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Cited by 274Cellular transport and secretionNeuroscience and Neuropharmacology ResearchExtracellular vesicles in disease

Synaptotagmin-1 functions as a Ca2+ sensor for spontaneous release

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Xu, Jun, Pang, Zhiping P, Shin, Ok-Ho, Südhof, Thomas C·2009·Nature Neuroscience
DOI 10.1038/nn.2320PMC PMC2739891
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Abstract

Spontaneous 'mini' release occurs at all synapses, but its nature remains enigmatic. We found that >95% of spontaneous release in murine cortical neurons was induced by Ca2+-binding to synaptotagmin-1 (Syt1), the Ca2+ sensor for fast synchronous neurotransmitter release. Thus, spontaneous and evoked release used the same Ca2+-dependent release mechanism. As a consequence, Syt1 mutations that altered its Ca2+ affinity altered spontaneous and evoked release correspondingly. Paradoxically, Syt1 deletions (as opposed to point mutations) massively increased spontaneous release. This increased spontaneous release remained Ca2+ dependent but was activated at lower Ca2+ concentrations and with a lower Ca2+ cooperativity than synaptotagmin-driven spontaneous release. Thus, in addition to serving as a Ca2+ sensor for spontaneous and evoked release, Syt1 clamped a second, more sensitive Ca2+ sensor for spontaneous release that resembles the Ca2+ sensor for evoked asynchronous release. These data suggest that Syt1 controls both evoked and spontaneous release at a synapse as a simultaneous Ca2+-dependent activator and clamp of exocytosis.

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  • Spontaneous release in the reconstituted system reflects fusion probability at exactly zero Ca2+ concentration, whereas spontaneous release in neurons is driven by resting Ca2+ concentrations and is largely blocked by removing all calcium.

    “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 [41]

    The Results section (“Spontaneous release is Ca2+-dependent”) reports that intracellular Ca2+ chelation blocked more than 95% of spontaneous mIPSCs, supporting the claim about removing calcium. But the Discussion says release is likely triggered by Ca2+ sparks rather than resting presynaptic Ca2+ concentrations. The citation is attached to the neuronal-release claim, not the description of the reconstituted system. (LLM, conf=0.88)

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Authors
Xu, J., Pang, Z. P., Shin, O.-H., & Südhof, T. C.
Affiliations
  • Stanford University (US)
  • Howard Hughes Medical Institute (US)
  • The University of Texas Medical Branch at Galveston (US)
Corresponding author
Südhof, Thomas C
ORCID
Venue
Nature Neuroscience
Publisher
Springer Science and Business Media LLC
Published
2009-05-03
Volume
12
Issue
6
Pages
759-766
ISSN
  • 1097-6256 (ISSN-L)
  • 1546-1726
DOI
10.1038/nn.2320
PMC
PMC2739891
OpenAlex
W2058035029
Cited by
274
References
2
Citations by year
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FWCI
8.02
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Neuroscience (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
Howard Hughes Medical Institute
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 › Extracellular vesicles in disease
Keywords
synaptotagmin-1, calcium sensor, spontaneous neurotransmitter release, evoked release, exocytosis, calcium cooperativity, cortical neurons, calcium affinity
MeSH terms
Animals, Calcium, Cerebral Cortex, Dose-Response Relationship, Drug, Exocytosis, Membrane Fusion, Membrane Potentials, Synaptic Transmission, Synaptic Membranes, Presynaptic Terminals, Neurotransmitter Agents, Calcium Signaling, Synaptotagmin I, Mice

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