Article abstract
Nature Neuroscience 10, 691 - 701 (2007)
Published online: 13 May 2007 | doi:10.1038/nn1904
RIM1 confers sustained activity and neurotransmitter vesicle anchoring to presynaptic Ca2+ channels
Shigeki Kiyonaka1, Minoru Wakamori1, Takafumi Miki1, Yoshitsugu Uriu1, Mio Nonaka2, Haruhiko Bito2, Aaron M Beedle3, Emiko Mori1, Yuji Hara1,3, Michel De Waard4, Motoi Kanagawa3, Makoto Itakura5, Masami Takahashi5, Kevin P Campbell3 & Yasuo Mori1
Abstract
The molecular organization of presynaptic active zones is important for the neurotransmitter release that is triggered by depolarization-induced Ca2+ influx. Here, we demonstrate a previously unknown interaction between two components of the presynaptic active zone, RIM1 and voltage-dependent Ca2+ channels (VDCCs), that controls neurotransmitter release in mammalian neurons. RIM1 associated with VDCC 
-subunits via its C terminus to markedly suppress voltage-dependent inactivation among different neuronal VDCCs. Consistently, in pheochromocytoma neuroendocrine PC12 cells, acetylcholine release was significantly potentiated by the full-length and C-terminal RIM1 constructs, but membrane docking of vesicles was enhanced only by the full-length RIM1. The construct beta-AID dominant negative, which disrupts the RIM1- association, accelerated the inactivation of native VDCC currents, suppressed vesicle docking and acetylcholine release in PC12 cells, and inhibited glutamate release in cultured cerebellar neurons. Thus, RIM1 association with in the presynaptic active zone supports release via two distinct mechanisms: sustaining Ca2+ influx through inhibition of channel inactivation, and anchoring neurotransmitter-containing vesicles in the vicinity of VDCCs.
- Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Katsura Campus, Nishikyo-ku, Kyoto 615-8510, Japan.
- Department of Neurochemistry, University of Tokyo Graduate School of Medicine, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.
- Howard Hughes Medical Institute and Departments of Physiology and Biophysics, Internal Medicine, and Neurology, University of Iowa Roy J. and Lucille A. Carver College of Medicine, 285 Newton Road, Iowa City, Iowa 52242-1101, USA.
- Inserm U607, Laboratoire Canaux Calciques, Fonctions et Pathologies, 17 Rue des Martyrs, Bâtiment C3, 38054 Grenoble Cedex 09, France.
- Department of Biochemistry, Kitasato University School of Medicine, Kitasato 1-15-1, Sagamihara, Kanagawa 228-8555, Japan.
Correspondence to: Yasuo Mori1 e-mail: mori@sbchem.kyoto-u.ac.jp
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