title: Antagonistic regulation of synaptic vesicle priming by Tomosyn and UNC-13.
abstract: 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.
authors.affiliation: Department of Molecular Biology, Massachusetts General Hospital, Simches Research Building, Seventh Floor, 185 Cambridge Street, Boston, Massachusetts 02114, USA.
authors.forename: Jason M
authors.initials: JM
authors.lastname: McEwen
authors.forename: Jon M
authors.initials: JM
authors.lastname: Madison
authors.forename: Michael
authors.initials: M
authors.lastname: Dybbs
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Kaplan
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000502:physiology*; D002352:Carrier Proteins; D008969:Molecular Sequence Data; D009154:Mutation; D050765:Qa-SNARE Proteins / Q000502:physiology; D050600:SNARE Proteins / Q000235:genetics / Q000502:physiology*; D013572:Synaptic Vesicles / Q000235:genetics / Q000502:physiology*
chemical_list: D029742:Caenorhabditis elegans Proteins; D002352:Carrier Proteins; D050765:Qa-SNARE Proteins; D050600:SNARE Proteins; C083141:phorbol ester binding protein; C513301:tom-1 protein, C elegans