Rapid Ca 2+ channel accumulation contributes to cAMP-mediated increase in transmission at hippocampal mossy fiber synapses
Open accessAbstract
Significance: Despite the importance of the activation of the cAMP/PKA signaling pathway for presynaptic modulation, its cellular and molecular mechanisms remain unclear. In this study, we tackled this issue at hippocampal mossy fiber-CA3 synapses by combining paired electrophysiological recordings, Ca 2+ uncaging, total internal reflection fluorescence (TIRF) microscopy for direct measurements of presynaptic active zone Ca 2+ influx, and superresolution time-gated STED microscopy for visualization of Ca 2+ channel clusters within active zones. Our results suggest that Ca 2+ channels near release sites might accumulate upon activation of the cAMP/PKA pathway in the time scale of only several minutes. Our findings may thus change the focus from release machinery to Ca 2+ channel clusters and their dynamics as a cell biological mechanism of cAMP-dependent synaptic modulation.
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Neither an increase in the number of Ca2+ channels nor a functional modulation of Ca2+ channels accounts for the Pr change upon induction of chemical potentiation.
“However, a previous study and our results show that neither of them accounts for Pr change upon the induction of chemical potentiation (Fig 4D and 4E) [47].”
From Presynaptic cAMP-PKA-mediated potentiation induces reconfiguration of synaptic vesicle pools and channel-vesicle coupling at hippocampal mossy fiber boutons (2024) · cites this paper as [47]
The Discussion section, “Increased Ca2+ Concentration at Mossy Fiber Release Sites under cAMP,” favors Ca2+ channel accumulation at release sites as a mechanism of potentiation and says an increase in channel numbers is consistent with the observed cluster expansion. That contradicts the claim that an increase in channel number does not account for the change in release probability. The Results report that forskolin did not amplify the overall inward Ca2+ current, but that does not negate the paper’s proposed local channel-accumulation mechanism. (LLM, conf=0.90)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredPrevious studies reported a lack of change in coupling distance between CaV2.1 and Munc13-1.
“However, previous studies reported a lack of change in coupling distance between CaV2.1 and Munc13-1 [46,47].”
From Presynaptic cAMP-PKA-mediated potentiation induces reconfiguration of synaptic vesicle pools and channel-vesicle coupling at hippocampal mossy fiber boutons (2024) · cites this paper as [47]
The Results (gSTED microscopy section) report similar measured peak-to-peak distances between CaV2.1 and Munc13-1 clusters under control and forskolin conditions. But the authors explicitly caution that these measurements cannot exclude subtle changes in physical coupling distance, so an unqualified lack of change in coupling distance overstates the finding. (LLM, conf=0.86)
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Blobby is a synaptic active zone assembly protein required for memory in Drosophila
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Self-citationThe flexible synapse – How mossy fiber architecture adapts to changing needs
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Self-citation
- Authors
- Fukaya, R., Maglione, M., Sigrist, S. J., & Sakaba, T.
- Affiliations
- Doshisha University (JP)
- NeuroCure Cluster of Excellence (DE)
- Corresponding author
- Fukaya, Ryota
- Maglione, Marta
- Sigrist, Stephan J.
- Sakaba, Takeshi
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2021-02-23
- Volume
- 118
- Issue
- 9
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC7936331
- OpenAlex
- W3131482140
- Cited by
- 42
- References
- 69
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 10 · 2023: 9 · 2022: 9 · 2021: 4
- FWCI
- 3.69
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Society for the Promotion of Science (18H02530, 20K15905, core-to-core program A)
- MEXT | Japan Society for the Promotion of Science (19H04760, 20KK0171)
- Deutsche Forschungsgemeinschaft (FOR2750, SFB1315)
- 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 › Cell Biology › Cellular transport and secretion
- Keywords
- cAMP/PKA signaling, presynaptic modulation, mossy fiber-CA3 synapses, hippocampus, active zone, calcium influx, synaptic transmission, calcium uncaging, STED microscopy
- MeSH terms
- Cyclic AMP, Calcium, Microscopy, Fluorescence, Synaptic Transmission, Neuronal Plasticity, Calcium Channels, Patch-Clamp Techniques, Mossy Fibers, Hippocampal
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