Neurotransmitter release is triggered by a calcium-induced rearrangement in the Synaptotagmin-1/SNARE complex primary interface
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Abstract
The Ca 2+ sensor synaptotagmin-1 (Syt1) triggers neurotransmitter release together with the neuronal sensitive factor attachment protein receptor (SNARE) complex formed by syntaxin-1, SNAP25, and synaptobrevin. Moreover, Syt1 increases synaptic vesicle (SV) priming and impairs spontaneous vesicle release. The Syt1 C 2 B domain binds to the SNARE complex through a primary interface via two regions (I and II), but how exactly this interface mediates distinct functions of Syt1 and the mechanism underlying Ca 2+ triggering of release are unknown. Using mutagenesis and electrophysiological experiments, we show that region II is functionally and spatially subdivided: Binding of C2B domain arginines to SNAP-25 acidic residues at one face of region II is crucial for Ca 2+ -evoked release but not for vesicle priming or clamping of spontaneous release, whereas other SNAP-25 and syntaxin-1 acidic residues at the other face mediate priming and clamping of spontaneous release but not evoked release. Mutations that disrupt region I impair the priming and clamping functions of Syt1 while, strikingly, mutations that enhance binding through this region increase vesicle priming and clamping of spontaneous release, but strongly inhibit evoked release and vesicle fusogenicity. These results support previous findings that the primary interface mediates the functions of Syt1 in vesicle priming and clamping of spontaneous release and, importantly, show that Ca 2+ triggering of release requires a rearrangement of the primary interface involving dissociation of region I, while region II remains bound. Together with biophysical studies presented in [K. Jaczynska et al. , bioRxiv [Preprint] (2024). https://doi.org/10.1101/2024.06.17.599417 (Accessed 18 June 2024)], our data suggest a model whereby this rearrangement pulls the SNARE complex to facilitate fast SV fusion.
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The lever model specifically accounts for synchronous release; asynchronous release likely involves high-affinity sensors such as Syt7 or Doc2.
“This lever model specifically accounts for synchronous release; in contrast, asynchronous release likely involves high-affinity sensors such as Syt7 or Doc2, which operate when the primary interface is not yet mechanically locked by Syt1 or through distinct Ca2+-independent reorientation pathways, reflecting the diverse calcium sensitivities observed in different release modes [24,27].”
From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [24]
The Discussion describes a Syt1–SNARE lever model that produces fast Ca2+-triggered fusion, consistent with its application to synchronous release. It discusses alternative pathways for spontaneous release, not asynchronous release, and does not identify Syt7 or Doc2 as high-affinity sensors for asynchronous release or describe the proposed unlocked-interface pathway. (LLM, conf=0.87)
Experimental — accuracy not yet measuredPrior to calcium influx, Syt-1 is bound to the SNARE complex, inhibiting neurotransmitter release; calcium triggering requires rearrangement of the primary interface involving dissociation of region I while region II remains bound.
“Prior to calcium influx, Syt-1 is already bound to the SNARE complex, a state that inhibits the release of neurotransmitters. Calcium triggering then requires a rearrangement of the primary interface involving the dissociation of region I, while region II remains bound to the SNARE complex.”
From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [24]
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“…been shown to perform redundant function to Syt1 in terms of pre - Ca 2+ functions, SV docking, priming, and clamping of spontaneous release (26, 27), we repeated the R398Q, R399Q mutagenesis experiments in absence of Syt7, in the Syt1/7 DKO background to isolate specifically the mechanism of…”
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“This action may facilitate zippering of the linkers, which is critical for neurotransmitter release ( 3 , 5 ), brings the TM regions to the membrane interface ( 42 ), and, based on our recent MD simulations ( 6 ), can lead to fast, microsecond scale membrane fusion.”
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Self-citationA lever hypothesis for Synaptotagmin-1 action in neurotransmitter releasePreprint
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“2 H and I , 3 H and I , and 6 D ) even though they impair C 2 B–SNARE complex binding ( 17 , 20 ).”
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“Conversely, a study of region II of syntaxin - 1 only mutated D231 among acidic residues in this region and found that a D231N mutation did not impair priming or evoked release but affected clamping ( 22 ).”
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A lever hypothesis for Synaptotagmin-1 action in neurotransmitter release
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“As mentioned earlier, this is triggered by the binding of free calcium ions to Syt1, which drives altered interactions with both the assembled SNARE complex and plasma membrane, resulting in the synchronisation of neurotransmitter release to neuronal activity (Hui et al. 2009; Toulmé et al. 2024).”
The lever model of synaptotagmin-1 function
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“Additionally, STX4, STX8, STXBP3, and VAMP2 are integral members of the SNARE complex that also facilitates neurotransmitter release by driving synaptic vesicle fusion to the presynaptic membrane regulated by calcium 50 .”
Haag, C., Gsell, F., Vinogradov, O., Oquendo, M. B., Liu, Y.-Y., Uysal, B., Löffler, H., Stehle, F., Klopfer, F., Crönlein, J., et al. (2026) · EBioMedicine · doi:10.1016/j.ebiom.2026.106451
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Guiding AlphaFold to predict how Munc13‐1 opens Syntaxin‐1
Chattopadhyay, M., Xu, J.-J., & Rizo, J. (2026) · FEBS Open Bio · doi:10.1002/2211-5463.70272
Self-citation
- Authors
- Toulmé, E., Salazar Lázaro, A., Trimbuch, T., Rizo, J., & Rosenmund, C.
- Affiliations
- Humboldt-Universität zu Berlin (DE)
- Institute of Neurophysiology, Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin 10117, Germany
- The University of Texas Southwestern Medical Center (US)
- Corresponding author
- Rizo, Josep
- Rosenmund, Christian
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2024-10-07
- Volume
- 121
- Issue
- 42
- Pages
- e2409636121-e2409636121
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC11494337
- OpenAlex
- W4403181079
- Cited by
- 27
- References
- 50
- Citations by year
- 2026: 14 · 2025: 10 · 2024: 3
- FWCI
- 6.07
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion, cc-by-nc-nd)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion, cc-by-nc-nd)
- Funders
- Deutsche Forschungsgemeinschaft (2778001972, 184695641, EXC-2049-390688087, 543999066)
- National Institute of Health (R35 NS097333)
- 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, SNARE complex, neurotransmitter release, calcium-triggered release, synaptic vesicle priming, spontaneous release, C2B domain, SNAP-25, syntaxin-1, synaptobrevin, vesicle fusion
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