Calmodulin shuttling mediates cytonuclear signaling to trigger experience-dependent transcription and memory
Open accessAbstract
Learning and memory depend on neuronal plasticity originating at the synapse and requiring nuclear gene expression to persist. However, how synapse-to-nucleus communication supports long-term plasticity and behavior has remained elusive. Among cytonuclear signaling proteins, γCaMKII stands out in its ability to rapidly shuttle Ca 2+ /CaM to the nucleus and thus activate CREB-dependent transcription. Here we show that elimination of γCaMKII prevents activity-dependent expression of key genes ( BDNF, c-Fos , Arc ), inhibits persistent synaptic strengthening, and impairs spatial memory in vivo. Deletion of γCaMKII in adult excitatory neurons exerts similar effects. A point mutation in γCaMKII, previously uncovered in a case of intellectual disability, selectively disrupts CaM sequestration and CaM shuttling. Remarkably, this mutation is sufficient to disrupt gene expression and spatial learning in vivo. Thus, this specific form of cytonuclear signaling plays a key role in learning and memory and contributes to neuropsychiatric disease.
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The same R292P mutation that increases autonomous activity produces a loss of function in shuttling Ca2+/CaM from synapse to nucleus.
“The same mutation that increases autonomous activity produces a loss of function in shuttling Ca2+/CaM from synapse to nucleus (433).”
From Synaptic memory and CaMKII (2023) · cites this paper as [433]
The Results section, under “ID-associated γCaMKII R292P mutation impairs CaM shuttling” (page unavailable), reports that R292P fails to support nuclear CaM translocation, supporting the shuttling loss-of-function claim. It says the mutant retains kinase activity, but does not establish the claimed increase in autonomous activity. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThe structural disruption caused by R292P greatly reduces CaM trapping and thereby blocks the ability of autonomous CaMKIIγ to carry the cargo of CaM that it normally releases in the nucleus to stimulate CREB phosphorylation and gene expression.
“The structural disruption caused by R292P greatly reduces CaM trapping and thereby blocks the ability of autonomous CaMKIIγ to carry the cargo of CaM that it normally releases in the nucleus to stimulate CREB phosphorylation and gene expression.”
From Synaptic memory and CaMKII (2023) · cites this paper as [433]
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredR292 is near residues that CaM interacts with after autophosphorylation to produce CaM trapping.
“R292 is near residues that CaM interacts with after autophosphorylation to produce CaM trapping.”
From Synaptic memory and CaMKII (2023) · cites this paper as [433]
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- Authors
- Cohen, S. M., Suutari, B., He, X., Wang, Y., Sanchez, S., Tirko, N. N., Mandelberg, N. J., Mullins, C., Zhou, G., Wang, S., Kats, I., Salah, A., Tsien, R. W., & Ma, H.
- Affiliations
- NYU Langone Health (US)
- Second Affiliated Hospital of Zhejiang University (CN)
- Corresponding author
- Tsien, Richard W.
- Ma, Huan
- ORCID
- Venue
- Nature Communications
- Published
- 2018-06-22
- Volume
- 9
- Issue
- 1
- Pages
- 2451-2451
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC6015085
- OpenAlex
- W2808832906
- Cited by
- 67
- References
- 61
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 14 · 2023: 7 · 2022: 9 · 2021: 10 · 2020: 10 · 2019: 8 · 2018: 1
- FWCI
- 4.32
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- U.S. Department of Health and Human Services (GM058234, MH071739, NS24067)
- National Natural Science Foundation of China (111 Project, 31771109, 31722023, B13026)
- Higher Education Discipline Innovation Project (B13026)
- National Institutes of Health (B13026)
- Fundamental Research Funds for the Central Universities (B13026, 2018XZZX002-02, 111 project)
- National Institute of Mental Health (MH071739, R01MH071739, R37MH071739)
- National Institute on Drug Abuse (R01DA040484)
- National Institute of General Medical Sciences (T32GM007308, GM058234, R01GM058234)
- National Institute of Neurological Disorders and Stroke (NS 24067, R01NS024067)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- 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
- Keywords
- spatial memory, synaptic plasticity, CREB-dependent transcription, brain-derived neurotrophic factor, c-fos, Arc, intellectual disability, excitatory neurons, long-term potentiation
- MeSH terms
- Animals, Calmodulin, Humans, Male, Memory, Mice, Inbred C57BL, Gene Expression, Rats, Sprague-Dawley, Point Mutation, Long-Term Potentiation, Mice, Knockout, Calcium Signaling, Calcium-Calmodulin-Dependent Protein Kinase Type 2, Primary Cell Culture, Spatial Learning
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