Molecular Mechanisms of Synaptic Vesicle Priming by Munc13 and Munc18

Ying Lai; Ucheor B Choi; Jeremy Leitz; Hong Jun Rhee; Choongku Lee; Bekir Altas; Minglei Zhao; Richard A Pfuetzner; Austin L Wang; Nils Brose; JeongSeop Rhee; Axel T Brunger

doi:10.1016/j.neuron.2017.07.004

Molecular Mechanisms of Synaptic Vesicle Priming by Munc13 and Munc18

Neuron. 2017 Aug 2;95(3):591-607.e10. doi: 10.1016/j.neuron.2017.07.004.

Authors

Affiliations

¹ Department of Molecular and Cellular Physiology, Stanford University, Stanford, CA 94305, USA; Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA 94305, USA; Department of Structural Biology, Stanford University, Stanford, CA 94305, USA; Department of Photon Science, Stanford University, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA.
² Department of Molecular Neurobiology, Max Planck Institute for Experimental Medicine, 37075 Göttingen, Germany.
³ Department of Molecular and Cellular Physiology, Stanford University, Stanford, CA 94305, USA; Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA 94305, USA; Department of Structural Biology, Stanford University, Stanford, CA 94305, USA; Department of Photon Science, Stanford University, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA. Electronic address: brunger@stanford.edu.

Abstract

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: Munc13; Munc18; complexin; neuronal SNAREs; neurotransmitter release; plasticity; priming; synaptotagmin.

MeSH terms

Animals
Cells, Cultured
Exocytosis / physiology*
Intracellular Signaling Peptides and Proteins / genetics
Intracellular Signaling Peptides and Proteins / metabolism*
Mice
Munc18 Proteins / metabolism*
Nerve Tissue Proteins / genetics
Nerve Tissue Proteins / metabolism*
Neurons / physiology
Neurotransmitter Agents / metabolism*
SNARE Proteins / metabolism*
Synaptic Transmission / physiology
Synaptic Vesicles / metabolism*

Substances

Intracellular Signaling Peptides and Proteins
Munc18 Proteins
Nerve Tissue Proteins
Neurotransmitter Agents
SNARE Proteins
Unc13a protein, mouse
Unc13b protein, mouse

Abstract

MeSH terms

Substances

Grants and funding