RIM1α SUMOylation Is Required for Fast Synaptic Vesicle Exocytosis

The rapid, activity-dependent quantal presynaptic release of neurotransmitter is vital for brain function. The complex process of vesicle priming, fusion, and retrieval is very precisely controlled and requires the spatiotemporal coordination of multiple protein-protein interactions. Here, we show that posttranslational modification of the active zone protein Rab3-interacting molecule 1 alpha (RIM1 alpha) by the small ubiquitin-like modifier 1 (SUMO-1) functions as a molecular switch to direct these interactions and is essential for fast synaptic vesicle exocytosis. RIM1 alpha SUMOylation at lysine residue K502 facilitates the clustering of Ca(V)2.1 calcium channels and enhances the Ca2+ influx necessary for vesicular release, whereas non-SUMOylated RIM1 alpha participates in the docking/priming of synaptic vesicles and maintenance of active zone structure. These results demonstrate that SUMOylation of RIM1 alpha is a key determinant of rapid, synchronous neurotransmitter release, and the SUMO-mediated switching of RIM1 alpha between binding proteins provides insight into the mechanisms underpinning synaptic function and dysfunction.