Neuron
Volume 95, Issue 3, 2 August 2017, Pages 591-607.e10
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Article
Molecular Mechanisms of Synaptic Vesicle Priming by Munc13 and Munc18

https://doi.org/10.1016/j.neuron.2017.07.004Get rights and content
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Highlights

  • Munc13-1 has a function independent from Munc18-1

  • Munc13-1 and Munc18-1 cooperate to promote proper SNARE complex assembly

  • Proper SNARE complex assembly yields near-physiological Ca2+ sensitivity in vitro

  • Bypass of Munc13 in neurons with an open mutant of syntaxin is incomplete

Summary

Munc13 catalyzes the transit of syntaxin from a closed complex with Munc18 into the ternary SNARE complex. Here we report a new function of Munc13, independent of Munc18: it promotes the proper syntaxin/synaptobrevin subconfiguration during assembly of the ternary SNARE complex. In cooperation with Munc18, Munc13 additionally ensures the proper syntaxin/SNAP-25 subconfiguration. In a reconstituted fusion assay with SNAREs, complexin, and synaptotagmin, inclusion of both Munc13 and Munc18 quadruples the Ca2+-triggered amplitude and achieves Ca2+ sensitivity at near-physiological concentrations. In Munc13-1/2 double-knockout neurons, expression of a constitutively open mutant of syntaxin could only minimally restore neurotransmitter release relative to Munc13-1 rescue. Together, the physiological functions of Munc13 may be related to regulation of proper SNARE complex assembly.

Keywords

neurotransmitter release
neuronal SNAREs
synaptotagmin
complexin
Munc13
Munc18
priming
plasticity

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These authors contributed equally

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