Synaptic neurotransmitter release is restricted to active zones, where the processes of synaptic vesicle tethering, priming to fusion competence, and Ca2+-triggered fusion are taking place in a highly coordinated manner. We show that the active zone components Munc13-1, an essential vesicle priming protein, and RIM1, a Rab3 effector with a putative role in vesicle tethering, interact functionally. Disruption of this interaction causes a loss of fusion-competent synaptic vesicles, creating a phenocopy of Munc13-1-deficient neurons. RIM1 binding and vesicle priming are mediated by two distinct structural modules of Munc13-1. The Munc13-1/RIM1 interaction may create a functional link between synaptic vesicle tethering and priming, or it may regulate the priming reaction itself, thereby determining the number of fusion-competent vesicles.
Bibliographical noteFunding Information:
We thank A. Bührmann, T. Hellmann, I. Herfort, and S. Wenger for excellent technical assistance; I. Thanhäuser and F. Benseler for DNA synthesis and sequencing; T. C. Südhof for plasmids, antibodies, and information on the RIM1 knockouts prior to publication; and R. Jahn, E. Neher, and B. Stahl for comments on the manuscript. We are grateful to E. Neher and T. C. Südhof for continued support and advice. This work was supported by grants from the Deutsche Forschungsgemeinschaft (SFB406/A1 to N. B.; Re1092/3-2 to J. R.; Ro1296/6-1 to C. R. and N. B.) and by a EU Network Grant (980236 to U. A.). N. B. and C. R. are Heisenberg Fellows of the Deutsche Forschungsgemeinschaft.