ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2012
Calcium binding by synaptotagmin's C2A domain is an essential element of the electrostatic switch that triggers synchronous synaptic transmission.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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Who cites it
40 citing papers in PubMed, 70 citations in OpenAlex.
- Disease-causing mutations in Synaptotagmin can act via dominant-negative, gain-of-function or haploinsufficient mechanisms.bioRxiv : the preprint server for biology · 2026Article
- The AD3 locus of synaptotagmin-1 C2 domains modulates domain stability.Biophysical journal · 2025Article
- Correlation between evoked neurotransmitter release and adaptive functions in SYT1-associated neurodevelopmental disorder.EBioMedicine · 2024Article
- Nano-organization of synaptic calcium signaling.Biochemical Society transactions · 2024Review
- Calcium Sensors of Neurotransmitter Release.Advances in neurobiology · 2023Article
- Article
- Polybasic Patches in Both C2 Domains of Synaptotagmin-1 Are Required for Evoked Neurotransmitter Release.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2022Article
- Molecular Mechanisms Underlying Neurotransmitter Release.Annual review of biophysics · 2022Review
- Synaptic Secretion and Beyond: Targeting Synapse and Neurotransmitters to Treat Neurodegenerative Diseases.Oxidative medicine and cellular longevity · 2022Review
- Function of Drosophila Synaptotagmins in membrane trafficking at synapses.Cellular and molecular life sciences : CMLS · 2021Review
- SNARE complex alters the interactions of the CaBiophysical journal · 2021Article
- SNARE Regulatory Proteins in Synaptic Vesicle Fusion and Recycling.Frontiers in molecular neuroscience · 2021Review
- Synaptotagmin-1 membrane binding is driven by the C2B domain and assisted cooperatively by the C2A domain.Scientific reports · 2020Article
- The C2A domain of synaptotagmin is an essential component of the calcium sensor for synaptic transmission.PloS one · 2020Article
- The role of the C2A domain of synaptotagmin 1 in asynchronous neurotransmitter release.PloS one · 2020Article
- Structural basis for the clamping and CaNature communications · 2019Article
- Mechanism of neurotransmitter release coming into focus.Protein science : a publication of the Protein Society · 2018Review
- The high-affinity calcium sensor synaptotagmin-7 serves multiple roles in regulated exocytosis.The Journal of general physiology · 2018Review
- Targeting Phosphatidylserine with Calcium-Dependent Protein-Drug Conjugates for the Treatment of Cancer.Molecular cancer therapeutics · 2018Article
- Article
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
Abstract
Synaptotagmin is the major calcium sensor for fast synaptic transmission that requires the synchronous fusion of synaptic vesicles. Synaptotagmin contains two calcium-binding domains: C2A and C2B. Mutation of a positively charged residue (R233Q in rat) showed that Ca2+-dependent interactions between the C2A domain and membranes play a role in the electrostatic switch that initiates fusion. Surprisingly, aspartate-to-asparagine mutations in C2A that inhibit Ca2+ binding support efficient synaptic transmission, suggesting that Ca2+ binding by C2A is not required for triggering synchronous fusion. Based on a structural analysis, we generated a novel mutation of a single Ca2+-binding residue in C2A (D229E in Drosophila) that inhibited Ca2+ binding but maintained the negative charge of the pocket. This C2A aspartate-to-glutamate mutation resulted in ∼80% decrease in synchronous transmitter release and a decrease in the apparent Ca2+ affinity of release. Previous aspartate-to-asparagine mutations in C2A partially mimicked Ca2+ binding by decreasing the negative charge of the pocket. We now show that the major function of Ca2+ binding to C2A is to neutralize the negative charge of the pocket, thereby unleashing the fusion-stimulating activity of synaptotagmin. Our results demonstrate that Ca2+ binding by C2A is a critical component of the electrostatic switch that triggers synchronous fusion. Thus, Ca2+ binding by C2B is necessary and sufficient to regulate the precise timing required for coupling vesicle fusion to Ca2+ influx, but Ca2+ binding by both C2 domains is required to flip the electrostatic switch that triggers efficient synchronous synaptic transmission.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.