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J. Biol. Chem., Vol. 281, Issue 28, 19720-19731, July 14, 2006

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Binding to Rab3A-interacting Molecule RIM Regulates the Presynaptic Recruitment of Munc13-1 and ubMunc13-2^*

From the Department of Molecular Neurobiology, Max Planck Institute of Experimental Medicine, Hermann-Rein-Strasse 3, D-37075 Göttingen, Germany

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 Munc13 isoforms Munc13-1 and ubMunc13-2 is regulated by their binding to the Rab3A-interacting molecule RIM1, 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 RIM1 binding in vitro and in cultured fibroblasts, and we demonstrate that RIM1 binding-deficient ubMunc13-2^I121 is not efficiently recruited to synapses. Moreover, the levels of Munc13-1 and ubMunc13-2 levels are decreased in RIM1-deficient brain, and Munc13-1 is not properly enriched at active zones of mossy fiber terminals of the mouse hippocampus if RIM1 is absent. We conclude that one function of the Munc13/RIM1 interaction is the active zone recruitment of Munc13-1 and ubMunc13-2.

Received for publication, February 14, 2006 , and in revised form, May 3, 2006.

^* This work was supported in part by German Research Foundation Grant SFB406/A1 (to N. B.) and a postdoctoral fellowship grant of the Japan Society for the Promotion of Science (to H. K.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 49-551-3899725; Fax: 49-551-3899715; E-mail: brose{at}em.mpg.de.

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