SCRAPPER-Dependent Ubiquitination of Active Zone Protein RIM1 Regulates Synaptic Vesicle Release
SCRAPPER-Dependent Ubiquitination of Active Zone Protein RIM1 Regulates Synaptic Vesicle Release
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DOI：
10.1016/j.cell.2007.09.015
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发表时间：
2007-10
期刊：
影响因子：
64.5
通讯作者：
I. Yao;H. Takagi;H. Ageta;T. Kahyo;Showbu Sato;Ken Hatanaka;Y. Fukuda;T. Chiba;N. Morone;S. Yuasa;K. Inokuchi;T. Ohtsuka;G. MacGregor;Keiji Tanaka;M. Setou
中科院分区：
文献类型：
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作者：
I. Yao;H. Takagi;H. Ageta;T. Kahyo;Showbu Sato;Ken Hatanaka;Y. Fukuda;T. Chiba;N. Morone;S. Yuasa;K. Inokuchi;T. Ohtsuka;G. MacGregor;Keiji Tanaka;M. Setou
人们对中枢神经系统中突触活动如何调节知之甚少。我们已经鉴定出 SCRAPPER，一种突触定位的 E3 泛素连接酶，可调节神经传递。 SCRAPPER 直接结合并泛素化突触前可塑性调节剂 RIM1。在 Scrapper 敲除 (SCR-KO) 小鼠的神经元中，RIM1 的半衰期更长，泛素化显着降低，表明 SCRAPPER 是介导 RIM1 降解的主要泛素连接酶。正如 RIM1 降解缺陷突变体中所预期的那样，SCR-KO 小鼠表现出电生理突触活动的改变，即微型兴奋性突触后电流的频率增加。 SCR-KO 小鼠的这种表型是通过 RIM1 过表达来复制的，并且可以通过 SCRAPPER 的重新表达或 RIM1 的敲低来挽救。蛋白酶体抑制剂的急性作用，例如 RIM1 的上调和释放概率，被 SCRAPPER 的损伤所阻断。因此，SCRAPPER 在调节突触调节所需的蛋白酶体介导的 RIM1 降解方面具有重要功能。
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 fromScrapper-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.