Genetic analysis of synaptotagmin-7 function in synaptic vesicle exocytosis

Anton Maximov, Ye Lao, Hongmei Li, Xiaocheng Chen, Jose Rizo-Rey, Jakob B. Sørensen, Thomas C. Südhof

Research output: Contribution to journalArticle

64 Scopus citations

Abstract

Synaptotagmin-7 is a candidate Ca2+ sensor for exocytosis that is at least partly localized to synapses. Similar to synaptotagmin-1, which functions as a Ca2+ sensor for fast synaptic vesicle (SV) exocytosis, synaptotagmin-7 contains C2A and C2B domains that exhibit Ca2+-dependent phospholipid binding. However, synaptotagmin-7 cannot replace synaptotagmin-1 as a Ca2+ sensor for fast SV exocytosis, raising questions about the physiological significance of its Ca 2+-binding properties. Here, we examine how synaptotagmin-7 binds Ca2+ and test whether this Ca2+ binding regulates Ca 2+-triggered SV exocytosis. We show that the synaptotagmin-7 C 2A domain exhibits a Ca2+-binding mode similar to that of the synaptotagmin-1 C2A domain, suggesting that the synaptotagmin-1 and -7 C2 domains generally employ comparable Ca2+-binding mechanisms. We then generated mutant mice that lack synaptotagmin-7 or contain point mutations inactivating Ca2+ binding either to both C 2 domains of synaptotagmin-7 or only to its C2B domain. Synaptotagmin-7-mutant mice were viable and fertile. Inactivation of Ca 2+ binding to both C2 domains caused an ≈70% reduction in synaptotagmin-7 levels, whereas inactivation of Ca2+ binding to only the C2B 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 Ca2+ binding to the synaptotagmin-7 C2 domains is physiologically important for stabilizing synaptotagmin-7, but that Ca2+ binding by synaptotagmin-7 likely does not regulate SV exocytosis, consistent with a role for synaptotagmin-7 in other forms of Ca2+-dependent synaptic exocytosis.

Original languageEnglish (US)
Pages (from-to)3986-3991
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number10
DOIs
StatePublished - Mar 25 2008

Keywords

  • Asynchronous release
  • Calcium-binding protein
  • Neurotransmitter release
  • Synaptic plasticity

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'Genetic analysis of synaptotagmin-7 function in synaptic vesicle exocytosis'. Together they form a unique fingerprint.

  • Cite this