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

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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)

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.

Suggested Citation

  • Chong Shen & Shailendra S. Rathore & Haijia Yu & Daniel R. Gulbranson & Rui Hua & Chen Zhang & Nathan E. Schoppa & Jingshi Shen, 2015. "The trans-SNARE-regulating function of Munc18-1 is essential to synaptic exocytosis," Nature Communications, Nature, vol. 6(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms9852
    DOI: 10.1038/ncomms9852
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    Cited by:

    1. Praveen Papareddy & Ines Tapken & Keshia Kroh & Ravi Kiran Varma Bhongir & Milladur Rahman & Maria Baumgarten & Eda Irem Cim & Lilla Györffy & Emanuel Smeds & Ariane Neumann & Srinivas Veerla & Jon Ol, 2024. "The role of extracellular vesicle fusion with target cells in triggering systemic inflammation," Nature Communications, Nature, vol. 15(1), pages 1-17, December.

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