Research Article

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

Science  25 Jan 2013:
Vol. 339, Issue 6118, pp. 421-425
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 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.

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