Research Article

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

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Science  20 Dec 2012:
1230473
DOI: 10.1126/science.1230473

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Abstract

Neurotransmitter release depends critically on Munc18-1, Munc13, the Ca2+ sensor synaptotagmin-1, and the 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. Here, 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.

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