Overlapping functions of stonin 2 and SV2 in sorting of the calcium sensor synaptotagmin 1 to synaptic vesicles
Open accessAbstract
Significance: Brain function depends on neurotransmission, and alterations in this process are linked to neurological disorders. Neurotransmitter release requires the rapid recycling of synaptic vesicles (SVs) by endocytosis. How synapses maintain the molecular composition of SVs during recycling is poorly understood. We demonstrate that overlapping functions of two completely distinct proteins, the vesicle protein SV2A/B and the adaptor stonin 2, mediate endocytic sorting of the vesicular calcium sensor synaptotagmin 1. As SV2A is the target of the commonly used antiepileptic drug levetiracetam and is linked to late onset Alzheimer’s disease, our findings bear implications for the treatment of neurological and neurodegenerative disorders.
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By binding synaptotagmin and regulating its endocytic retrieval, SV2A ensures accurate recycling and vesicular packaging of this sensor, a requirement for synchronous release and high-fidelity signaling.
“By binding synaptotagmin and regulating its endocytic retrieval, SV2A ensures accurate recycling and vesicular packaging of this sensor, a requirement for synchronous release and high fidelity signaling [191,192,193].”
From Synaptic Plasticity—Intrinsic Excitability and Antidepressant Discovery (2026) · cites this paper as [193]
The introduction describes SV2A’s association with synaptotagmin 1, and the Results section ‘SV2 Regulates Syt1 Sorting to SVs During Neuronal Activity’ reports that loss of SV2A impairs its endocytic retrieval and partially depletes it from recycling vesicles (page numbers unavailable). The paper also links impaired sorting to reduced neurotransmission, but does not establish that SV2A-dependent sorting is required specifically for synchronous release or high-fidelity signaling. (LLM, conf=0.84)
Experimental — accuracy not yet measuredDuring heightened plasticity, SV2A nanoclusters with synaptotagmin support rapid vesicle recycling and preserve presynaptic identity.
“During periods of heightened plasticity, SV2A nanoclusters with synaptotagmin support rapid vesicle recycling and preserve presynaptic identity as demand for precise excitation secretion coupling increases [189,192,193].”
From Synaptic Plasticity—Intrinsic Excitability and Antidepressant Discovery (2026) · cites this paper as [193]
The Results section, “SV2 Regulates Syt1 Sorting to SVs During Neuronal Activity” (page unavailable), reports that loss of SV2A partially depletes synaptotagmin 1 from recycling vesicles. The paper also examines short-term plasticity, but it does not establish that SV2A–synaptotagmin nanoclusters support rapid recycling or preserve presynaptic identity during heightened plasticity. (LLM, conf=0.86)
Experimental — accuracy not yet measured
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Synaptic Plasticity—Intrinsic Excitability and Antidepressant Discovery
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- Authors
- Kaempf, N., Kochlamazashvili, G., Puchkov, D., Maritzen, T., Bajjalieh, S. M., Kononenko, N. L., & Haucke, V.
- Affiliations
- Leibniz-Forschungsinstitut für Molekulare Pharmakologie (DE)
- University of Washington (US)
- Corresponding author
- Kononenko, Natalia L.
- Haucke, Volker
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2015-05-26
- Volume
- 112
- Issue
- 23
- Pages
- 7297-7302
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC4466747
- OpenAlex
- W1510727439
- Cited by
- 63
- References
- 44
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 9 · 2023: 4 · 2022: 4 · 2021: 9 · 2020: 7 · 2019: 5 · 2018: 3 · 2017: 11 · 2016: 4 · 2015: 3
- FWCI
- 3.73
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Informationszentrum Lebenswissenschaften (ZB MED) (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft (SFB958/ A01)
- 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, endocytic sorting, synaptic vesicle exocytosis, neurotransmission, synaptic vesicle retrieval, protein-protein interaction, hippocampal synapses, calcium sensor
- MeSH terms
- Animals, Calcium, Cells, Cultured, Membrane Glycoproteins, Nerve Tissue Proteins, Neurons, Synaptic Vesicles, Adaptor Proteins, Vesicular Transport, Synaptotagmin I, Mice
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