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

Marcial Camacho, Jayeeta Basu, Thorsten Trimbuch, Shuwen Chang, Cristina Pulido-Lozano, Shwu Shin Chang, Irina Duluvova, Masin Abo-Rady, Jose Rizo-Rey, Christian Rosenmund

Research output: Contribution to journalArticle

26 Scopus citations

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 C2A 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 C2A 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 C2A domain. Using electron microscopy and electrophysiology in hippocampal cultures, we show that the C2A 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 C2A 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.

Original languageEnglish (US)
Article number15293
JournalNature communications
Volume8
DOIs
StatePublished - 2017

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Camacho, M., Basu, J., Trimbuch, T., Chang, S., Pulido-Lozano, C., Chang, S. S., Duluvova, I., Abo-Rady, M., Rizo-Rey, J., & Rosenmund, C. (2017). Heterodimerization of Munc13 C2A domain with RIM regulates synaptic vesicle docking and priming. Nature communications, 8, [15293]. https://doi.org/10.1038/ncomms15293