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Published online
doi:10.1083/jcb.200805150
The Journal of Cell Biology, Vol. 183, No. 2, 323-337
The Rockefeller University Press, 0021-9525 $30.00
© Sakisaka et al.
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Article

Dual inhibition of SNARE complex formation by tomosyn ensures controlled neurotransmitter release



Toshiaki Sakisaka1, Yasunori Yamamoto1, Sumiko Mochida3, Michiko Nakamura4, Kouki Nishikawa5, Hiroyoshi Ishizaki6, Miki Okamoto-Tanaka6, Jun Miyoshi6, Yoshinori Fujiyoshi5, Toshiya Manabe4,7, and Yoshimi Takai2

1 Division of Membrane Dynamics, Department of Physiology and Cell Biology, and 2 Division of Molecular and Cellular Biology, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan
3 Department of Physiology, Tokyo Medical University, Tokyo 160-8402, Japan
4 Division of Neuronal Network, Department of Basic Medical Sciences, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
5 Department of Biophysics, Kyoto University Graduate School of Science, Kyoto 606-8502, Japan
6 Department of Molecular Biology, Osaka Medical Center for Cancer and Cardiovascular Disease, Osaka 537-8511, Japan
7 Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Kawaguchi 332-0012, Japan

Correspondence to Y. Takai: ytakai{at}med.kobe-u.ac.jp

Neurotransmitter release from presynaptic nerve terminals is regulated by soluble NSF attachment protein receptor (SNARE) complex–mediated synaptic vesicle fusion. Tomosyn inhibits SNARE complex formation and neurotransmitter release by sequestering syntaxin-1 through its C-terminal vesicle-associated membrane protein (VAMP)–like domain (VLD). However, in tomosyn-deficient mice, the SNARE complex formation is unexpectedly decreased. In this study, we demonstrate that the N-terminal WD-40 repeat domain of tomosyn catalyzes the oligomerization of the SNARE complex. Microinjection of the tomosyn N-terminal WD-40 repeat domain into neurons prevented stimulated acetylcholine release. Thus, tomosyn inhibits neurotransmitter release by catalyzing oligomerization of the SNARE complex through the N-terminal WD-40 repeat domain in addition to the inhibitory activity of the C-terminal VLD.

T. Sakisaka and Y. Yamamoto contributed equally to this paper.

Abbreviations used in this paper: Ab, antibody; CSM, crude synaptic membrane; EPSP, excitatory postsynaptic potential; ES, embryonic stem; Lgl, lethal giant larvae; LTP, long-term potentiation; MBP, maltose-binding protein; PPF, paired-pulse facilitation; SCG, superior cervical ganglion; VAMP, vesicle-associated membrane protein; VLD, VAMP-like domain.

© 2008 Sakisaka et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jcb.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).


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