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BIOLOGICAL SCIENCES / NEUROSCIENCE
Genetic analysis of synaptotagmin-7 function in synaptic vesicle exocytosis

Anton Maximov^*,,,, Ye Lao^*,,, Hongmei Li^*,,,¶,||, Xiaocheng Chen^¶,||, Josep Rizo^¶,||, Jakob B. Sørensen^**, and Thomas C. Südhof^*,,,

Departments of *Neuroscience, Molecular Genetics, ^¶Pharmacology, and ^||Biochemistry and Howard Hughes Medical Institute, UT Southwestern Medical Center, Dallas, TX 75390-9111; and **Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, D-37077 Göttingen, Germany

Contributed by Thomas C. Südhof, December 31, 2007 (received for review November 29, 2007)

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 Ca²⁺-binding properties. Here, we examine how synaptotagmin-7 binds Ca²⁺ and test whether this Ca²⁺ binding regulates Ca²⁺-triggered SV exocytosis. We show that the synaptotagmin-7 C₂A 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 C₂ domains of synaptotagmin-7 or only to its C₂B domain. Synaptotagmin-7-mutant mice were viable and fertile. Inactivation of Ca²⁺ 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.

asynchronous release | calcium-binding protein | neurotransmitter release | synaptic plasticity

Present address: Department of Cell Biology, The Scripps Research Institute, 10550 North Torrey Pines, La Jolla, CA 92037.

The authors declare no conflict of interest.

This article contains supporting information online at www.pnas.org/cgi/content/full/0712372105/DC1.

To whom correspondence should be addressed. E-mail: thomas.sudhof{at}utsouthwestern.edu

© 2008 by The National Academy of Sciences of the USA

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