Gelinas Jennifer N, Banko Jessica L, Hou Lingfei, Sonenberg Nahum, Weeber Edwin J, Klann Eric, Nguyen Peter V
Departments of Physiology and University of Alberta School of Medicine, Edmonton, Alberta T6G 2H7, Canada.
Departments of Molecular Physiology and Biophysics and Vanderbilt Medical Center, Nashville, Tennessee 37232.
J Biol Chem. 2007 Sep 14;282(37):27527-27535. doi: 10.1074/jbc.M701077200. Epub 2007 Jul 16.
beta-Adrenergic receptors critically modulate long-lasting synaptic plasticity and long-term memory in the mammalian hippocampus. Persistent long-term potentiation of synaptic strength requires protein synthesis and has been correlated with some forms of hippocampal long-term memory. However, the intracellular processes that initiate protein synthesis downstream of the beta-adrenergic receptor are unidentified. Here we report that activation of beta-adrenergic receptors recruits ERK and mammalian target of rapamycin signaling to facilitate long-term potentiation maintenance at the level of translation initiation. Treatment of mouse hippocampal slices with a beta-adrenergic receptor agonist results in activation of eukaryotic initiation factor 4E and the eukaryotic initiation factor 4E kinase Mnk1, along with inhibition of the translation repressor 4E-BP. This coordinated activation of translation machinery requires concomitant ERK and mammalian target of rapamycin signaling. Taken together, our data identify distinct signaling pathways that converge to regulate beta-adrenergic receptor-dependent protein synthesis during long-term synaptic potentiation in the hippocampus. We suggest that beta-adrenergic receptors play a crucial role in gating the induction of long-lasting synaptic plasticity at the level of translation initiation, a mechanism that may underlie the ability of these receptors to influence the formation of long-lasting memories.
β-肾上腺素能受体在哺乳动物海马体中对持久的突触可塑性和长期记忆起着关键的调节作用。突触强度的持续性长时程增强需要蛋白质合成，并且与某些形式的海马体长期记忆相关。然而，在β-肾上腺素能受体下游启动蛋白质合成的细胞内过程尚不清楚。在此，我们报告β-肾上腺素能受体的激活会募集细胞外信号调节激酶（ERK）和雷帕霉素哺乳动物靶蛋白信号，以在翻译起始水平促进长时程增强的维持。用β-肾上腺素能受体激动剂处理小鼠海马切片会导致真核起始因子4E（eukaryotic initiation factor 4E，eIF4E）和真核起始因子4E激酶Mnk1的激活，同时抑制翻译阻遏物4E结合蛋白（4E-BP）。翻译机制的这种协同激活需要ERK和雷帕霉素哺乳动物靶蛋白信号的同时存在。综上所述，我们的数据确定了在海马体长期突触增强过程中汇聚以调节β-肾上腺素能受体依赖性蛋白质合成的不同信号通路。我们认为，β-肾上腺素能受体在翻译起始水平控制持久突触可塑性的诱导中起着关键作用，这一机制可能是这些受体影响持久记忆形成能力的基础。
