CaMKIIα-driven, phosphatase-checked postsynaptic plasticity via phase separation
Open accessAbstract
Ca 2+/calmodulin-dependent kinase IIα (CaMKIIα) is essential for synaptic plasticity and learning by decoding synaptic Ca 2+ oscillations. Despite decades of extensive research, new mechanisms underlying CaMKIIα's function in synapses are still being discovered. Here, we discover that Shank3 is a specific binding partner for autoinhibited CaMKIIα. We demonstrate that Shank3 and GluN2B, via combined actions of Ca 2+ and phosphatases, reciprocally bind to CaMKIIα. Under basal condition, CaMKIIα is recruited to the Shank3 subcompartment of postsynaptic density (PSD) via phase separation. Rise of Ca 2+ concentration induces GluN2B-mediated recruitment of active CaMKIIα and formation of the CaMKIIα/GluN2B/PSD-95 condensates, which are autonomously dispersed upon Ca 2+ removal. Protein phosphatases control the Ca 2+-dependent shuttling of CaMKIIα between the two PSD subcompartments and PSD condensate formation. Activation of CaMKIIα further enlarges the PSD assembly and induces structural LTP. Thus, Ca 2+-induced and phosphatase-checked shuttling of CaMKIIα between distinct PSD nano-domains can regulate phase separation-mediated PSD assembly and synaptic plasticity.
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Our findings in HEK cells confirm prior results with cell-free assays indicating that Ca2+/CaM stimulation is sufficient for the induction of condensation but that pT286 is required for its maintenance beyond the initial stimulus.
“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 [21]
The condensate experiments (Fig. 5, ‘Ca²⁺ oscillation-modulated upper layer PSD assembly formation’; page unavailable) show that Ca²⁺/CaM stimulation promotes CaMKIIα enrichment in GluN2B/PSD-95 droplets. The Results (Fig. 3; page unavailable) show that T286 phosphorylation enhances GluN2B binding and that purified phosphorylated CaMKIIα retains binding after Ca²⁺/CaM removal. They do not directly establish that pT286 is required to maintain the condensates beyond stimulation; in the tested mixture containing PP2A, the condensates dispersed after Ca²⁺ removal. (LLM, conf=0.84)
Experimental — accuracy not yet measuredInactive CaMKIIα, but not β, binds to Shank3, and when it is activated it dissociates.
“Inactive CaMKIIα, but not β, binds to Shank3, and when it is activated it dissociates (161).”
From Synaptic memory and CaMKII (2023) · cites this paper as [161]
The CaMKIIα-Shank3 complex may serve as a nearby tethered reservoir pool of CaMKII.
“It is proposed that this CaMKIIα-Shank3 complex may serve as a nearby tethered reservoir pool of CaMKII (161).”
From Synaptic memory and CaMKII (2023) · cites this paper as [161]
Phosphatase PP2A rapidly dephosphorylates CaMKII, which results in the dissolution of the CaMKII-GluN2B complex.
“Further support for the role of T286 phosphorylation in maintaining the condensates and the binding of CaMKII to GluN2B in the absence of Ca2+/CaM is the finding that phosphatase PP2A rapidly dephosphorylates CaMKII, which results in the dissolution of the CaMKII-GluN2B complex (161).”
From Synaptic memory and CaMKII (2023) · cites this paper as [161]
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CaMKII activation persistently segregates postsynaptic proteins via liquid phase separation
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“It is proposed that this CaMKII a -Shank3 complex may serve as a nearby tethered reservoir pool of CaMKII (161).”
BackgroundInfluentialLTP expression mediated by autonomous activity of GluN2B-bound CaMKII
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- Authors
- Cai, Q., Zeng, M., Wu, X., Wu, H., Zhan, Y., Tian, R., & Zhang, M.
- Affiliations
- Hong Kong University of Science and Technology (HK)
- McGovern Institute for Brain Research (US)
- Southern University of Science and Technology (CN)
- Corresponding author
- Zhang, Mingjie
- Venue
- Cell Research
- Published
- 2020-11-24
- Volume
- 31
- Issue
- 1
- Pages
- 37-51
- ISSN
- 1001-0602 (ISSN-L)
- 1748-7838
- PMC
- PMC7852677
- OpenAlex
- W3106713453
- Cited by
- 83
- References
- 19
- Citations by year
- 2026: 15 · 2025: 16 · 2024: 17 · 2023: 17 · 2022: 9 · 2021: 8 · 2020: 1
- FWCI
- 4.01
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cell Research (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
- Funders
- Simons Foundation (510178)
- Research Grants Council, University Grants Committee (AoE-M09-12, C6004-17G, 16101419)
- 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 › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- CaMKIIα, SHANK3, GluN2B, PSD-95, phase separation, postsynaptic density, synaptic plasticity, long-term potentiation, protein phosphatase, calcium oscillations, autoinhibition, liquid-liquid phase separation
- MeSH terms
- SAP90-PSD95 Associated Proteins, Disks Large Homolog 4 Protein, Animals, Binding Sites, Calcium, Humans, Nerve Tissue Proteins, Neuronal Plasticity, Phosphoprotein Phosphatases, Phosphorylation, Protein Binding, Receptors, N-Methyl-D-Aspartate, Mice, Rats, Calcium-Calmodulin-Dependent Protein Kinase Type 2, HEK293 Cells, Molecular Docking Simulation
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