Alternative splicing modulates the frequency‐dependent response of CaMKII to Ca2+ oscillations
Open accessAbstract
Ca(2+) oscillations are required in various signal trans duction pathways, and contain information both in their amplitude and frequency. Remarkably, the Ca(2+)/calmodulin(CaM)-dependent protein kinase II (CaMKII) can decode such frequencies. A Ca(2+)/CaM-stimulated autophosphorylation leads to Ca(2+)/CaM-independent (autonomous) activity of the kinase that outlasts the initial stimulation. This autonomous activity increases exponentially with the frequency of Ca(2+) oscillations. Here we show that three beta-CaMKII splice variants (beta(M), beta and beta(e)') have very similar specific activity and maximal autonomy. However, their autonomy generated by Ca(2+) oscillations differs significantly. A mechanistic basis was found in alterations of the CaM activation constant and of the initial rate of autophosphorylation. Structurally, the splice variants differ only in a variable 'linker' region between the kinase and association domains. Therefore, we propose that differences in relative positioning of kinase domains within multimeric holoenzymes are responsible for the observed effects. Notably, the beta-CaMKII splice variants are differentially expressed, even among individual hippocampal neurons. Taken together, our results suggest that alternative splicing provides cells with a mechanism to modulate their sensitivity to Ca(2+) oscillations.
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The linker length affects CaM affinity and Ca2+ spike frequency sensitivity as well as rates of autophosphorylation.
“The linker length affects CaM affinity and Ca2+ spike frequency sensitivity (69, 158) as well as rates of autophosphorylation (159).”
From Synaptic memory and CaMKII (2023) · cites this paper as [158]
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“The linker length affects CaM af fi nity and Ca 2 1 spike frequency sensitivity (69, 158) as well as rates of autophosphorylation (159).”
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Intersubunit capture of regulatory segments is a component of cooperative CaMKII activation
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- Authors
- Bayer, K. U., Koninck, P. D., & Schulman, H.
- Affiliations
- Stanford Medicine (US)
- Université Laval (CA)
- Corresponding author
- Bayer, K. Ulrich
- Schulman, Howard
- Venue
- The EMBO Journal
- Published
- 2002-07-15
- Volume
- 21
- Issue
- 14
- Pages
- 3590-3597
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC126106
- OpenAlex
- W2122409525
- Cited by
- 112
- References
- 6
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 5 · 2023: 7 · 2022: 4 · 2021: 4 · 2020: 5 · 2019: 6 · 2018: 5 · 2017: 2 · 2016: 1 · 2015: 3 · 2014: 3 · 2013: 4 · 2012: 6
- FWCI
- 2.90
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- The EMBO Journal (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Burroughs Wellcome Fund
- Deutsche Forschungsgemeinschaft
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- CaMKII, alternative splicing, calcium oscillations, calmodulin, autophosphorylation, hippocampal neurons, calcium signaling
- MeSH terms
- Amino Acid Sequence, Animals, Base Sequence, Brain, Calcium, Cloning, Molecular, Molecular Sequence Data, Phosphorylation, Alternative Splicing, Calcium-Calmodulin-Dependent Protein Kinases, COS Cells, Calcium-Calmodulin-Dependent Protein Kinase Type 2
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