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Cited by 95Cellular transport and secretionNeuroscience and Neuropharmacology ResearchExtracellular vesicles in disease

Heterodimerization of Munc13 C2A domain with RIM regulates synaptic vesicle docking and priming

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Camacho, Marcial, Basu, Jayeeta, Trimbuch, Thorsten, Chang, Shuwen, Pulido-Lozano, Cristina, Chang, Shwu-Shin, Duluvova, Irina, Abo-Rady, Masin +2 more·2017·Nature Communications
DOI 10.1038/ncomms15293PMC PMC5436228
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Abstract

The presynaptic active zone protein Munc13 is essential for neurotransmitter release, playing key roles in vesicle docking and priming. Mechanistically, it is thought that the C 2 A domain of Munc13 inhibits the priming function by homodimerization, and that RIM disrupts the autoinhibitory homodimerization forming monomeric priming-competent Munc13. However, it is unclear whether the C 2 A domain mediates other Munc13 functions in addition to this inactivation–activation switch. Here, we utilize mutations that modulate the homodimerization and heterodimerization states to define additional roles of the Munc13 C 2 A domain. Using electron microscopy and electrophysiology in hippocampal cultures, we show that the C 2 A domain is critical for additional steps of vesicular release, including vesicle docking. Optimal vesicle docking and priming is only possible when Munc13 heterodimerizes with RIM via its C 2 A domain. Beyond being a switching module, our data suggest that the Munc13-RIM heterodimer is an active component of the vesicle docking, priming and release complex.

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Authors
Camacho, M., Basu, J., Trimbuch, T., Chang, S., Pulido-Lozano, C., Chang, S.-S., Duluvova, I., Abo-Rady, M., Rizo, J., & Rosenmund, C.
Affiliations
  • Baylor College of Medicine (US)
  • NeuroCure Cluster of Excellence (DE)
  • The University of Texas Southwestern Medical Center (US)
Corresponding author
Rosenmund, Christian
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2017-05-10
Volume
8
Issue
1
Pages
15293-15293
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/ncomms15293
PMC
PMC5436228
OpenAlex
W2613882793
Cited by
95
References
47
Citations by year
2026: 7 · 2025: 11 · 2024: 5 · 2023: 13 · 2022: 16 · 2021: 9 · 2020: 7 · 2019: 13 · 2018: 6 · 2017: 7 · 2014: 1
FWCI
4.82
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Refubium (Universitätsbibliothek der Freien Universität Berlin) (submittedVersion, cc-by)
  • Universitätsbibliothek der FU Berlin Hochschulschriftenstelle u. Dokumentenserver (cc-by)
Funders
  • Ministerio de Ciencia e Innovación
  • National Institutes of Health (NS097333)
  • National Institute of Neurological Disorders and Stroke (R35NS097333)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
Keywords
Munc13, RIM, C2A domain, heterodimerization, homodimerization, synaptic vesicle docking, vesicle priming, neurotransmitter release, active zone, autoinhibition, hippocampal neurons
MeSH terms
Protein Domains, Animals, Binding Sites, Cells, Cultured, Hippocampus, Humans, Nerve Tissue Proteins, Synaptic Transmission, Neurons, Synaptic Vesicles, Mice, Knockout, Microscopy, Electron, Transmission, Intracellular Signaling Peptides and Proteins, Protein Multimerization, HEK293 Cells

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