TY - JOUR
T1 - SCRAPPER-Dependent Ubiquitination of Active Zone Protein RIM1 Regulates Synaptic Vesicle Release
AU - Yao, Ikuko
AU - Takagi, Hiroshi
AU - Ageta, Hiroshi
AU - Kahyo, Tomoaki
AU - Sato, Showbu
AU - Hatanaka, Ken
AU - Fukuda, Yoshiyuki
AU - Chiba, Tomoki
AU - Morone, Nobuhiro
AU - Yuasa, Shigeki
AU - Inokuchi, Kaoru
AU - Ohtsuka, Toshihisa
AU - MacGregor, Grant R.
AU - Tanaka, Keiji
AU - Setou, Mitsutoshi
N1 - Funding Information:
We are grateful to K. Nakamura, R. Migishima, and T. Hino, Mouse Genome Technology Center at MITILS, for generating SCR-KO and SCR-TG mice. We also wish to thank T. Sekiya, S. Song, A. Omori, S. Kamijyo, and K. Nagayama and M. Arai, Y. F.-Tsukamoto, Y. Hinohara, and other members of the Setou group and MITILS. We thank Profs. Mayford and Kida for the CaMKII promoter vector, Dr. Seino for the RIM1 constructs, and Ms. Takamura for critical reading of this manuscript. We thank three anonymous reviewers for constructive criticism and superb suggestions for experiments to strengthen the study. This work was supported by Research Grants for PRESTO and SENTAN, from JST and a Grant-In-Aid for Young Scientists A to M.S., by a Grant-In-Aid for Young Scientists B to I.Y., by NANO-001 (N.M.), NIBIO 05-32 (S.Y.) to N.M., and in part by a grant from company, MITILS. A portion of this study was presented at 46th Annual Meeting of the ASCB.
PY - 2007/9/7
Y1 - 2007/9/7
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=34548243126&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=34548243126&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2007.06.052
DO - 10.1016/j.cell.2007.06.052
M3 - Article
C2 - 17803915
AN - SCOPUS:34548243126
SN - 0092-8674
VL - 130
SP - 943
EP - 957
JO - Cell
JF - Cell
IS - 5
ER -