CoChat
Sign Up
Cited by 285Cellular transport and secretionNeuroscience and Neuropharmacology ResearchCalcium signaling and nucleotide metabolism

The DOI matches its Crossref record; 2 of the 2 references it cites were found in a registry or an index.

Synaptotagmin I Functions as a Calcium Sensor to Synchronize Neurotransmitter Release

Open access
Yoshihara, Motojiro, Littleton, J.Troy·2002·Neuron
DOI 10.1016/s0896-6273(02)01065-6
Open this paper in CoChat — free accountOpen PDF

Abstract

To characterize Ca(2+)-mediated synaptic vesicle fusion, we analyzed Drosophila synaptotagmin I mutants deficient in specific interactions mediated by its two Ca(2+) binding C2 domains. In the absence of synaptotagmin I, synchronous release is abolished and a kinetically distinct delayed asynchronous release pathway is uncovered. Synapses containing only the C2A domain of synaptotagmin partially recover synchronous fusion, but have an abolished Ca(2+) cooperativity. Mutants that disrupt Ca(2+) sensing by the C2B domain have synchronous release with normal Ca(2+) cooperativity, but with reduced release probability. Our data suggest the Ca(2+) cooperativity of neurotransmitter release is likely mediated through synaptotagmin-SNARE interactions, while phospholipid binding and oligomerization trigger rapid fusion with increased release probability. These results indicate that synaptotagmin is the major Ca(2+) sensor for evoked release and functions to trigger synchronous fusion in response to Ca(2+), while suppressing asynchronous release.

Overview

Integrity signals

Registry

Crossref · 10.1016/s0896-6273(02)01065-6

Cites

2 of 2 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Verification

Claims the paper makes

We couldn’t retrieve this paper’s full text, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Syt1 also clamps the frequency of miniature spontaneous events.

    “In addition to its role in evoked synchronous release, Syt1 also clamps the frequency of miniature spontaneous events11–13.”

    From Architecture of the synaptotagmin–SNARE machinery for neuronal exocytosis (2015) · cites this paper as [11]

  • The primary Syt1-SNARE interface is critical for the role of Syt1 as a Ca2+ sensor of evoked release, but is not required for spontaneous release in neurons.

    “Together, these observations support the notion that the primary Syt1-SNARE interface is critical for the role of Syt1 as a Ca2+ sensor of evoked release, but that this Syt1-SNARE interface is not required for spontaneous release in neurons, consistent with the differential effect of Syt1 mutations on spontaneous and evoked release11–13.”

    From Architecture of the synaptotagmin–SNARE machinery for neuronal exocytosis (2015) · cites this paper as [11]

