Homer interactions are necessary for metabotropic glutamate receptor-induced long-term depression and translational activation
Homer interactions are necessary for metabotropic glutamate receptor-induced long-term depression and translational activation
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DOI：
10.1523/jneurosci.5019-07.2008
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发表时间：
2008-01-09
影响因子：
5.3
通讯作者：
Huber, Kimberly M.
中科院分区：
文献类型：
--
作者：
Ronesi, Jennifer A.;Huber, Kimberly M.
I组代谢型谷氨酸受体（mGluRs）在海马CA 1区诱导需要快速蛋白质合成的一种形式的长时程突触抑制（mGluR-LTD）。尽管人们对mGluR-LTD的机制了解很多，但尚不清楚mGluR如何与翻译启动所需的效应子偶联。线索来自脆性X综合征小鼠模型[Fmr 1敲除（KO）小鼠]的工作，其中不存在蛋白质合成的第1组mGluR刺激，并且mGluR与突触后支架蛋白Homer的相关性较低（Giuffrida等人，2005年）。在这里，我们研究了野生型和Fmr 1基因敲除动物中Homer相互作用在mGluR-LTD和mGluR信号传导到蛋白质合成机制中的作用。一种模拟mGluR 5（mGluR 5ct）C-末端尾部的肽，先前显示破坏Homer与mGluR的相互作用，阻断野生型动物中mGluR-LTD和mGluR信号传导至蛋白质合成起始。mGluR-Homer相互作用的破坏选择性地阻断磷酸肌醇3-激酶（PI 3 K）-Akt-哺乳动物雷帕霉素靶标（mTOR）的mGluR活化，但不阻断ERK（细胞外信号调节激酶）途径和含有mRNA（延伸因子1 α）的5'末端寡嘧啶段的翻译。在Fmr 1 KO小鼠中，mGluR-LTD对Homer相互作用的破坏不敏感，并且PI 3 K-mTOR的mGluR活化丧失。我们的研究结果发现荷马在mGluR信号和可塑性的具体作用，并表明减少mGluR-Homer在Fmr 1基因敲除小鼠的相互作用导致翻译起始的mGluR刺激的赤字。
Group I metabotropic glutamate receptors (mGluRs) induce a form of long-term synaptic depression (mGluR-LTD) in area CA1 of the hippocampus that requires rapid protein synthesis. Although much is known about the mechanisms underlying mGluR-LTD, it is unclear how mGluRs couple to the effectors necessary for translation initiation. A clue comes from work in the mouse model of Fragile X syndrome [Fmr1 knock-out ( KO) mice], where group 1 mGluR stimulation of protein synthesis is absent and mGluRs are less associated with the postsynaptic scaffolding protein Homer (Giuffrida et al., 2005). Here, we examined the role of Homer interactions in mGluR-LTD and mGluR signaling to protein synthesis machinery in wild-type and Fmr1 KO animals. A peptide that mimics the C-terminal tail of mGluR5 (mGluR5ct), shown previously to disrupt Homer interactions with mGluRs, blocks mGluR-LTD and mGluR-signaling to protein synthesis initiation in wild-type animals. Disruption of mGluR-Homer interactions selectively blocks mGluR activation of the phosphoinositide 3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR), but not ERK (extracellular signal-regulated kinase), pathway and translation of a 5' terminal oligopyrimidine tract containing mRNA, Elongation factor 1 alpha. In Fmr1 KO mice, mGluR-LTD is insensitive to disruption of Homer interactions and mGluR activation of PI3K-mTOR is lost. Our results find specific roles for Homer in mGluR signaling and plasticity and suggest that reduced mGluR-Homer interactions in Fmr1 KO mice lead to a deficit in mGluR stimulation of translation initiation.