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

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.