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The Journal of Neuroscience, June 21, 2006, 26(25):6668-6676; doi:10.1523/JNEUROSCI.5272-05.2006
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Cellular/Molecular
Structural Determinants of Synaptobrevin 2 Function in Synaptic Vesicle Fusion
Ferenc Deák,1,2 Ok-Ho Shin,1 Ege T. Kavalali,1,4 andThomas C. Südhof1,2,3 1Center for Basic Neuroscience, 2Howard Hughes Medical Institute, Departments of 3Molecular Genetics and 4Physiology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390-9111
Correspondence should be addressed to Dr. Thomas C. Südhof or Dr. Ege T. Kavalali, Center for Basic Neuroscience, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9111. Email: thomas.sudhof{at}utsouthwestern.edu and ege.kavalali{at}utsouthwestern.edu
Deletion of synaptobrevin/vesicle-associated membrane protein, the major synaptic vesicle soluble N-ethylmaleimide-sensitive factor attachment protein receptor (R-SNARE), severely decreases but does not abolish spontaneous and evoked synaptic vesicle exocytosis. We now show that the closely related R-SNARE protein cellubrevin rescues synaptic transmission in synaptobrevin-deficient neurons but that deletion of both cellubrevin and synaptobrevin does not cause a more severe decrease in exocytosis than deletion of synaptobrevin alone. We then examined the structural requirements for synaptobrevin to function in exocytosis. We found that substituting glutamine for arginine in the zero-layer of the SNARE motif did not significantly impair synaptobrevin-dependent exocytosis, whereas insertion of 12 or 24 residues between the SNARE motif and transmembrane region abolished the ability of synaptobrevin to mediate Ca2+-evoked exocytosis. Surprisingly, however, synaptobrevin with the 12-residue but not the 24-residue insertion restored spontaneous release in synaptobrevin-deficient neurons. Our data suggest that synaptobrevin mediates Ca2+-triggered exocytosis by tight coupling of the SNARE motif to the transmembrane region and hence forcing the membranes into close proximity for fusion. Furthermore, the fusion reactions underlying evoked and spontaneous release differ mechanistically.
Key words: exocytosis; endocytosis; synaptic vesicle recycling; SNARE; spontaneous fusion; hippocampus; synapse; whole-cell patch-clamp
Received Dec. 9, 2005; revised May 3, 2006; accepted May 3, 2006.
Correspondence should be addressed to Dr. Thomas C. Südhof or Dr. Ege T. Kavalali, Center for Basic Neuroscience, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9111. Email: thomas.sudhof{at}utsouthwestern.edu and ege.kavalali{at}utsouthwestern.edu
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