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Science 339 (6118): 421-425

Copyright © 2013 by the American Association for the Advancement of Science

Reconstitution of the Vital Functions of Munc18 and Munc13 in Neurotransmitter Release

Cong Ma,1,2,3,4,*,{dagger} Lijing Su,2,3,4,* Alpay B. Seven,2,3,4 Yibin Xu,2,3,4 Josep Rizo2,3,4,{dagger}

Abstract: Neurotransmitter release depends critically on Munc18-1, Munc13, the Ca2+ sensor synaptotagmin-1, and the soluble N-ethylmaleimide–sensitive factor (NSF) attachment protein (SNAP) receptors (SNAREs) syntaxin-1, synaptobrevin, and SNAP-25. In vitro reconstitutions have shown that syntaxin-1–SNAP-25 liposomes fuse efficiently with synaptobrevin liposomes in the presence of synaptotagmin-1–Ca2+, but neurotransmitter release also requires Munc18-1 and Munc13 in vivo. We found that Munc18-1 could displace SNAP-25 from syntaxin-1 and that fusion of syntaxin-1–Munc18-1 liposomes with synaptobrevin liposomes required Munc13, in addition to SNAP-25 and synaptotagmin-1-Ca2+. Moreover, when starting with syntaxin-1–SNAP-25 liposomes, NSF–α-SNAP disassembled the syntaxin-1–SNAP-25 heterodimers and abrogated fusion, which then required Munc18-1 and Munc13. We propose that fusion does not proceed through syntaxin-1–SNAP-25 heterodimers but starts with the syntaxin-1–Munc18-1 complex; Munc18-1 and Munc13 then orchestrate membrane fusion together with the SNAREs and synaptotagmin-1-Ca2+ in an NSF- and SNAP-resistant manner.

1 Key Laboratory of Molecular Biophysics, Ministry of Education, and Institute of Biophysics and Biochemistry, Huazhong University of Science and Technology, Wuhan 430074, China.
2 Department of Biophysics, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390, USA.
3 Department of Biochemistry, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390, USA.
4 Department of Pharmacology, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390, USA.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: cong.ma7{at} (C.M.); jose{at} (J.R.)

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