Citations

Cites

Flagged first, then by citations

Research works printed but not linked: 60

  1. Adolfsen, 2001, Genetic and molecular analysis of the synaptotagmin family, Cell. Mol. Life Sci., 58, 393, 10.1007/PL00000865 · DOI
  2. Broadie, 1994, Absence of synaptotagmin disrupts excitation-secretion coupling during synaptic transmission, Proc. Natl. Acad. Sci. USA, 91, 10727, 10.1073/pnas.91.22.10727 · DOI
  3. Brose, 1992, Synaptotagmin, Science, 256, 1021, 10.1126/science.1589771 · DOI · Paper page
  4. Chapman, 1994, Calcium-dependent interaction of the cytoplasmic region of synaptotagmin with membranes, J. Biol. Chem., 269, 5735, 10.1016/S0021-9258(17)37523-3 · DOI
  5. Chapman, 1995, Ca2+ regulates the interaction between synaptotagmin and syntaxin 1, J. Biol. Chem., 270, 23667, 10.1074/jbc.270.40.23667 · DOI
  6. Chapman, 1996, A novel function for the second C2 domain of synaptotagmin, J. Biol. Chem., 271, 5844, 10.1074/jbc.271.10.5844 · DOI
  7. Chen, 1999, Contributions of residual calcium to fast synaptic transmission, J. Neurosci., 19, 6257, 10.1523/JNEUROSCI.19-15-06257.1999 · DOI
  8. Chen, 1999, SNARE complex formation is triggered by Ca2+ and drives membrane fusion, Cell, 97, 165, 10.1016/S0092-8674(00)80727-8 · DOI
  9. Craxton, 2001, Genomic analysis of synaptotagmin genes, Genomics, 77, 43, 10.1006/geno.2001.6619 · DOI
  10. Davis, 1999, Kinetics of synaptotagmin responses to Ca2+ and assembly with the core SNARE complex onto membranes, Neuron, 24, 363, 10.1016/S0896-6273(00)80850-8 · DOI
  11. DiAntonio, 1994, The effect on synaptic physiology of synaptotagmin mutations in Drosophila, Neuron, 12, 909, 10.1016/0896-6273(94)90342-5 · DOI
  12. Dodge, 1967, Co-operative action of calcium ions in transmitter release at the neuromuscular junction, J. Physiol., 193, 419, 10.1113/jphysiol.1967.sp008367 · DOI
  13. Earles, 2001, The tandem C2 domains of synaptotagmin contain redundant Ca2+ binding sites that cooperate to engage t-SNAREs and trigger exocytosis, J. Cell Biol., 154, 1117, 10.1083/jcb.200105020 · DOI
  14. Fergestad, 2001, Targeted mutations in the syntaxin H3 domain specifically disrupt SNARE complex function in synaptic transmission, J. Neurosci., 21, 9142, 10.1523/JNEUROSCI.21-23-09142.2001 · DOI
  15. Fernandez, 2001, Three-dimensional structure of the synaptotagmin 1 C2B-domain. Synaptotagmin 1 as a phospholipid binding machine, Neuron, 32, 1057, 10.1016/S0896-6273(01)00548-7 · DOI
  16. Fernández-Chacón, 2001, Synaptotagmin I functions as a calcium regulator of release probability, Nature, 410, 41, 10.1038/35065004 · DOI · Paper page
  17. Fernández-Chacón, 2002, Structure/function analysis of Ca2+ binding to the C2A domain of synaptotagmin 1, J. Neurosci., 22, 8438, 10.1523/JNEUROSCI.22-19-08438.2002 · DOI
  18. Fukuda, 2000, Drosophila AD3 mutation of synaptotagmin impairs calcium-dependent self-oligomerization activity, FEBS Lett., 482, 269, 10.1016/S0014-5793(00)02064-0 · DOI
  19. Gerona, 2000, The C terminus of SNAP25 is essential for Ca2+-dependent binding of synaptotagmin to SNARE complexes, J. Biol. Chem., 275, 6328, 10.1074/jbc.275.9.6328 · DOI
  20. Goda, 1994, Two components of transmitter release at a central synapse, Proc. Natl. Acad. Sci. USA, 91, 12942, 10.1073/pnas.91.26.12942 · DOI
  21. Harrison, 1994, Mutations in the Drosophila Rop gene suggest a function in general secretion and synaptic transmission, Neuron, 13, 555, 10.1016/0896-6273(94)90025-6 · DOI
  22. Heidelberger, 1994, Calcium dependence of the rate of exocytosis in a synaptic terminal, Nature, 371, 513, 10.1038/371513a0 · DOI
  23. Hilgenberg, 2002, Agrin regulates neuronal responses to excitatory neurotransmitters in vitro and in vivo, Mol. Cell. Neurosci., 19, 97, 10.1006/mcne.2001.1056 · DOI
  24. Hu, 2002, Vesicular restriction of synaptobrevin suggests a role for calcium in membrane fusion, Nature, 415, 646, 10.1038/415646a · DOI
  25. Jan, 1976, Properties of the larval neuromuscular junction in Drosophila melanogaster, J. Physiol., 262, 189, 10.1113/jphysiol.1976.sp011592 · DOI
  26. Jorgensen, 1995, Defective recycling of synaptic vesicles in synaptotagmin mutants of Caenorhabditis elegans, Nature, 378, 196, 10.1038/378196a0 · DOI
  27. Kamiya, 1994, Residual Ca2+ and short-term synaptic plasticity, Nature, 371, 603, 10.1038/371603a0 · DOI
  28. Katz, 1967, The timing of calcium action during neuromuscular transmission, J. Physiol., 189, 535, 10.1113/jphysiol.1967.sp008183 · DOI
  29. Kee, 1996, Localization of synaptotagmin-binding domains on syntaxin, J. Neurosci., 16, 1975, 10.1523/JNEUROSCI.16-06-01975.1996 · DOI
  30. Lander, 2001, Initial sequencing and analysis of the human genome, Nature, 409, 860, 10.1038/35057062 · DOI · Paper page
  31. Littleton, 1993, Expression of synaptotagmin in Drosophila reveals transport and localization of synaptic vesicles to the synapse, Development, 118, 1077, 10.1242/dev.118.4.1077 · DOI
