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Papers In Press, published online ahead of print May 16, 2006
Department of Molecular Neurobiology, MaxPlanck-Institute of Experimental Medicine, Go¨ttingen D-37075
Corresponding Author: brose{at}em.mpg.de
Transmitter release at synapses between nerve cells is spatially restricted to active zones, where synaptic vesicle docking, priming, and Ca2+-dependent fusion take place in a temporally highly coordinated manner. Munc13s are essential for priming synaptic vesicles to a fusion competent state, and their specific active zone localization contributes to the active zone restriction of transmitter release and the speed of excitation-secretion coupling. However, the molecular mechanism of the active zone recruitment of Munc13s is not known. We show here that the active zone recruitment of the Munc13 isoforms Munc13-1 and ubMunc13-2 is regulated by their binding to the Rab3A-interacting molecule RIM1a, a key determinant of long-term potentiation of synaptic transmission at mossy fiber synapses in the hippocampus. We identify a single point mutation in Munc13-1 and ubMunc13-2 (I121N) that, depending on the type of assay used, strongly perturbs or abolishes RIM1a binding in vitro and in cultured fibroblasts, and we demonstrate that RIM1a binding deficient ubMunc13-2I121 is not efficiently recruited to synapses. Moreover, the levels of Munc13-1 and ubMunc13-2 levels are decreased in RIM1a deficient brain, and Munc13-1 is not properly enriched at active zones of mossy fiber terminals of the mouse hippocampus if RIM1a is absent. We conclude that one function of the Munc13/RIM1a interaction is the active zone recruitment of Munc13-1 and ubMunc13-2.
J. Biol. Chem, 10.1074/jbc.M601421200
Submitted on February 14, 2006
Revised on May 3, 2006
Accepted on May 15, 2006
Binding to RAB3a-interacting-molecule rim regulates the presynaptic recruitment of MUNC13-1 and ubMUNC13-2
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