DOI: 10.1523/jneurosci.3804-06.2006. A Gain-of-Function Mutation in Synaptotagmin-1 Reveals a Critical Role of Ca<sup>2+</sup>-Dependent Soluble<i>N</i>-Ethylmaleimide-Sensitive Factor Attachment Protein Receptor Complex Binding in Synaptic Exocytosis

A Gain-of-Function Mutation in Synaptotagmin-1 Reveals a Critical Role of Ca2+-Dependent SolubleN-Ethylmaleimide-Sensitive Factor Attachment Protein Receptor Complex Binding in Synaptic Exocytosis

10.1523/jneurosci.3804-06.2006

Crossref journal-article

Society for Neuroscience

The Journal of Neuroscience (393)

Abstract

Synaptotagmin-1, the Ca2+sensor for fast neurotransmitter release, was proposed to function by Ca2+-dependent phospholipid binding and/or by Ca2+-dependent solubleN-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex binding. Extensivein vivodata support the first hypothesis, but testing the second hypothesis has been difficult because no synaptotagmin-1 mutation is known that selectively interferes with SNARE complex binding. Using knock-in mice that carry aspartate-to-asparagine substitutions in a Ca2+-binding site of synaptotagmin-1 (the D232N or D238N substitutions), we now show that the D232N mutation dramatically increases Ca2+-dependent SNARE complex binding by native synaptotagmin-1, but leaves phospholipid binding unchanged. In contrast, the adjacent D238N mutation does not significantly affect SNARE complex binding, but decreases phospholipid binding. Electrophysiological recordings revealed that the D232N mutation increased Ca2+-triggered release, whereas the D238N mutation decreased release. These data establish that fast vesicle exocytosis is driven by a dual Ca2+-dependent activity of synaptotagmin-1, namely Ca2+-dependent binding both to SNARE complexes and to phospholipids.

Bibliography

Pang, Z. P., Shin, O.-H., Meyer, A. C., Rosenmund, C., & SÃ¼dhof, T. C. (2006). A Gain-of-Function Mutation in Synaptotagmin-1 Reveals a Critical Role of Ca2+-Dependent SolubleN-Ethylmaleimide-Sensitive Factor Attachment Protein Receptor Complex Binding in Synaptic Exocytosis. The Journal of Neuroscience, 26(48), 12556â12565.

Authors 5

Zhiping P. Pang (first)
Ok-Ho Shin (additional)
Alexander C. Meyer (additional)
Christian Rosenmund (additional)
Thomas C. Südhof (additional)

References 40 Referenced 102

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Dates

Type	When
Created	18 years, 9 months ago (Nov. 29, 2006, 5:55 p.m.)
Deposited	2 years, 4 months ago (April 13, 2023, 1:44 p.m.)
Indexed	2 weeks, 5 days ago (Aug. 19, 2025, 6:48 a.m.)
Issued	18 years, 9 months ago (Nov. 29, 2006)
Published	18 years, 9 months ago (Nov. 29, 2006)
Published Online	18 years, 9 months ago (Nov. 29, 2006)
Published Print	18 years, 9 months ago (Nov. 29, 2006)

Funders 0

None

BibTeX

@article{Pang_2006, title={A Gain-of-Function Mutation in Synaptotagmin-1 Reveals a Critical Role of Ca2+-Dependent SolubleN-Ethylmaleimide-Sensitive Factor Attachment Protein Receptor Complex Binding in Synaptic Exocytosis}, volume={26}, ISSN={1529-2401}, url={http://dx.doi.org/10.1523/jneurosci.3804-06.2006}, DOI={10.1523/jneurosci.3804-06.2006}, number={48}, journal={The Journal of Neuroscience}, publisher={Society for Neuroscience}, author={Pang, Zhiping P. and Shin, Ok-Ho and Meyer, Alexander C. and Rosenmund, Christian and Südhof, Thomas C.}, year={2006}, month=nov, pages={12556–12565} }

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