Synaptotagmin I functions as a calcium regulator of release probability
Abstract
In all synapses, Ca2+ triggers neurotransmitter release to initiate signal transmission. Ca2+ presumably acts by activating synaptic Ca2+ sensors, but the nature of these sensors--which are the gatekeepers to neurotransmission--remains unclear. One of the candidate Ca2+ sensors in release is the synaptic Ca2+-binding protein synaptotagmin I. Here we have studied a point mutation in synaptotagmin I that causes a twofold decrease in overall Ca2+ affinity without inducing structural or conformational changes. When introduced by homologous recombination into the endogenous synaptotagmin I gene in mice, this point mutation decreases the Ca2+ sensitivity of neurotransmitter release twofold, but does not alter spontaneous release or the size of the readily releasable pool of neurotransmitters. Therefore, Ca2+ binding to synaptotagmin I participates in triggering neurotransmitter release at the synapse.
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Syt1 binds in a Ca2+-dependent manner to anionic membranes, with anionic phospholipids and synaptotagmin C2 domains together coordinating calcium.
“Syt1 binds in a Ca2+-dependent manner to anionic membranes; during binding, anionic phospholipids and synaptotagmin C2 domains together coordinate calcium14–17.”
From Architecture of the synaptotagmin–SNARE machinery for neuronal exocytosis (2015) · cites this paper as [16]
The Ca2+ affinity of Syt1 for binding to anionic membranes and the Ca2+ sensitivity of neurotransmitter release are tightly correlated.
“The membrane-synaptotagmin interaction has functional significance since the Ca2+ affinity of Syt1 for binding to anionic membranes and the Ca2+ sensitivity of neurotransmitter release are tightly correlated16,18.”
From Architecture of the synaptotagmin–SNARE machinery for neuronal exocytosis (2015) · cites this paper as [16]
Cites
Synaptotagmin I: A major Ca2+ sensor for transmitter release at a central synapse
Geppert, M., Goda, Y., Hammer, R. E., Li, C., Rosahl, T. W., Stevens, C. F., & Südhof, T. C. (1994) · Cell · doi:10.1016/0092-8674(94)90556-8 · Cited by 1,483 · see citing works
Self-citationA single C2 domain from synaptotagmin I is sufficient for high affinity Ca2+/phospholipid binding.
Davletov, B. A., & Südhof, T. C. (1993) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)74326-9 · Cited by 480 · see citing works
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Schoch, S., Castillo, P. E., Jo, T., Mukherjee, K., Geppert, M., Wang, Y., Schmitz, F., Malenka, R. C., & Südhof, T. C. (2002) · Nature · doi:10.1038/415321a · Cited by 579 · see citing works
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Burgoyne, R. D. (2007) · Nature Reviews Neuroscience · doi:10.1038/nrn2093 · Cited by 527 · see citing works
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Custer, K. L., Austin, N. S., Sullivan, J. M., & Bajjalieh, S. M. (2006) · The Journal of Neuroscience · doi:10.1523/jneurosci.2699-05.2006 · Cited by 211 · see citing works
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“…is what is the role of the Syt1 C 2 A domain, as Ca 2+ binding to this domain contributes to trigger neurotransmitter release even if it is not as critical as Ca 2+ binding to the C 2 B domain ( 28 , 32 , 34 ), and a Syt1 mutant lacking the C 2 A domain cannot rescue Syt1 function ( 71 , 72 ).”
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“…intracellular free calcium ([Ca 2+ ] i ) (Neher and Sakaba 2008), which is sensed by the calcium trigger for synchronous neurotransmitter release, synaptotagmin-1 (Syt1) that binds calcium with extremely low affinity (Fernández-Chacón et al. 2001; Geppert et al. 1994; Nishiki and Augustine 2004).”
- Authors
- Fernández-Chacón, R., Königstorfer, A., Gerber, S. H., García, J., Matos, M. F., Stevens, C. F., Brose, N., Rizo, J., Rosenmund, C., & Südhof, T. C.
- Affiliations
- Max Planck Society (DE)
- Howard Hughes Medical Institute (US)
- The University of Texas Southwestern Medical Center (US)
- Max Planck Institute for Biophysical Chemistry (DE)
- Corresponding author
- Südhof, Thomas C.
- Venue
- Nature
- Published
- 2001-03
- Volume
- 410
- Issue
- 6824
- Pages
- 41-49
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2123355036
- Cited by
- 961
- References
- 2
- Citations by year
- 2026: 16 · 2025: 18 · 2024: 37 · 2023: 22 · 2022: 31 · 2021: 28 · 2020: 43 · 2019: 26 · 2018: 23 · 2017: 33 · 2016: 27 · 2015: 37 · 2014: 41 · 2013: 37 · 2012: 49
- FWCI
- 22.09
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Max Planck Institute for Plasma Physics (submittedVersion)
- GRO (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Funders
- US-UK Fulbright Commission
- Deutsche Forschungsgemeinschaft
- 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 › Physiology › Calcium signaling and nucleotide metabolism
- Keywords
- synaptotagmin-1, calcium binding, neurotransmitter release, release probability, point mutations, calcium affinity, readily releasable pool, spontaneous release, synaptic transmission, homologous recombination
- MeSH terms
- Animals, Calcium, Calcium-Binding Proteins, Cells, Cultured, Membrane Glycoproteins, Nerve Tissue Proteins, Neurons, Protein Binding, Protein Conformation, Synapses, Synaptic Vesicles, Mutagenesis, Site-Directed, Point Mutation, Neurotransmitter Agents, Synaptotagmins, Synaptotagmin I, Mice
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