Banko Jessica L, Hou Lingfei, Poulin Francis, Sonenberg Nahum, Klann Eric
Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas 77030, USA.
J Neurosci. 2006 Feb 22;26(8):2167-73. doi: 10.1523/JNEUROSCI.5196-05.2006.
Long-term depression (LTD) is an activity-dependent decrease in synaptic efficacy that can be induced in hippocampal area CA1 by pharmacological application of the selective group I metabotropic glutamate receptor (mGluR) agonist 3,5-diyhroxyphenylglycine (DHPG). Recent work has demonstrated that DHPG-induced LTD recruits at least two signal transduction pathways known to couple to translation, the mitogen-activated protein kinase kinase (MEK)-extracellular signal-regulated kinase (ERK) signaling pathway and the phosphoinositide 3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR) signaling pathway. However, it remains unclear which translation factors are engaged by these two signaling pathways during mGluR-LTD. In this study, we investigated whether the group I mGluRs couple to the cap-dependent translation proteins: Mnk1, eIF4E, and 4E-BP. We found that both the MEK-ERK and PI3K-mTOR signaling pathways are critical for the DHPG-induced regulation of these translation factors. Furthermore, we demonstrate that increasing eIF4F complex availability via the genetic elimination of 4E-BP2 can enhance the degree of LTD achieved by DHPG application in an ERK-dependent manner. Our results provide direct evidence that cap-dependent translation is engaged during mGluR-LTD and demonstrate that the MEK-ERK and PI3K-mTOR signaling pathways converge to regulate eIF4E activity after induction of DHPG-LTD.
长时程抑制（LTD）是一种依赖于活动的突触效能降低现象，通过药理学方法应用选择性I组代谢型谷氨酸受体（mGluR）激动剂3,5-二羟基苯甘氨酸（DHPG）可在海马CA1区诱导产生。最近的研究表明，DHPG诱导的LTD至少招募了两条已知与翻译偶联的信号转导通路，即丝裂原活化蛋白激酶激酶（MEK）-细胞外信号调节激酶（ERK）信号通路和磷脂酰肌醇3激酶（PI3K）-蛋白激酶B（Akt）-雷帕霉素哺乳动物靶蛋白（mTOR）信号通路。然而，在mGluR-LTD过程中，这两条信号通路激活哪些翻译因子仍不清楚。在本研究中，我们调查了I组mGluR是否与帽依赖性翻译蛋白：Mnk1、真核生物翻译起始因子4E（eIF4E）和4E结合蛋白（4E-BP）偶联。我们发现，MEK-ERK和PI3K-mTOR信号通路对于DHPG诱导的这些翻译因子的调节都至关重要。此外，我们证明，通过基因敲除4E-BP2来增加eIF4F复合物的可用性，可以以ERK依赖的方式增强DHPG应用所实现的LTD程度。我们的结果提供了直接证据，表明在mGluR-LTD过程中发生了帽依赖性翻译，并证明在诱导DHPG-LTD后，MEK-ERK和PI3K-mTOR信号通路汇聚以调节eIF4E的活性。
