Tomosyn inhibits synaptotagmin-1-mediated step of Ca2+-dependent neurotransmitter release through its N-terminal WD40 repeats |
| |
Authors: | Yamamoto Yasunori Mochida Sumiko Miyazaki Naoyuki Kawai Katsuhisa Fujikura Kohei Kurooka Takao Iwasaki Kenji Sakisaka Toshiaki |
| |
Affiliation: | Division of Membrane Dynamics, Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan. |
| |
Abstract: | Neurotransmitter release is triggered by Ca(2+) binding to a low affinity Ca(2+) sensor, mostly synaptotagmin-1, which catalyzes SNARE-mediated synaptic vesicle fusion. Tomosyn negatively regulates Ca(2+)-dependent neurotransmitter release by sequestering target SNAREs through the C-terminal VAMP-like domain. In addition to the C terminus, the N-terminal WD40 repeats of tomosyn also have potent inhibitory activity toward Ca(2+)-dependent neurotransmitter release, although the molecular mechanism underlying this effect remains elusive. Here, we show that through its N-terminal WD40 repeats tomosyn directly binds to synaptotagmin-1 in a Ca(2+)-dependent manner. The N-terminal WD40 repeats impaired the activities of synaptotagmin-1 to promote SNARE complex-mediated membrane fusion and to bend the lipid bilayers. Decreased acetylcholine release from N-terminal WD40 repeat-microinjected superior cervical ganglion neurons was relieved by microinjection of the cytoplasmic domain of synaptotagmin-1. These results indicate that, upon direct binding, the N-terminal WD40 repeats negatively regulate the synaptotagmin-1-mediated step of Ca(2+)-dependent neurotransmitter release. Furthermore, we show that synaptotagmin-1 binding enhances the target SNARE-sequestering activity of tomosyn. These results suggest that the interplay between tomosyn and synaptotagmin-1 underlies inhibitory control of Ca(2+)-dependent neurotransmitter release. |
| |
Keywords: | Exocytosis Membrane Fusion Membrane Trafficking Protein-Protein Interactions Signal Transduction |
本文献已被 PubMed 等数据库收录! |
|