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 1α (RIM1α) 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. RIM1α SUMOylation at lysine residue K502 
facilitates the clustering of CaV2.1 calcium channels and enhances the Ca(2+) 
influx necessary for vesicular release, whereas non-SUMOylated RIM1α 
participates in the docking/priming of synaptic vesicles and maintenance of 
active zone structure. These results demonstrate that SUMOylation of RIM1α is a 
key determinant of rapid, synchronous neurotransmitter release, and the 
SUMO-mediated "switching" of RIM1α between binding proteins provides insight 
into the mechanisms underpinning synaptic function and dysfunction.