The trans-SNARE-regulating function of Munc18-1 is essential to synaptic exocytosis

Chong Shen, Shailendra S. Rathore, Haijia Yu, Daniel R. Gulbranson, Rui Hua, Chen Zhang, Nathan E. Schoppa and Jingshi Shen ()
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Chong Shen: Cellular and Developmental Biology, University of Colorado at Boulder
Shailendra S. Rathore: Cellular and Developmental Biology, University of Colorado at Boulder
Haijia Yu: Cellular and Developmental Biology, University of Colorado at Boulder
Daniel R. Gulbranson: Cellular and Developmental Biology, University of Colorado at Boulder
Rui Hua: State Key Laboratory of Membrane Biology, School of Life Sciences, PKU-IDG/McGovern Institute for Brain Research, Peking University
Chen Zhang: State Key Laboratory of Membrane Biology, School of Life Sciences, PKU-IDG/McGovern Institute for Brain Research, Peking University
Nathan E. Schoppa: University of Colorado School of Medicine
Jingshi Shen: Cellular and Developmental Biology, University of Colorado at Boulder

Nature Communications, 2015, vol. 6, issue 1, 1-10

Abstract: Abstract The fusion of neurotransmitter-filled synaptic vesicles with the plasma membrane requires two classes of molecules—SNAP receptor (SNARE) and Sec1/Munc18 (SM) protein. Reconstitution studies suggest that the SM protein Munc18-1 promotes the zippering of trans-SNARE complexes and accelerates the kinetics of SNARE-dependent membrane fusion. However, the physiological role of this trans-SNARE-regulating function in synaptic exocytosis remains to be established. Here we first demonstrate that two mutations in the vesicle-anchored v-SNARE selectively impair the ability of Munc18-1 to promote trans-SNARE zippering, whereas other known Munc18-1/SNARE-binding modes are unaffected. In cultured neurons, these v-SNARE mutations strongly inhibit spontaneous as well as evoked neurotransmitter release, providing genetic evidence for the trans-SNARE-regulating function of Munc18-1 in synaptic exocytosis. Finally, we show that the trans-SNARE-regulating function of Munc18-1 is compromised by a mutation associated with Ohtahara Syndrome, a severe form of epilepsy.

Date: 2015
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DOI: 10.1038/ncomms9852

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