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蛋白酶体抑制增强晚期长时程增强的诱导,但损害其维持。

Proteasome inhibition enhances the induction and impairs the maintenance of late-phase long-term potentiation.

作者信息

Dong Chenghai, Upadhya Sudarshan C, Ding Lan, Smith Thuy K, Hegde Ashok N

机构信息

Department of Neurobiology and Anatomy, Wake Forest University Health Sciences, Winston-Salem, North Carolina 27157, USA.

出版信息

Learn Mem. 2008 Apr 25;15(5):335-47. doi: 10.1101/lm.984508. Print 2008 May.

Abstract

Protein degradation by the ubiquitin-proteasome pathway plays important roles in synaptic plasticity, but the molecular mechanisms by which proteolysis regulates synaptic strength are not well understood. We investigated the role of the proteasome in hippocampal late-phase long-term potentiation (L-LTP), a model for enduring synaptic plasticity. We show here that inhibition of the proteasome enhances the induction of L-LTP, but inhibits its maintenance. Proteasome inhibitor-mediated enhancement of the early part of L-LTP requires activation of NMDA receptors and the cAMP-dependent protein kinase. Augmentation of L-LTP induction by proteasome inhibition is blocked by a protein synthesis inhibitor anisomycin and is sensitive to the drug rapamycin. Our findings indicate that proteasome inhibition increases the induction of L-LTP by stabilizing locally translated proteins in dendrites. In addition, our data show that inhibition of the proteasome blocks transcription of brain-derived neurotrophic factor (BDNF), which is a cAMP-responsive element-binding protein (CREB)-inducible gene. Furthermore, our results demonstrate that the proteasome inhibitors block degradation of ATF4, a CREB repressor. Thus, proteasome inhibition appears to hinder CREB-mediated transcription. Our results indicate that blockade of proteasome activity obstructs the maintenance of L-LTP by interfering with transcription as well as translation required to sustain L-LTP. Thus, proteasome-mediated proteolysis has different roles during the induction and the maintenance of L-LTP.

摘要

泛素 - 蛋白酶体途径介导的蛋白质降解在突触可塑性中发挥重要作用,但蛋白水解调节突触强度的分子机制尚不清楚。我们研究了蛋白酶体在海马晚期长时程增强(L-LTP)中的作用,L-LTP是一种持久突触可塑性的模型。我们在此表明,蛋白酶体的抑制增强了L-LTP的诱导,但抑制了其维持。蛋白酶体抑制剂介导的L-LTP早期增强需要NMDA受体和cAMP依赖性蛋白激酶的激活。蛋白酶体抑制对L-LTP诱导的增强作用被蛋白质合成抑制剂茴香霉素阻断,并且对药物雷帕霉素敏感。我们的研究结果表明,蛋白酶体抑制通过稳定树突中局部翻译的蛋白质来增加L-LTP的诱导。此外,我们的数据表明,蛋白酶体的抑制会阻断脑源性神经营养因子(BDNF)的转录,BDNF是一种cAMP反应元件结合蛋白(CREB)诱导型基因。此外,我们的结果表明,蛋白酶体抑制剂阻断了CREB阻遏物ATF4的降解。因此,蛋白酶体抑制似乎阻碍了CREB介导的转录。我们的研究结果表明,蛋白酶体活性的阻断通过干扰维持L-LTP所需的转录和翻译来阻碍L-LTP的维持。因此,蛋白酶体介导的蛋白水解在L-LTP的诱导和维持过程中具有不同的作用。

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