CaV1 and CaV2 calcium channels mediate the release of distinct pools of synaptic vesicles
- Howard Hughes Medical Institute, University of Utah, United States
- University of Connecticut Health Center, United States
- University of Utah, United States
Abstract
Activation of voltage-gated calcium channels at presynaptic terminals leads to local increases in calcium and the fusion of synaptic vesicles containing neurotransmitter. Presynaptic output is a function of the density of calcium channels, the dynamic properties of the channel, the distance to docked vesicles, and the release probability at the docking site. We demonstrate that at C. elegans neuromuscular junctions two different classes of voltage-gated calcium channels, CaV2 and CaV1, mediate the release of distinct pools of synaptic vesicles. CaV2 channels are concentrated in densely packed clusters ~250 nm in diameter with the active zone proteins Neurexin, α-Liprin, SYDE, ELKS/CAST, RIM-BP, α‑Catulin, and MAGI1. CaV2 channels are colocalized with the priming protein UNC-13L and mediate the fusion of vesicles docked within 33 nm of the dense projection. CaV2 activity is amplified by ryanodine receptor release of calcium from internal stores, triggering fusion up to 165 nm from the dense projection. By contrast, CaV1 channels are dispersed in the synaptic varicosity, and are colocalized with UNC-13S. CaV1 and ryanodine receptors are separated by just 40nm, and vesicle fusion mediated by CaV1 is completely dependent on the ryanodine receptor. Distinct synaptic vesicle pools, released by different calcium channels, could be used to tune the speed, voltage-dependence, and quantal content of neurotransmitter release.
Data availability
All data generated and analyzed during this study have been included as supporting files; Source Data files have been provided. Github links to scripts used for analysis are noted in the methods.
Article and author information
Author details
Funding
National Science Foundation (NeuroNex 2014862)
- Erik M Jorgensen
National Institutes of Health (R01 NS034307)
- Erik M Jorgensen
National Institutes of Health (R01 MH085927)
- Zhao-Wen Wang
National Institutes of Health (R01 NS109388)
- Zhao-Wen Wang
National Institutes of Health (R01 NS094421)
- Andres Villu Maricq
National Institutes of Health (F31 NS084826)
- Sean A Merrill
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Reinhard Jahn, Max Planck Institute for Biophysical Chemistry, Germany
Version history
- Preprint posted: May 3, 2022 (view preprint)
- Received: June 25, 2022
- Accepted: February 22, 2023
- Accepted Manuscript published: February 23, 2023 (version 1)
- Version of Record published: March 17, 2023 (version 2)
- Version of Record updated: March 28, 2023 (version 3)
Copyright
© 2023, Mueller et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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CaV1 and CaV2 calcium channels mediate the release of distinct pools of synaptic vesicles
eLife 12:e81407.
https://doi.org/10.7554/eLife.81407
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