SCRAPPER-Dependent Ubiquitination of Active Zone Protein RIM1 Regulates Synaptic Vesicle Release

Ikuko Yao, Hiroshi Takagi, Hiroshi Ageta, Tomoaki Kahyo, Showbu Sato, Ken Hatanaka, Yoshiyuki Fukuda, Tomoki Chiba, Nobuhiro Morone, Shigeki Yuasa, Kaoru Inokuchi, Toshihisa Ohtsuka, Grant R. MacGregor, Keiji Tanaka, Mitsutoshi Setou

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Abstract

Little is known about how synaptic activity is modulated in the central nervous system. We have identified SCRAPPER, a synapse-localized E3 ubiquitin ligase, which regulates neural transmission. SCRAPPER directly binds and ubiquitinates RIM1, a modulator of presynaptic plasticity. In neurons from Scrapper-knockout (SCR-KO) mice, RIM1 had a longer half-life with significant reduction in ubiquitination, indicating that SCRAPPER is the predominant ubiquitin ligase that mediates RIM1 degradation. As anticipated in a RIM1 degradation defect mutant, SCR-KO mice displayed altered electrophysiological synaptic activity, i.e., increased frequency of miniature excitatory postsynaptic currents. This phenotype of SCR-KO mice was phenocopied by RIM1 overexpression and could be rescued by re-expression of SCRAPPER or knockdown of RIM1. The acute effects of proteasome inhibitors, such as upregulation of RIM1 and the release probability, were blocked by the impairment of SCRAPPER. Thus, SCRAPPER has an essential function in regulating proteasome-mediated degradation of RIM1 required for synaptic tuning.

Original languageEnglish
Pages (from-to)943-957
Number of pages15
JournalCell
Volume130
Issue number5
DOIs
Publication statusPublished - 07-09-2007

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All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Yao, I., Takagi, H., Ageta, H., Kahyo, T., Sato, S., Hatanaka, K., Fukuda, Y., Chiba, T., Morone, N., Yuasa, S., Inokuchi, K., Ohtsuka, T., MacGregor, G. R., Tanaka, K., & Setou, M. (2007). SCRAPPER-Dependent Ubiquitination of Active Zone Protein RIM1 Regulates Synaptic Vesicle Release. Cell, 130(5), 943-957. https://doi.org/10.1016/j.cell.2007.06.052