Membrane bridging by Munc13-1 is crucial for neurotransmitter release
- University of Texas Southwestern Medical Center, United States
- Charité-Universitätsmedizin Berlin, Germany
Abstract
Munc13-1 plays a crucial role in neurotransmitter release. We recently proposed that the C-terminal region encompassing the C1, C2B, MUN and C2C domains of Munc13-1 (C1C2BMUNC2C) bridges the synaptic vesicle and plasma membranes through interactions involving the C2C domain and the C1-C2B region. However, the physiological relevance of this model has not been demonstrated. Here we show that C1C2BMUNC2C bridges membranes through opposite ends of its elongated structure. Mutations in putative membrane-binding sites of the C2C domain disrupt the ability of C1C2BMUNC2C to bridge liposomes and to mediate liposome fusion in vitro. These mutations lead to corresponding disruptive effects on synaptic vesicle docking, priming, and Ca2+-triggered neurotransmitter release in mouse neurons. Remarkably, these effects include an almost complete abrogation of release by a single residue substitution in this 200 kDa protein. These results show that bridging the synaptic vesicle and plasma membranes is a central function of Munc13-1.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files
Article and author information
Author details
Christian Rosenmund
Funding
National Institute of Neurological Disorders and Stroke (R35 NS097333)
- Josep Rizo
Welch Foundation (I-1304)
- Josep Rizo
Deutsche Forschungsgemeinschaft (SFB958)
- Christian Rosenmund
Deutsche Forschungsgemeinschaft (SFB 1315)
- Christian Rosenmund
Deutsche Forschungsgemeinschaft (Ro1296/7-1)
- Christian Rosenmund
Deutsche Forschungsgemeinschaft (8-1)
- Christian Rosenmund
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All animal experiments were conducted according to the rules of the Berlin state government agency for Health and Social Services and the animal welfare committees of Charité Medical University Berlin, Germany (license no. T 0220/09).
Copyright
© 2019, Quade et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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