foundation (510178)
- Naito Foundation
- Takeda Science Foundation
- Novartis Foundation
- Japan Foundation for Applied Enzymology
- Uehara Memorial Foundation
- Agence Nationale de la Recherche
- Ministry of Education, Culture, Sports, Science and Technology (17K14947, 18H04733, 22110006, 18H05434, 20240032, 18KK0421)
- Centre National de la Recherche Scientifique
- Research Foundation for Opto-Science and Technology
- National Institutes of Health (16H01292)
- Japan Society for the Promotion of Science (20240032, 16H01292, 20K21462, 22110006, 18H05428, 18H05434, 18H04733, 18KK0421, 22KF0163, 19K06885, 17K14947)
- RIKEN (22110006, 20240032, 18H04733, 18H05434)
- 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 › RNA Research and Splicing
- Keywords
- CaMKII, liquid-liquid phase separation, GluN2B, NMDA receptor, AMPA receptors, neuroligins, postsynaptic proteins, synaptic plasticity, calcium signaling, autophosphorylation, memory engrams, synaptic transmission
- MeSH terms
- Amino Acid Sequence, Animals, Enzyme Activation, Female, Male, Membrane Proteins, Receptors, N-Methyl-D-Aspartate, Rats, Sprague-Dawley, Receptors, AMPA, Mice, Rats, Calcium-Calmodulin-Dependent Protein Kinase Type 2, Liquid-Liquid Extraction
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