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The Journal of Neuroscience, September 29, 2004, 24(39):8542-8550; doi:10.1523/JNEUROSCI.2545-04.2004

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Cellular/Molecular
Dual Roles of the C₂B Domain of Synaptotagmin I in Synchronizing Ca²⁺-Dependent Neurotransmitter Release

Tei-ichi Nishiki and George J. Augustine

Department of Neurobiology, Duke University Medical Center, Durham, North Carolina 27710

Although the vesicular protein synaptotagmin I contains two Ca²⁺-binding domains (C₂A and C₂B), Ca²⁺ binding to the C₂B domain is more important for triggering synchronous neurotransmitter release. We have used point mutagenesis to determine the functional contributions of the five negatively charged aspartate (Asp) residues that constitute the Ca²⁺-binding sites in the C₂B domain of synaptotagmin I. Transfecting wild-type synaptotagmin I DNA into cultured hippocampal neurons from synaptotagmin I knock-out mice rescued Ca²⁺-dependent synchronous transmitter release and reduced a slower, asynchronous component of release, indicating that synaptotagmin I suppresses asynchronous release. Mutating either the second or third Asp residues of the C₂B domain potently inhibited the ability of synaptotagmin I to rescue synchronous release but did not change its ability to suppress asynchronous release. Synaptotagmin I with mutations in the first or fourth Asp residues of the C₂B domain partially rescued synchronous release and partially suppressed asynchronous release, whereas neutralizing the fifth Asp residue had no effect on the ability of synaptotagmin I to rescue transmitter release. Thus, we conclude that the C₂B domain of synaptotagmin I regulates neurotransmitter release in at least two ways. Synchronous release absolutely requires binding of Ca²⁺ to the second and third Asp residues in this domain. For the suppression of asynchronous release, Ca²⁺ binding to the C₂B domain of synaptotagmin I apparently is not necessary because mutation of the second Asp residue inhibits Ca²⁺ binding, yet still allows this protein to suppress asynchronous release.

Key words: synaptic transmission; synaptic vesicle; calcium; exocytosis; SNARE; hippocampal neurons

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Received June 26, 2004; revised August 23, 2004; accepted August 23, 2004.

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