  32. Littleton, 1993, Mutational analysis of Drosophila synaptotagmin demonstrates its essential role in Ca2+-activated neurotransmitter release, Cell, 74, 1125, 10.1016/0092-8674(93)90733-7 · DOI
  33. Littleton, 1994, Calcium dependence of neurotransmitter release and rate of spontaneous vesicle fusions are altered in Drosophila synaptotagmin mutants, Proc. Natl. Acad. Sci. USA, 91, 10888, 10.1073/pnas.91.23.10888 · DOI
  34. Littleton, 1998, Temperature-sensitive paralytic mutations demonstrate that synaptic exocytosis requires SNARE complex assembly and disassembly, Neuron, 21, 401, 10.1016/S0896-6273(00)80549-8 · DOI
  35. Littleton, 1999, Synaptic function modulated by changes in the ratio of synaptotagmin I and IV, Nature, 400, 757, 10.1038/23462 · DOI
  36. Littleton, 2001, synaptotagmin mutants reveal essential functions for the C2B-domain in Ca2+-triggered fusion and recycling of synaptic vesicles in vivo, J. Neurosci., 21, 1421, 10.1523/JNEUROSCI.21-05-01421.2001 · DOI
  37. Mackler, 2002, The C2B Ca2+-binding motif of synaptotagmin is required for synaptic transmission in vivo, Nature, 418, 340, 10.1038/nature00846 · DOI
  38. Marek, 2002, Transgenically encoded protein photoinactivation (FLASH-FALI), Neuron, 36, 805, 10.1016/S0896-6273(02)01068-1 · DOI
  39. Morimoto, 1995, Calcium-dependent transmitter secretion from fibroblasts, Neuron, 15, 689, 10.1016/0896-6273(95)90156-6 · DOI
  40. Nishizuka, 1988, The molecular heterogeneity of protein kinase C and its implications for cellular regulation, Nature, 334, 661, 10.1038/334661a0 · DOI
  41. Osborne, 1999, Calcium-dependent oligomerization of synaptotagmins I and II, J. Biol. Chem., 274, 59, 10.1074/jbc.274.1.59 · DOI
  42. Perin, 1990, Phospholipid binding by a synaptic vesicle protein homologous to the regulatory region of protein kinase C, Nature, 345, 260, 10.1038/345260a0 · DOI
  43. Reist, 1998, Morphologically docked synaptic vesicles are reduced in synaptotagmin mutants of Drosophila, J. Neurosci., 18, 7662, 10.1523/JNEUROSCI.18-19-07662.1998 · DOI
  44. Robinson, 2002, Synaptotagmins I and IV promote transmitter release independently of Ca2+ binding in the C2A domain, Nature, 418, 336, 10.1038/nature00915 · DOI
  45. Rosenmund, 1996, Definition of the readily releasable pool of vesicles at hippocampal synapses, Neuron, 16, 1197, 10.1016/S0896-6273(00)80146-4 · DOI
  46. Schiavo, 1997, Binding of the synaptic vesicle v-SNARE, synaptotagmin, to the plasma membrane t-SNARE, SNAP-25, can explain docked vesicles at neurotoxin-treated synapses, Proc. Natl. Acad. Sci. USA, 94, 997, 10.1073/pnas.94.3.997 · DOI
  47. Schulze, 1995, Genetic and electrophysiological studies of Drosophila syntaxin-1A demonstrate its role in nonneuronal secretion and neurotransmission, Cell, 80, 311, 10.1016/0092-8674(95)90414-X · DOI
  48. Söllner, 1993, SNAP receptors implicated in vesicle targeting and fusion, Nature, 362, 318, 10.1038/362318a0 · DOI
  49. Stewart, 2000, SNARE proteins contribute to calcium cooperativity of synaptic transmission, Proc. Natl. Acad. Sci. USA, 97, 13955, 10.1073/pnas.250491397 · DOI
  50. Südhof, 1996, Synaptotagmins, Neuron, 17, 379, 10.1016/S0896-6273(00)80171-3 · DOI
  51. Sugita, 1996, Distinct Ca2+-dependent properties of the first and second C2-domains of synaptotagmin I, J. Biol. Chem., 271, 1262, 10.1074/jbc.271.3.1262 · DOI
  52. van de Goor, 1995, Redistribution of synaptic vesicles and their proteins in temperature-sensitive shibirets1 mutant Drosophila, Proc. Natl. Acad. Sci. USA, 92, 5739, 10.1073/pnas.92.12.5739 · DOI
  53. Wang, 2001, Synaptotagmin modulation of fusion pore kinetics in regulated exocytosis of dense-core vesicles, Science, 294, 1111, 10.1126/science.1064002 · DOI
  54. Weber, 1998, SNAREpins, Cell, 92, 759, 10.1016/S0092-8674(00)81404-X · DOI
  55. Yoshihara, 1997, Transition from growth cone to functional motor nerve terminal in Drosophila embryos, J. Neurosci., 17, 8408, 10.1523/JNEUROSCI.17-21-08408.1997 · DOI
  56. Yoshihara, 1999, Selective effects of neuronal-synaptobrevin mutations on transmitter release evoked by sustained versus transient Ca2+ increases and by cAMP, J. Neurosci., 19, 2432, 10.1523/JNEUROSCI.19-07-02432.1999 · DOI
  57. Yoshihara, 2000, Two independent pathways mediated by cAMP and protein kinase A enhance spontaneous transmitter release at Drosophila neuromuscular junctions, J. Neurosci., 20, 8315, 10.1523/JNEUROSCI.20-22-08315.2000 · DOI
  58. Zhang, 1994, Synaptotagmin I is a high affinity receptor for clathrin AP-2, Cell, 78, 751, 10.1016/S0092-8674(94)90442-1 · DOI
  59. Zhang, 2002, Ca2+-dependent synaptotagmin binding to SNAP-25 is essential for Ca2+-triggered exocytosis, Neuron, 34, 599, 10.1016/S0896-6273(02)00671-2 · DOI
  60. Zhong, 1991, Altered synaptic plasticity in Drosophila memory mutants with a defective cyclic AMP cascade, Science, 251, 198, 10.1126/science.1670967 · DOI

