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The Journal of Neuroscience, September 19, 2007, 27(38):10176-10184; doi:10.1523/JNEUROSCI.2339-07.2007

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Cellular/Molecular
Tomosyn Negatively Regulates CAPS-Dependent Peptide Release at Caenorhabditis elegans Synapses

Elena O. Gracheva, Anna O. Burdina, Denis Touroutine, Martine Berthelot-Grosjean, Hetal Parekh, and Janet E. Richmond

Department of Biological Sciences, Science and Engineering Labs, University of Illinois at Chicago, Chicago, Illinois 60607

Correspondence should be addressed to Dr. Janet E. Richmond, Department of Biological Sciences, Science and Engineering Labs, 840 West Taylor Street, University of Illinois at Chicago, Chicago, IL 60607. Email: jer{at}uic.edu

The syntaxin-interacting protein tomosyn is thought to be a key regulator of exocytosis, although its precise mechanism of action has yet to be elucidated. Here we examined the role of tomosyn in peptide secretion in Caenorhabditis elegans tomosyn (tom-1) mutants. Ultrastructural analysis of tom-1 mutants revealed a 50% reduction in presynaptic dense-core vesicles (DCVs) corresponding to enhanced neuropeptide release. Conversely, overexpression of TOM-1 led to an accumulation of DCVs. Together, these data provide the first in vivo evidence that TOM-1 negatively regulates DCV exocytosis. In C. elegans, neuropeptide release is promoted by the calcium-dependent activator protein for secretion (CAPS) homolog UNC-31. To test for a genetic interaction between tomosyn and CAPS, we generated tom-1;unc-31 double mutants. Loss of TOM-1 suppressed the behavioral, electrophysiological, and DCV ultrastructural phenotypes of unc-31 mutants, indicating that TOM-1 antagonizes UNC-31-dependent DCV release. Because unc-31 mutants exhibit synaptic transmission defects, we postulated that loss of DCV release in these mutants and the subsequent suppression by tom-1 mutants could simply reflect alterations in synaptic activity, rather than direct regulation of DCV release. To distinguish between these two possibilities, we analyzed C. elegans Rim mutants (unc-10), which have a comparable reduction in synaptic transmission to unc-31 mutants, specifically attributed to defects in synaptic vesicle (SV) exocytosis. Based on this analysis, we conclude that the changes in DCV release in tom-1 and unc-31 mutants reflect direct effects of TOM-1 and UNC-31 on DCV exocytosis, rather than altered SV release.

Key words: tomosyn; CAPS; C. elegans; peptidergic transmission; neuromuscular junction; UNC-31; TOM-1

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Received May 22, 2007; revised Aug. 5, 2007; accepted Aug. 8, 2007.

Correspondence should be addressed to Dr. Janet E. Richmond, Department of Biological Sciences, Science and Engineering Labs, 840 West Taylor Street, University of Illinois at Chicago, Chicago, IL 60607. Email: jer{at}uic.edu

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