Adenylyl cyclase-dependent form of chemical long-term potentiation triggers translational regulation at the elongation step
Adenylyl cyclase-dependent form of chemical long-term potentiation triggers translational regulation at the elongation step
复制标题
DOI：
10.1016/s0306-4522(02)00797-2
复制
发表时间：
2003-01-01
期刊：
影响因子：
3.3
通讯作者：
Watson, JB
中科院分区：
文献类型：
--
作者：
Chotiner, JK;Khorasani, H;Watson, JB
长时程增强的持续维持需要信使RNA和蛋白质的合成。虽然越来越多的证据表明蛋白质合成在海马体长时程增强中起着积极的作用，但其调控机制的本质尚未确定。我们使用了之前描述的化学长时程增强方案[J Neurosci 19(1999)2500]来解决这一假说，即参与长时间长时程增强的信号机制直接调节蛋白质的合成。化学长时程增强是一种依赖N-甲基-D-天冬氨酸受体的可塑性形式，它既依赖于由高浓度K+和Ca~(2+)诱导的自发突触活动，也依赖于环AMP/腺苷环化酶信号。我们发现，小鼠海马区CA1中的化学长期增强至少持续3个小时，需要信使RNA和蛋白质合成。然而，令人惊讶的是，在长时程增强诱导后1小时，总蛋白合成却反常地减少。与增强的CA1的总蛋白质合成减少一致，真核延伸因子2的磷酸化增加，可能是抑制延伸步骤翻译的原因。真核延长因子2的磷酸化增加依赖于一致的环状AMP/腺苷环化酶激活和突触活性，并需要N-甲基-D-天冬氨酸受体的激活。尽管总蛋白合成受到抑制，但即刻早期基因蛋白Arc(活性调节细胞骨架相关蛋白)的水平在化学长时间增强诱导后1h升高。综上所述，这些结果表明，蛋白质合成伸长阶段的调节有助于持久的长期增强。(C)2003年IBRO。爱思唯尔科学有限公司出版。版权所有。
The persistent maintenance of long-term potentiation requires both messenger RNA and protein synthesis. While there is mounting evidence for an active role of protein synthesis in hippocampal long-term potentiation, the nature of mechanisms underlying its regulation has not yet been established. We used a previously described chemical long-term potentiation protocol [J Neurosci 19 (1999) 2500] to address the hypothesis that signaling mechanisms, involved in long-lasting long-term potentiation, directly regulate protein synthesis. Chemical long-term potentiation is an N-methyl-D-aspartate receptor-dependent form of plasticity, which relies on both synaptic activity, in the form of spontaneous bursting induced by high concentrations of K+ and Ca2+, and cyclic AMP/adenylyl cyclase signaling. We found that chemical long-term potentiation in CA1 of the mouse hippocampus lasts for at least 3 hours and requires both messenger RNA and protein synthesis. However, surprisingly de novo total protein synthesis was paradoxically decreased at 1 hour after long-term potentiation induction. Consistent with the decrease in total protein synthesis in potentiated CA1, phosphorylation of eukaryotic elongation factor 2 was increased and is likely responsible for inhibition of translation at the elongation step. Increased phosphorylation of eukaryotic elongation factor 2 was dependent on coincident cyclic AMP/adenylyl cyclase activation and synaptic activity and required N-methyl-D-aspartate receptor activation. Despite the inhibition in total protein synthesis, the level of the immediate early gene protein Arc (activity regulated cytoskeleton-associated protein) increased at 1 hour after chemical long-term potentiation induction. Taken together, the results suggest that regulation at the elongation step of protein synthesis contributes to persistent forms of long-term potentiation. (C) 2003 IBRO. Published by Elsevier Science Ltd. All rights reserved.