Heterodimerization of Munc13 C<sub>2</sub>A domain with RIM regulates synaptic vesicle docking and priming.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 28489077.
- Also identified by DOI 10.1038/ncomms15293 and PMC identifier 5436228.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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<sub>2</sub>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<sub>2</sub>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<sub>2</sub>A domain. Using electron microscopy and electrophysiology in hippocampal cultures, we show that the C<sub>2</sub>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<sub>2</sub>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.
Medical subject headings
- Intracellular Signaling Peptides and Proteins
- Nerve Tissue Proteins
- Neurons
- Synaptic Vesicles