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Genetic analysis of synaptotagmin-7 function in synaptic vesicle exocytosis

Academic Article
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Overview

authors

  • Maximov, Anton
  • Lao, Y.
  • Li, H.
  • Chen, X. C.
  • Rizo, J.
  • Sorensen, J. B.
  • Sudhof, T. C.

publication date

  • 2008

journal

  • Proceedings of the National Academy of Sciences of the United States of America  Journal

abstract

  • Synaptotagmin-7 is a candidate Ca(2+) sensor for exocytosis that is at least partly localized to synapses. Similar to synaptotagmin-1, which functions as a Ca(2+) sensor for fast synaptic vesicle (SV) exocytosis, synaptotagmin-7 contains C(2)A and C(2)B domains that exhibit Ca(2+)-dependent phospholipid binding. However, synaptotagmin-7 cannot replace synaptotagmin-1 as a Ca(2+) sensor for fast SV exocytosis, raising questions about the physiological significance of its Ca(2+)-binding properties. Here, we examine how synaptotagmin-7 binds Ca(2+) and test whether this Ca(2+) binding regulates Ca(2+)-triggered SV exocytosis. We show that the synaptotagmin-7 C(2)A domain exhibits a Ca(2+)-binding mode similar to that of the synaptotagmin-1 C(2)A domain, suggesting that the synaptotagmin-1 and -7 C(2) domains generally employ comparable Ca(2+)-binding mechanisms. We then generated mutant mice that lack synaptotagmin-7 or contain point mutations inactivating Ca(2+) binding either to both C(2) domains of synaptotagmin-7 or only to its C(2)B domain. Synaptotagmin-7-mutant mice were viable and fertile. Inactivation of Ca(2+) binding to both C(2) domains caused an approximately 70% reduction in synaptotagmin-7 levels, whereas inactivation of Ca(2+) binding to only the C(2)B domain did not alter synaptotagmin-7 levels. The synaptotagmin-7 deletion did not change fast synchronous release, slow asynchronous release, or short-term synaptic plasticity of release of neurotransmitters. Thus, our results show that Ca(2+) binding to the synaptotagmin-7 C(2) domains is physiologically important for stabilizing synaptotagmin-7, but that Ca(2+) binding by synaptotagmin-7 likely does not regulate SV exocytosis, consistent with a role for synaptotagmin-7 in other forms of Ca(2+)-dependent synaptic exocytosis.

subject areas

  • Action Potentials
  • Animals
  • Calcium
  • Cells, Cultured
  • Exocytosis
  • Gene Targeting
  • Magnetic Resonance Spectroscopy
  • Mice
  • Mutation
  • Neurons
  • Protein Binding
  • Protein Structure, Tertiary
  • Synaptic Transmission
  • Synaptic Vesicles
  • Synaptotagmin I
  • Synaptotagmins
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Research

keywords

  • asynchronous release
  • calcium-binding protein
  • neurotransmitter release
  • synaptic plasticity
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Identity

PubMed Central ID

  • PMC2268828

International Standard Serial Number (ISSN)

  • 0027-8424

Digital Object Identifier (DOI)

  • 10.1073/pnas.0712372105

PubMed ID

  • 18308933
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Additional Document Info

start page

  • 3986

end page

  • 3991

volume

  • 105

issue

  • 10

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