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Title: RIM1α SUMOylation is required for fast synaptic vesicle exocytosis
Author: Girach , Fatima
ISNI:       0000 0004 5924 0711
Awarding Body: University of Bristol
Current Institution: University of Bristol
Date of Award: 2014
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Activity-dependent neurotransmitter release is mediated by the Ca2+ -dependent fusion of synaptic vesicles at the active zone of the presynaptic plasma membrane and is vital for brain function. The process of vesicle priming, fusion and retrieval is precisely controlled and requires tight spatiotemporal coordination of multiple protein-protein interactions. This study shows that post-translational modification of the active zone protein Rab3 Interacting Molecule Ia (RIMIa) by Small Ubiquitinlike MOdifier I (SUMO-I) directs such interactions and is essential for fast synaptic vesicle exocytosis. Post-translational protein modification by SUMOylation is a fundamentally impOliant regulatory mechanism in nearly all cellular pathways with key roles in neuronal function including synapse formation and receptor trafficking. Presynaptically, SUMOylation has previously been shown to regulate neurotransmitter release, however the specific SUMO substrate proteins involved are unknown. Here, RIMIa is identified as a synaptic SUMO substrate where abrogation ofRIMIa SUMOylation at lysine residue 502 in neurons leads to severe defects in action potential-evoked presynaptic exocytosis and Ca2+ entry. SUMOylation of RIMIa promotes interactions with Ca2+ channel subunit Cav2.1 in a PDZ-dependent manner, with no apparent effects on vesicle docking or priming. FUlihermore, SUMO-l conjugation to RIMIa is required for the correct clustering of Cav2.1 and enhances the Ca2+ influx necessary for vesicular release. It is postulated that RIM I a exists as two populations with SUMOylation generating a 'molecular switch' whereby the unmodified form is responsible for vesicle docking and fusion events and upon SUMO-I conjugation, is responsible for Ca2+ channel clustering and mediating Ca2+ responses prior to release. This novel finding implicates SUMOylation as a regulator of synaptic vesicle exocytosis and more specifically, demonstrates that SUMOylation of RIMIa is a key determinant of rapid, synchronous neurotransmitter release. Results here provide further insight into the mechanisms underpinning synaptic function and dysfunction.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available