title: RIM1α SUMOylation is required for fast synaptic vesicle exocytosis.
abstract: 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.
authors.affiliation: Department of Biochemistry, School of Medical Sciences, University Walk, University of Bristol, Bristol BS8 1TD, UK.
authors.forename: Fatima
authors.initials: F
authors.lastname: Girach
authors.affiliation: Department of Biochemistry, School of Medical Sciences, University Walk, University of Bristol, Bristol BS8 1TD, UK.
authors.forename: Tim J
authors.initials: TJ
authors.lastname: Craig
authors.affiliation: Department of Biochemistry, School of Medical Sciences, University Walk, University of Bristol, Bristol BS8 1TD, UK.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Rocca
authors.affiliation: Department of Biochemistry, School of Medical Sciences, University Walk, University of Bristol, Bristol BS8 1TD, UK. Electronic address: anjmh@bristol.ac.uk.
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Henley
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D020864:Calcium Channels, N-Type / Q000378:metabolism; D002478:Cells, Cultured; D005089:Exocytosis; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D009154:Mutation; D011485:Protein Binding; D051381:Rats; D025842:SUMO-1 Protein / Q000378:metabolism*; D058207:Sumoylation; D013569:Synapses / Q000378:metabolism; D013572:Synaptic Vesicles / Q000378:metabolism*
chemical_list: D002118:Calcium; D020864:Calcium Channels, N-Type; D019204:GTP-Binding Proteins; D025842:SUMO-1 Protein; C491489:Rims1 protein, rat