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

Research output: Contribution to journalArticle

144 Citations (Scopus)

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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Synaptic Vesicles
Ubiquitination
Knockout Mice
Degradation
Proteins
Proteasome Inhibitors
Ubiquitin-Protein Ligases
Excitatory Postsynaptic Potentials
Neurology
Proteasome Endopeptidase Complex
Ligases
Ubiquitin
Synaptic Transmission
Synapses
Modulators
Neurons
Plasticity
Half-Life
Up-Regulation
Central Nervous System

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Yao, Ikuko ; Takagi, Hiroshi ; Ageta, Hiroshi ; Kahyo, Tomoaki ; Sato, Showbu ; Hatanaka, Ken ; Fukuda, Yoshiyuki ; Chiba, Tomoki ; Morone, Nobuhiro ; Yuasa, Shigeki ; Inokuchi, Kaoru ; Ohtsuka, Toshihisa ; MacGregor, Grant R. ; Tanaka, Keiji ; Setou, Mitsutoshi. / SCRAPPER-Dependent Ubiquitination of Active Zone Protein RIM1 Regulates Synaptic Vesicle Release. In: Cell. 2007 ; Vol. 130, No. 5. pp. 943-957.
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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.",
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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, GR, Tanaka, K & Setou, M 2007, 'SCRAPPER-Dependent Ubiquitination of Active Zone Protein RIM1 Regulates Synaptic Vesicle Release', Cell, vol. 130, no. 5, pp. 943-957. https://doi.org/10.1016/j.cell.2007.06.052

SCRAPPER-Dependent Ubiquitination of Active Zone Protein RIM1 Regulates Synaptic Vesicle Release. / Yao, Ikuko; Takagi, Hiroshi; Ageta, Hiroshi; Kahyo, Tomoaki; Sato, Showbu; Hatanaka, Ken; Fukuda, Yoshiyuki; Chiba, Tomoki; Morone, Nobuhiro; Yuasa, Shigeki; Inokuchi, Kaoru; Ohtsuka, Toshihisa; MacGregor, Grant R.; Tanaka, Keiji; Setou, Mitsutoshi.

In: Cell, Vol. 130, No. 5, 07.09.2007, p. 943-957.

Research output: Contribution to journalArticle

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

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.

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