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  • Title: Reconstitution of the vital functions of Munc18 and Munc13 in neurotransmitter release.
    Author: Ma C, Su L, Seven AB, Xu Y, Rizo J.
    Journal: Science; 2013 Jan 25; 339(6118):421-5. PubMed ID: 23258414.
    Abstract:
    Neurotransmitter release depends critically on Munc18-1, Munc13, the Ca(2+) 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-Ca(2+), 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-Ca(2+). 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-Ca(2+) in an NSF- and SNAP-resistant manner.
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