Synaptotagmin-1 drives synchronous Ca2+-triggered fusion by C2B-domain-mediated synaptic-vesicle-membrane attachment

Nat Neurosci. 2018 Jan;21(1):33-40. doi: 10.1038/s41593-017-0037-5. Epub 2017 Dec 11.


The synaptic vesicle (SV) protein synaptotagmin-1 (Syt1) is the Ca2+ sensor for fast synchronous release. Biochemical and structural data suggest that Syt1 interacts with phospholipids and SNARE complex, but the manner in which these interactions translate into SV fusion remains poorly understood. Using flash-and-freeze electron microscopy, which triggers action potentials with light and coordinately arrests synaptic structures with rapid freezing, we found that synchronous-release-impairing mutations in the Syt1 C2B domain (K325, 327; R398, 399) also disrupt SV-active-zone plasma-membrane attachment. Single action potential induction rescued membrane attachment in these mutants within less than 10 ms through activation of the Syt1 Ca2+-binding site. The rapid SV membrane translocation temporarily correlates with resynchronization of release and paired pulse facilitation. On the basis of these findings, we redefine the role of Syt1 as part of the Ca2+-dependent vesicle translocation machinery and propose that Syt1 enables fast neurotransmitter release by means of its dynamic membrane attachment activities.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Calcium / metabolism*
  • Calcium / pharmacology
  • Cells, Cultured
  • Female
  • Hippocampus / cytology
  • Male
  • Membrane Fusion / drug effects*
  • Membrane Potentials / drug effects
  • Membrane Potentials / genetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Microtubule-Associated Proteins / metabolism
  • Neurons / ultrastructure*
  • Protein Structure, Tertiary
  • Synapsins / genetics
  • Synapsins / metabolism
  • Synapsins / ultrastructure
  • Synaptic Vesicles / metabolism*
  • Synaptic Vesicles / ultrastructure
  • Synaptosomal-Associated Protein 25 / metabolism
  • Synaptotagmin I / genetics
  • Synaptotagmin I / metabolism*
  • Vesicular Glutamate Transport Protein 1 / metabolism


  • Microtubule-Associated Proteins
  • Mtap2 protein, mouse
  • Synapsins
  • Synaptosomal-Associated Protein 25
  • Synaptotagmin I
  • Syt1 protein, mouse
  • Vesicular Glutamate Transport Protein 1
  • Calcium