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Complexin inhibits spontaneous release and synchronizes Ca2+-triggered synaptic vesicle fusion by distinct mechanisms
Open accessAbstract
Previously we showed that fast Ca2+-triggered vesicle fusion with reconstituted neuronal SNAREs and synaptotagmin-1 begins from an initial hemifusion-free membrane point contact, rather than a hemifusion diaphragm, using a single vesicle–vesicle lipid/content mixing assay (Diao et al., 2012). When complexin-1 was included, a more pronounced Ca2+-triggered fusion burst was observed, effectively synchronizing the process. Here we show that complexin-1 also reduces spontaneous fusion in the same assay. Moreover, distinct effects of several complexin-1 truncation mutants on spontaneous and Ca2+-triggered fusion closely mimic those observed in neuronal cultures. The very N-terminal domain is essential for synchronization of Ca2+-triggered fusion, but not for suppression of spontaneous fusion, whereas the opposite is true for the C-terminal domain. By systematically varying the complexin-1 concentration, we observed differences in titration behavior for spontaneous and Ca2+-triggered fusion. Taken together, complexin-1 utilizes distinct mechanisms for synchronization of Ca2+-triggered fusion and inhibition of spontaneous fusion.
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“Recent evidence for this notion came from a reconstituted single vesicle-vesicle assay that discriminates among vesicle association, lipid mixing, and content mixing37,38,81.”
From Architecture of the synaptotagmin–SNARE machinery for neuronal exocytosis (2015) · cites this paper as [38]
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“We note that spontaneous release observed in our reconstituted system38 reflects the fusion probability at exactly zero Ca2+ concentration (that is, in absence of a Ca2+-sensor for mini-release) whereas spontaneous release in neurons is driven by resting Ca2+-concentrations and is largely blocked by removing all calcium41.”
From Architecture of the synaptotagmin–SNARE machinery for neuronal exocytosis (2015) · cites this paper as [38]
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“Our single vesicle-vesicle assay thus uses full-length Syt1 and it monitors content mixing, a correlate for neurotransmitter release37,38,81.”
From Architecture of the synaptotagmin–SNARE machinery for neuronal exocytosis (2015) · cites this paper as [38]
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“A variety of complexin-1 truncations and mutations qualitatively reproduced effects observed in neuronal cultures for both spontaneous and Ca2+-triggered release38, lending credence to this reconstituted system to investigate mechanistic questions.”
From Architecture of the synaptotagmin–SNARE machinery for neuronal exocytosis (2015) · cites this paper as [38]
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“Moreover, addition of complexin-1 greatly enhanced Ca2+-triggered amplitude and synchronization, and suppressed spontaneous release in this system38.”
From Architecture of the synaptotagmin–SNARE machinery for neuronal exocytosis (2015) · cites this paper as [38]
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“Neuronal SNAREs and Syt1 represent a minimal system for Ca2+-triggered membrane fusion.”
From Architecture of the synaptotagmin–SNARE machinery for neuronal exocytosis (2015) · cites this paper as [38]
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Citations
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Research works printed but not linked: 1
- Reim, 2001, Complexins regulate a late step in Ca2+-dependent neurotransmitter release, Cell, 104, 71, 10.1016/S0092-8674(01)00192-1 · DOI
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Metadata
- Authors
- Lai, Y., Diao, J., Cipriano, D. J., Zhang, Y., Pfuetzner, R. A., Padolina, M. S., & Brunger, A. T.
- Affiliations
- Stanford University (US)
- Howard Hughes Medical Institute (US)
- Department of Molecular and Cellular Physiology, Stanford University, Stanford, United States
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2014-08-13
- Volume
- 3
- Pages
- e03756-e03756
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC4130161
- OpenAlex
- W2128246609
- Cited by
- 107
- References
- 40
- Citations by year
- 2026: 1 · 2025: 7 · 2024: 13 · 2023: 8 · 2022: 9 · 2021: 2 · 2020: 3 · 2019: 4 · 2018: 16 · 2017: 17 · 2016: 12 · 2015: 11 · 2014: 4
- FWCI
- 7.31
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health (R37-MH63105)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Lipid Membrane Structure and Behavior
- Keywords
- complexin-1, synaptic vesicle fusion, spontaneous release, calcium-triggered release, SNARE proteins, synaptotagmin-1, hemifusion, truncation mutants, N-terminal domain, C-terminal domain, neurotransmitter release
- MeSH terms
- Animals, Biological Assay, Biological Transport, Calcium, Escherichia coli, Exocytosis, Membrane Fusion, Models, Biological, Mutation, Nerve Tissue Proteins, Neurons, Protein Binding, Recombinant Proteins, Synaptic Vesicles, Gene Expression, Protein Structure, Tertiary, Adaptor Proteins, Vesicular Transport, Synaptosomal-Associated Protein 25, Syntaxin 1, Synaptotagmin I, Vesicle-Associated Membrane Protein 2, Rats, Protein Refolding
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