Neuronal L-Type Calcium Channel Signaling to the Nucleus Requires a Novel CaMKIIα-Shank3 Interaction
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Abstract
The activation of neuronal plasma membrane Ca 2+ channels stimulates many intracellular responses. Scaffolding proteins can preferentially couple specific Ca 2+ channels to distinct downstream outputs, such as increased gene expression, but the molecular mechanisms that underlie the exquisite specificity of these signaling pathways are incompletely understood. Here, we show that complexes containing CaMKII and Shank3, a postsynaptic scaffolding protein known to interact with L-type calcium channels (LTCCs), can be specifically coimmunoprecipitated from mouse forebrain extracts. Activated purified CaMKIIα also directly binds Shank3 between residues 829 and 1130. Mutation of Shank3 residues 949 Arg-Arg-Lys 951 to three alanines disrupts CaMKII binding in vitro and CaMKII association with Shank3 in heterologous cells. Our shRNA/rescue studies revealed that Shank3 binding to both CaMKII and LTCCs is important for increased phosphorylation of the nuclear CREB transcription factor and expression of c-Fos induced by depolarization of cultured hippocampal neurons. Thus, this novel CaMKII-Shank3 interaction is essential for the initiation of a specific long-range signal from LTCCs in the plasma membrane to the nucleus that is required for activity-dependent changes in neuronal gene expression during learning and memory. SIGNIFICANCE STATEMENT Precise neuronal expression of genes is essential for normal brain function. Proteins involved in signaling pathways that underlie activity-dependent gene expression, such as CaMKII, Shank3, and L-type calcium channels, are often mutated in multiple neuropsychiatric disorders. Shank3 and CaMKII were previously shown to bind L-type calcium channels, and we show here that Shank3 also binds to CaMKII. Our data show that each of these interactions is required for depolarization-induced phosphorylation of the CREB nuclear transcription factor, which stimulates the expression of c-Fos, a neuronal immediate early gene with key roles in synaptic plasticity, brain development, and behavior.
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CaMKIIα can also bind to a distinct domain of Shank3, which plays a role in gene transcription.
“Interestingly, CaMKIIα can also bind to a distinct domain of Shank3, which plays a role in gene transcription (163).”
From Synaptic memory and CaMKII (2023) · cites this paper as [163]
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“Interestingly, CaMKII a can also bind to a distinct domain of Shank3, which plays a role in gene transcription (163).”
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Excitation–transcription coupling, neuronal gene expression and synaptic plasticity
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Self-citationCaMKIIα-driven, phosphatase-checked postsynaptic plasticity via phase separation
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Activity-dependent redistribution of CaMKII in the postsynaptic compartment of hippocampal neurons
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Role of calcium/calmodulin-dependent kinase 2 in neurodevelopmental disorders
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A bidirectional switch in the Shank3 phosphorylation state biases synapses toward up- or downscaling
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CaMKII Phosphorylation Regulates Synaptic Enrichment of Shank3
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Acetylation of calmodulin regulates synaptic plasticity and fear learning
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Spontaneous motor-behavior abnormalities in two Drosophila models of neurodevelopmental disorders
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Variants in LRRC7 lead to intellectual disability, autism, aggression and abnormal eating behaviors
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Contribution of membrane-associated oscillators to biological timing at different timescales
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CaMKIIα phosphorylation of Shank3 modulates ABI1-Shank3 interaction
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Self-citationShank promotes action potential repolarization by recruiting BK channels to calcium microdomains
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Clustering of Ca V 1 .3 L‐type calcium channels by Shank3
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Calcium Signaling to the Nucleus
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Mini review of molecules involved in altered postnatal neurogenesis in autism
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Rigter, P. M. F., Bezstarosti, K., Koc, O. C., Perfitt, T. L., Demmers, J., Colbran, R. J., Stratton, M. M., Elgersma, Y., & van Woerden, G. M. (2026) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.5c00779 · Cited by 1 · see citing works
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Angelman Syndrome and Angelman-like Syndromes Share the Same Calcium-Related Gene Signatures
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Neurotransmitters, neuromodulators, synapses
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Simultaneous loss of CAMK2A and CAMK2B reveals endogenous in vivo substratesPreprint
Rigter, P. M. F., Bezstarosti, K., Koc, O. C., Perfitt, T. L., Demmers, J., Colbran, R. J., Stratton, M. M., Elgersma, Y., & van Woerden, G. M. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.11.17.624016
Self-citationCaMKII clusters neuronal LTCCs in biomolecular condensates to gate excitation-transcription couplingPreprint
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Self-citationβ-hydroxybutyrate restores social deficits by suppressing HDAC9 in the ACC of Shank3B-deficient mice
Hu, E., Li, J., Qi, C., Ge, J., Li, Y., Xue, Q., Wu, S., & Wang, W. (2026) · EMBO Molecular Medicine · doi:10.1038/s44321-026-00491-9
- Authors
- Perfitt, T. L., Wang, X., Dickerson, M. T., Stephenson, J. R., Nakagawa, T., Jacobson, D. A., & Colbran, R. J.
- Affiliations
- Vanderbilt University (US)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2020-02-04
- Volume
- 40
- Issue
- 10
- Pages
- 2000-2014
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC7055140
- OpenAlex
- W3004628053
- Cited by
- 54
- References
- 90
- Citations by year
- 2026: 3 · 2025: 1 · 2024: 11 · 2023: 8 · 2022: 8 · 2021: 8 · 2020: 15
- FWCI
- 4.47
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Heart Association (18PRE33960034, 14PRE18420020, DK20593)
- Vanderbilt University (DK59637, DK20593, DK58404, CA68485, EY08126, DK115620)
- National Institutes of Health (1s10od021630-01, 3p60dk020593-31s3, DK-59637, EY08126, CA68485, DK 20593, DK-58404, DK007563)
- National Institute of Mental Health (R01MH063232, T32MH065215)
- National Eye Institute (P30EY008126)
- National Cancer Institute (P30CA068485)
- National Institute of Diabetes and Digestive and Kidney Diseases (U2CDK059637, U24DK059637, R01DK097392, R13DK067392, T32DK007563, P30DK058404, T32DK101003, P30DK020593, R01DK115620)
- National Institute of Neurological Disorders and Stroke (R01NS078291)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD061543, U54HD083211)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- L-type calcium channels, CaMKIIα, SHANK3, postsynaptic scaffolding proteins, CREB phosphorylation, Fos expression, immediate early genes, hippocampal neurons, depolarization, activity-dependent gene expression, synaptic plasticity, neuropsychiatric disorders
- MeSH terms
- Animals, Cell Nucleus, Gene Expression Regulation, Hippocampus, Mice, Inbred C57BL, Microfilament Proteins, Nerve Tissue Proteins, Neurons, Signal Transduction, Calcium Channels, L-Type, Mice, Calcium-Calmodulin-Dependent Protein Kinase Type 2
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
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