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

• Published in: Nature communications Vol. 8; no. 1; pp. 15293 - 13
• Main Authors: Camacho, Marcial, Basu, Jayeeta, Trimbuch, Thorsten, Chang, Shuwen, Pulido-Lozano, Cristina, Chang, Shwu-Shin, Duluvova, Irina, Abo-Rady, Masin, Rizo, Josep, Rosenmund, Christian
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 10.05.2017; Nature Publishing Group; Nature Portfolio
• Subjects: 13/106; 13/109; 13/51; 631/378/548/2589; 631/378/548/2590; 64/60; 82/80; 9/74; Humanities and Social Sciences; Inactivation; Microscopy; multidisciplinary; Nervous system; Neurosciences; Proteins; Science; Science (multidisciplinary); New York; United States > US; Berlin Germany; Texas; Germany
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms15293

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. The interaction between RIM and the C 2 A domain of Munc13 is known to be required for synaptic vesicle priming. Here the authors show new implications of the C 2 A domain of Munc13, through its dynamic interaction with RIM, in orchestrating a wide range of modulatory operations that shape vesicle docking, priming and neurotransmitter release.