Ca2+-dependent neurotransmitter release requires synaptotagmins as Ca2+ sensors to trigger synaptic vesicle (SV) exocytosis via binding of their tandem C2 domains—C2A and C2B—to Ca2+. We have previously demonstrated that SNT-1, a mouse synaptotagmin-1 (Syt1) homologue, functions as the fast Ca2+ sensor in Caenorhabditis elegans. Here, we report a new Ca2+ sensor, SNT-3, which triggers delayed Ca2+-dependent neurotransmitter release. snt-1;snt-3 double mutants abolish evoked synaptic transmission, demonstrating that C. elegans NMJs use a dual Ca2+ sensor system. SNT-3 possesses canonical aspartate residues in both C2 domains, but lacks an N-terminal transmembrane (TM) domain. Biochemical evidence demonstrates that SNT-3 binds both Ca2+ and the plasma membrane. Functional analysis shows that SNT-3 is activated when SNT-1 function is impaired, triggering SV release that is loosely coupled to Ca2+ entry. Compared with SNT-1, which is tethered to SVs, SNT-3 is not associated with SV. Eliminating the SV tethering of SNT-1 by removing the TM domain or the whole N terminus rescues fast release kinetics, demonstrating that cytoplasmic SNT-1 is still functional and triggers fast neurotransmitter release, but also exhibits decreased evoked amplitude and release probability. These results suggest that the fast and slow properties of SV release are determined by the intrinsically different C2 domains in SNT-1 and SNT-3, rather than their N-termini–mediated membrane tethering. Our findings therefore reveal a novel dual Ca2+ sensor system in C. elegans and provide significant insights into Ca2+-regulated exocytosis.
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5 April 2021
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February 11 2021
A novel dual Ca2+ sensor system regulates Ca2+-dependent neurotransmitter release
Lei Li
,
1
Queensland Brain Institute, Clem Jones Centre for Ageing Dementia Research, The University of Queensland, Brisbane, Queensland, Australia
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Haowen Liu
,
1
Queensland Brain Institute, Clem Jones Centre for Ageing Dementia Research, The University of Queensland, Brisbane, Queensland, Australia
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Mia Krout
,
Mia Krout
2
Department of Biological Sciences, University of Illinois at Chicago, Chicago, IL
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Janet E. Richmond
,
Janet E. Richmond
2
Department of Biological Sciences, University of Illinois at Chicago, Chicago, IL
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Yu Wang
,
Yu Wang
3
Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA
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Jihong Bai
,
Jihong Bai
3
Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA
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Saroja Weeratunga
,
Saroja Weeratunga
4
Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia
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Brett M. Collins
,
Brett M. Collins
4
Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia
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Donovan Ventimiglia
,
Donovan Ventimiglia
5
Lulu and Anthony Wang Laboratory of Neural Circuits and Behavior, The Rockefeller University, New York, NY
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Yi Yu
,
Yi Yu
1
Queensland Brain Institute, Clem Jones Centre for Ageing Dementia Research, The University of Queensland, Brisbane, Queensland, Australia
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Jingyao Xia
,
Jingyao Xia
1
Queensland Brain Institute, Clem Jones Centre for Ageing Dementia Research, The University of Queensland, Brisbane, Queensland, Australia
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Jing Tang
,
Jing Tang
1
Queensland Brain Institute, Clem Jones Centre for Ageing Dementia Research, The University of Queensland, Brisbane, Queensland, Australia
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Jie Liu
,
Jie Liu
6
Neuroscience Program, Monash Biomedicine Discovery Institute and Department of Anatomy and Developmental Biology, Monash University, Melbourne, Victoria, Australia
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Zhitao Hu
1
Queensland Brain Institute, Clem Jones Centre for Ageing Dementia Research, The University of Queensland, Brisbane, Queensland, Australia
Correspondence to Zhitao Hu: z.hu1@uq.edu.au
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Lei Li
1
Queensland Brain Institute, Clem Jones Centre for Ageing Dementia Research, The University of Queensland, Brisbane, Queensland, Australia
Haowen Liu
1
Queensland Brain Institute, Clem Jones Centre for Ageing Dementia Research, The University of Queensland, Brisbane, Queensland, Australia
Mia Krout
2
Department of Biological Sciences, University of Illinois at Chicago, Chicago, IL
Janet E. Richmond
2
Department of Biological Sciences, University of Illinois at Chicago, Chicago, IL
Yu Wang
3
Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA
Jihong Bai
3
Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA
Saroja Weeratunga
4
Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia
Brett M. Collins
4
Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia
Donovan Ventimiglia
5
Lulu and Anthony Wang Laboratory of Neural Circuits and Behavior, The Rockefeller University, New York, NY
Yi Yu
1
Queensland Brain Institute, Clem Jones Centre for Ageing Dementia Research, The University of Queensland, Brisbane, Queensland, Australia
Jingyao Xia
1
Queensland Brain Institute, Clem Jones Centre for Ageing Dementia Research, The University of Queensland, Brisbane, Queensland, Australia
Jing Tang
1
Queensland Brain Institute, Clem Jones Centre for Ageing Dementia Research, The University of Queensland, Brisbane, Queensland, Australia
6
Neuroscience Program, Monash Biomedicine Discovery Institute and Department of Anatomy and Developmental Biology, Monash University, Melbourne, Victoria, Australia
Zhitao Hu
1
Queensland Brain Institute, Clem Jones Centre for Ageing Dementia Research, The University of Queensland, Brisbane, Queensland, Australia
Correspondence to Zhitao Hu: z.hu1@uq.edu.au
*
L. Li and H Liu contributed equally to this paper.
D. Ventimiglia’s present address is Molecular Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA.
Received:
August 23 2020
Revision Received:
December 19 2020
Accepted:
January 15 2021
Online Issn: 1540-8140
Print Issn: 0021-9525
Funding:
Australian Research Council
(DP160100849)
Brain and Behavior Research Foundation
(24980)
National Eye Institute
(1R21EY029450-01)
National Health and Medical Research Council
(GNT1122351)
National Institutes of Health
(R01GM127857)
© 2021 Li et al.
2021
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
J Cell Biol (2021) 220 (4): e202008121.
Article history
Received:
August 23 2020
Revision Received:
December 19 2020
Accepted:
January 15 2021
Citation
Lei Li, Haowen Liu, Mia Krout, Janet E. Richmond, Yu Wang, Jihong Bai, Saroja Weeratunga, Brett M. Collins, Donovan Ventimiglia, Yi Yu, Jingyao Xia, Jing Tang, Jie Liu, Zhitao Hu; A novel dual Ca2+ sensor system regulates Ca2+-dependent neurotransmitter release. J Cell Biol 5 April 2021; 220 (4): e202008121. doi: https://doi.org/10.1083/jcb.202008121
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