Antagonistic Regulation of Synaptic Vesicle Priming by Tomosyn and UNC-13

• Published in: Neuron (Cambridge, Mass.) Mass.), 2006-08, Vol.51 (3), p.303-315
• Main Authors: McEwen, Jason M., Madison, Jon M., Dybbs, Michael, Kaplan, Joshua M.
• Format: Article
• Language: English
• Subjects: Animals; Behavior; Caenorhabditis elegans; Caenorhabditis elegans Proteins - genetics; Caenorhabditis elegans Proteins - physiology; Carrier Proteins; CELLBIO; Hypotheses; Molecular Sequence Data; Mutation; Plasma; Proteins; Qa-SNARE Proteins - physiology; SIGNALING; SNARE Proteins - genetics; SNARE Proteins - physiology; Software; Sucrose; Synaptic Vesicles - genetics; Synaptic Vesicles - physiology
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2006.06.025

Priming of synaptic vesicles (SVs) is essential for synaptic transmission. UNC-13 proteins are required for priming. Current models propose that UNC-13 stabilizes the open conformation of Syntaxin, in which the SNARE helix is available for interactions with Synaptobrevin and SNAP-25. Here we show that Tomosyn inhibits SV priming. Tomosyn contains a SNARE motif, which forms an inhibitory SNARE complex with Syntaxin and SNAP-25. Mutants lacking Tomosyn have increased synaptic transmission, an increased pool of primed vesicles, and increased abundance of UNC-13 at synapses. Behavioral, imaging, and electrophysiological studies suggest that SV priming was reconstituted in unc-13 mutants by expressing a constitutively open mutant Syntaxin, or by mutations eliminating Tomosyn. Thus, priming is modulated by the balance between Tomosyn and UNC-13, perhaps by regulating the availability of open-Syntaxin. Even when priming was restored, synaptic transmission remained defective in unc-13 mutants, suggesting that UNC-13 is also required for other aspects of secretion.