TY - JOUR
T1 - Heterodimerization of Munc13 C2A domain with RIM regulates synaptic vesicle docking and priming
AU - Camacho, Marcial
AU - Basu, Jayeeta
AU - Trimbuch, Thorsten
AU - Chang, Shuwen
AU - Pulido-Lozano, Cristina
AU - Chang, Shwu Shin
AU - Duluvova, Irina
AU - Abo-Rady, Masin
AU - Rizo-Rey, Jose
AU - Rosenmund, Christian
N1 - Funding Information:
This research was supported by the German Research Council grant SFB958 (to C.R. and M.C.), the ERC grant SynVglut (to C.R.), the National Institutes of Health grant R35 NS097333 (to J.R.) and the Spanish Foundation of Manuel Morales and the Spanish Ministry of Science and Innovation (to M.C.). We thank Rike Dannenberg, Annegret Felies, Berit Söhl-Kielczynski, Sabine Lenz, Bettina Brokowski and Katja Pötschke for technical assistance, and the Charite viral core facility for virus production and characterization. We thank Dr Melissa Herman and Dr Benjamin Rost for fruitful discussions and comments on the manuscript and Dr Tanja Rosenmund for assistance with animal care.
Publisher Copyright:
© 2017 The Author(s).
PY - 2017
Y1 - 2017
N2 - 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.
AB - 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.
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U2 - 10.1038/ncomms15293
DO - 10.1038/ncomms15293
M3 - Article
C2 - 28489077
AN - SCOPUS:85028992890
SN - 2041-1723
VL - 8
JO - Nature communications
JF - Nature communications
M1 - 15293
ER -