Nanoscale Distribution of Presynaptic Ca2+ Channels and Its Impact on Vesicular Release during Development
Open accessAbstract
Synaptic efficacy and precision are influenced by the coupling of voltage-gated Ca(2+) channels (VGCCs) to vesicles. But because the topography of VGCCs and their proximity to vesicles is unknown, a quantitative understanding of the determinants of vesicular release at nanometer scale is lacking. To investigate this, we combined freeze-fracture replica immunogold labeling of Cav2.1 channels, local [Ca(2+)] imaging, and patch pipette perfusion of EGTA at the calyx of Held. Between postnatal day 7 and 21, VGCCs formed variable sized clusters and vesicular release became less sensitive to EGTA, whereas fixed Ca(2+) buffer properties remained constant. Experimentally constrained reaction-diffusion simulations suggest that Ca(2+) sensors for vesicular release are located at the perimeter of VGCC clusters (<30 nm) and predict that VGCC number per cluster determines vesicular release probability without altering release time course. This "perimeter release model" provides a unifying framework accounting for developmental changes in both synaptic efficacy and time course.
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Observations in small CNS synapses of both clustered and random distribution of Ca2+ channels, and emerging evidence for channel mobility as an equalizer of Pr for vesicles independent of channel positioning, suggest that their precise distribution may not be the sole determinant of the active zone release likelihood landscape.
“However, observations in small CNS synapses of both clustered24,25 and random distribution of Ca2+ channels26, and emerging evidence for channel mobility as an equalizer of Pr for vesicles independent of channel positioning27 suggest that their precise distribution may not be the sole determinant of the AZ release likelihood landscape.”
From A trans-synaptic nanocolumn aligns neurotransmitter release to receptors (2016) · cites this paper as [25]
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Experimental — accuracy not yet measuredModeling of Ca2+ domains showed that tightening of coupling increases Pr approximately 10-fold per 20 nm change in coupling distance.
“Modeling of Ca2+ domains showed that tightening of coupling increases Pr approximately 10-fold per 20 nm change in coupling distance [87,88].”
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 [88]
The Results (‘Estimating the VGCC-Sensor Distance’; page unavailable) describe Ca2+-domain simulations in which vesicular release probability falls with increasing distance from Ca2+ channels. The Results (‘Estimating the Vesicular Release Probability in the Vicinity of a VGCC Cluster’; page unavailable) likewise report that probability decreases outside the channel cluster. Neither passage establishes an approximately 10-fold increase for each 20 nm of tighter coupling. (LLM, conf=0.84)
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- Authors
- Nakamura, Y., Harada, H., Kamasawa, N., Matsui, K., Rothman, J. S., Shigemoto, R., Silver, R. A., DiGregorio, D. A., & Takahashi, T.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Institute of Science and Technology Austria (AT)
- National Institute for Physiological Sciences (JP)
- University College London (GB)
- Doshisha University (JP)
- Corresponding author
- DiGregorio, David A.
- Takahashi, Tomoyuki
- ORCID
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2015-01
- Volume
- 85
- Issue
- 1
- Pages
- 145-158
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC4305191
- OpenAlex
- W2030428080
- Cited by
- 245
- References
- 60
- Citations by year
- 2026: 10 · 2025: 18 · 2024: 26 · 2023: 19 · 2022: 22 · 2021: 23 · 2020: 27 · 2019: 24 · 2018: 22 · 2017: 21 · 2016: 14 · 2015: 18 · 2014: 1
- FWCI
- 8.23
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Neuron (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Funders
- Core Research for Evolutional Science and Technology (CREST) of Japan Science and Technology Agency
- Okinawa Institute of Science and Technology (OIST)
- JSPS
- Japanese Ministry of Education, Culture, Sports, Science and Technology (23700474)
- Centre National de la Recherche Scientifique
- Fondation Fyssen
- Fondation pour la Recherche Medicale
- Federation pour la Recherche sur le Cerveau
- Agence Nationale de la Recherche (ANR-2007-Neuro-008-01, ANR-2010-BLAN-1411-01)
- European Commission Coordination Action ENINET (LSHM-CT-2005-19063)
- Wellcome Trust (064413, 095667)
- ERC (294667)
- 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
- voltage-gated calcium channels, Cav2.1, presynaptic calcium channels, synaptic vesicle release, release probability, calyx of Held, synaptic development, reaction-diffusion simulation
- MeSH terms
- Action Potentials, Animals, Calcium, Egtazic Acid, Exocytosis, Synapses, Synaptic Vesicles, Presynaptic Terminals, Patch-Clamp Techniques, Calcium Channels, N-Type, Mice, Rats, Calcium Chelating Agents
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