Cited by

Sorted by citations

Metadata

Authors
Yoshihara, M., & Littleton, J. T.
Affiliations
Massachusetts Institute of Technology (US)
Corresponding author
Yoshihara, Motojiro
ORCID
Venue
Neuron
Publisher
Elsevier BV
Published
2002-12
Volume
36
Issue
5
Pages
897-908
ISSN
0896-6273 (ISSN-L)
DOI
10.1016/s0896-6273(02)01065-6
OpenAlex
W1963551844
Cited by
285
References
2
Citations by year
2026: 8 · 2025: 4 · 2024: 8 · 2023: 6 · 2022: 7 · 2021: 14 · 2020: 7 · 2019: 4 · 2018: 3 · 2017: 9 · 2016: 4 · 2015: 10 · 2014: 15 · 2013: 10 · 2012: 12
FWCI
6.79
Type
journal article
Language
en
Open access
Licence
Locations
  • Neuron (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Institute of Neurological Disorders and Stroke (R01NS040296)
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 sensor, asynchronous release, synaptic vesicle fusion, C2 domain, C2A domain, C2B domain, calcium cooperativity, release probability, phospholipid binding, oligomerization
MeSH terms
Animals, Binding Sites, Calcium, Calcium-Binding Proteins, Drosophila melanogaster, Electric Stimulation, Embryo, Nonmammalian, Genotype, Membrane Fusion, Membrane Glycoproteins, Membrane Proteins, Models, Biological, Mutation, Nerve Tissue Proteins, Synaptic Transmission, Protein Binding, Synapses, Synaptic Vesicles, Time Factors, Protein Structure, Tertiary, Neurotransmitter Agents, Patch-Clamp Techniques, Vesicular Transport Proteins, SNARE Proteins, Synaptotagmins, Synaptotagmin I

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review