Augmenting neurotransmitter release by enhancing the apparent Ca 2+ affinity of synaptotagmin 1
Open accessAbstract
Synaptotagmin 1 likely acts as a Ca2+ sensor in neurotransmitter release by Ca2+-binding to its two C2 domains. This notion was strongly supported by the observation that a mutation in the C2A domain causes parallel decreases in the apparent Ca2+ affinity of synaptotagmin 1 and in the Ca2+ sensitivity of release. However, this study was based on a single loss-of-function mutation. We now show that tryptophan substitutions in the synaptotagmin 1 C2 domains act as gain-of-function mutations to increase the apparent Ca2+ affinity of synaptotagmin 1. The same substitutions, when introduced into synaptotagmin 1 expressed in neurons, enhance the Ca2+ sensitivity of release. Mutations in the two C2 domains lead to comparable and additive effects in release. Our results thus show that the apparent Ca2+ sensitivity of release is dictated by the apparent Ca2+ affinity of synaptotagmin 1 in both directions, and that Ca2+ binding to both C2 domains contributes to Ca2+ triggering of release.
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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 [18]
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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Architecture of the synaptotagmin–SNARE machinery for neuronal exocytosis
Zhou, Q., Lai, Y., Bacaj, T., Zhao, M., Lyubimov, A. Y., Uervirojnangkoorn, M., Zeldin, O. B., Brewster, A. S., Sauter, N. K., Cohen, A. E., et al. (2015) · Nature · doi:10.1038/nature14975 · Cited by 348 · see citing works
Self-citationMunc13 C2B domain is an activity-dependent Ca2+ regulator of synaptic exocytosis
Shin, O.-H., Lu, J., Rhee, J.-S., Tomchick, D. R., Pang, Z. P., Wojcik, S. M., Camacho-Perez, M., Brose, N., Machius, M., Rizo, J., et al. (2010) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.1758 · Cited by 243 · see citing works
Self-citationMechanism of neurotransmitter release coming into focus
Rizo, J. (2018) · Protein Science · doi:10.1002/pro.3445 · Cited by 210 · see citing works
Self-citationPang, Z. P., Shin, O.-H., Meyer, A. C., Rosenmund, C., & Südhof, T. C. (2006) · The Journal of Neuroscience · doi:10.1523/jneurosci.3804-06.2006 · Cited by 113 · see citing works
“In vivo, mutations that selectively decrease synaptotagmin-1 phospholipid binding cause a corresponding decrease of release (Fernandez-Chacon et al., 2001; Li et al., 2006), whereas mutations that enhance phospholipid binding produce an increase of release (Rhee et al., 2005).”
BackgroundMethodInfluentialSelf-citationGustavsson, N., & Han, W. (2009) · Bioscience Reports · doi:10.1042/bsr20090031 · Cited by 91 · see citing works
Kerr, A. M., Reisinger, E., & Jonas, P. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0800621105 · Cited by 75 · see citing works
Long-term culture of astrocytes attenuates the readily releasable pool of synaptic vesicles
Kawano, H., Katsurabayashi, S., Kakazu, Y., Yamashita, Y., Kubo, N., Kubo, M., Okuda, H., Takasaki, K., Kubota, K., Mishima, K., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0048034 · Cited by 68 · see citing works
Toulmé, E., Salazar Lázaro, A., Trimbuch, T., Rizo, J., & Rosenmund, C. (2024) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2409636121 · Cited by 27 · see citing works
Self-citationA lever hypothesis for Synaptotagmin-1 action in neurotransmitter release
Jaczynska, K., Esser, V., Xu, J., Sari, L., Lin, M. M., Rosenmund, C., & Rizo, J. (2025) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2417941121 · Cited by 13 · see citing works
“…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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- Authors
- Rhee, J.-S., Li, L. Y., Shin, O.-H., Rah, J.-C., Rizo, J., Südhof, T. C., & Rosenmund, C.
- Affiliations
- Howard Hughes Medical Institute (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2005-12-13
- Volume
- 102
- Issue
- 51
- Pages
- 18664-18669
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC1311909
- OpenAlex
- W2022294768
- Cited by
- 155
- References
- 2
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 6 · 2023: 8 · 2022: 6 · 2021: 8 · 2020: 8 · 2019: 8 · 2018: 7 · 2017: 5 · 2016: 6 · 2015: 9 · 2014: 8 · 2013: 7 · 2012: 9
- FWCI
- 4.47
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Max Planck Institute for Plasma Physics (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion, other-oa)
- Funders
- National Institutes of Health
- National Institute of Neurological Disorders and Stroke (NS40944, R01NS050655, NS50655, R01NS040944)
- 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, neurotransmitter release, calcium affinity, C2 domain, C2A domain, tryptophan substitution, gain-of-function mutations, calcium-triggered release, calcium sensor, synaptic vesicle exocytosis
- MeSH terms
- Animals, Calcium, Cations, Divalent, Cells, Cultured, Models, Molecular, Mutation, Time Factors, Tryptophan, Protein Structure, Tertiary, Mice, Knockout, Glutamic Acid, Synaptotagmin I, Mice
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