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The Journal of Neuroscience, November 29, 2006, 26(48):12556-12565; doi:10.1523/JNEUROSCI.3804-06.2006

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

Zhiping P. Pang,^1 * Ok-Ho Shin,^1 * Alexander C. Meyer,^4 * Christian Rosenmund,^4,5 and Thomas C. Südhof^1,2,3

¹Center for Basic Neuroscience, ²Department of Molecular Genetics, and ³Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas 75390, ⁴Department of Membrane Biophysics, Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany, and ⁵Departments of Neuroscience and Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030

Correspondence should be addressed to Thomas C. Südhof at the above address. Email: thomas.sudhof{at}utsouthwestern.edu

Synaptotagmin-1, the Ca²⁺ sensor for fast neurotransmitter release, was proposed to function by Ca²⁺-dependent phospholipid binding and/or by Ca²⁺-dependent soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex binding. Extensive in vivo data 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.

Key words: Ca²⁺-dependent; exocytosis; phospholipids; synapse; synaptotagmin; SNARE

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Received Aug. 31, 2006; revised Oct. 7, 2006; accepted Oct. 9, 2006.

Correspondence should be addressed to Thomas C. Südhof at the above address. Email: thomas.sudhof{at}utsouthwestern.edu

This article has been cited by other articles:

				G. Nagy, I. Milosevic, R. Mohrmann, K. Wiederhold, A. M. Walter, and J. B. Sorensen The SNAP-25 Linker as an Adaptation Toward Fast Exocytosis Mol. Biol. Cell, September 1, 2008; 19(9): 3769 - 3781. [Abstract] [Full Text] [PDF]

				B. E. Paddock, A. R. Striegel, E. Hui, E. R. Chapman, and N. E. Reist Ca2+-Dependent, Phospholipid-Binding Residues of Synaptotagmin Are Critical for Excitation-Secretion Coupling In Vivo J. Neurosci., July 23, 2008; 28(30): 7458 - 7466. [Abstract] [Full Text] [PDF]

				K. L. Lynch, R.R.L. Gerona, E. C. Larsen, R. F. Marcia, J. C. Mitchell, and T.F.J. Martin Synaptotagmin C2A Loop 2 Mediates Ca2+-dependent SNARE Interactions Essential for Ca2+-triggered Vesicle Exocytosis Mol. Biol. Cell, December 1, 2007; 18(12): 4957 - 4968. [Abstract] [Full Text] [PDF]

				S.-W. Min, W.-P. Chang, and T. C. Sudhof E-Syts, a family of membranous Ca2+-sensor proteins with multiple C2 domains PNAS, March 6, 2007; 104(10): 3823 - 3828. [Abstract] [Full Text] [PDF]

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