Synaptically driven phosphorylation of ribosomal protein S6 is differentially regulated at active synapses versus dendrites and cell bodies by MAPK and PI3K/mTOR signaling pathways.
Synaptically driven phosphorylation of ribosomal protein S6 is differentially regulated at active synapses versus dendrites and cell bodies by MAPK and PI3K/mTOR signaling pathways.
复制标题
DOI：
10.1101/lm.044974.117
复制
发表时间：
2017-08
期刊：
影响因子：
--
通讯作者：
Steward O
中科院分区：
文献类型：
--
作者：
Pirbhoy PS;Farris S;Steward O
高频刺激内侧穿通通路触发了激活的树突结构域和颗粒细胞体中核糖体蛋白S6（rpS 6）的强烈磷酸化。在这里，我们解剖的信号通路负责突触驱动的rpS 6磷酸化的齿状回使用药物抑制PI 3-激酶/mTOR和MAPK/ERK依赖性激酶。使用磷酸化特异性抗体的rpS 6在不同的网站（ser 235/236与ser 240/244），我们表明，交付的PI 3-激酶抑制剂，渥曼青霉素，降低rpS 6磷酸化整个体树突状细胞室（颗粒细胞层，内分子层，外分子层），特别是在颗粒细胞体，而在激活的突触（中间分子层）的磷酸化。相比之下，U 0126，一种MEK抑制剂，衰减rpS 6磷酸化，特别是在树突状细胞层中留下完整的颗粒细胞体中的磷酸化。mTOR抑制剂雷帕霉素的递送废除了颗粒细胞体和树突中rpS 6磷酸化的激活，而选择性S6 K1抑制剂PF 4708671或RSK抑制剂SL 0101 -1的递送减弱了整个突触后细胞中的rpS 6磷酸化。这些结果表明，MAPK/ERK依赖的信号转导是主要负责在活性突触的rpS 6磷酸化的选择性诱导。相反，PI 3-激酶/mTOR依赖性信号诱导rpS 6磷酸化整个体树突隔室，但在活跃的突触中发挥最小的作用。总的来说，这些结果表明一个潜在的机制，PI 3-激酶/mTOR和MAPK/ERK途径调节翻译在特定的亚细胞区室响应突触活动。
High-frequency stimulation of the medial perforant path triggers robust phosphorylation of ribosomal protein S6 (rpS6) in activated dendritic domains and granule cell bodies. Here we dissect the signaling pathways responsible for synaptically driven rpS6 phosphorylation in the dentate gyrus using pharmacological agents to inhibit PI3-kinase/mTOR and MAPK/ERK-dependent kinases. Using phospho-specific antibodies for rpS6 at different sites (ser235/236 versus ser240/244), we show that delivery of the PI3-kinase inhibitor, wortmannin, decreased rpS6 phosphorylation throughout the somatodendritic compartment (granule cell layer, inner molecular layer, outer molecular layer), especially in granule cell bodies while sparing phosphorylation at activated synapses (middle molecular layer). In contrast, delivery of U0126, an MEK inhibitor, attenuated rpS6 phosphorylation specifically in the dendritic laminae leaving phosphorylation in the granule cell bodies intact. Delivery of the mTOR inhibitor, rapamycin, abolished activation of rpS6 phosphorylation in granule cell bodies and dendrites, whereas delivery of a selective S6K1 inhibitor, PF4708671, or RSK inhibitor, SL0101-1, attenuated rpS6 phosphorylation throughout the postsynaptic cell. These results reveal that MAPK/ERK-dependent signaling is predominately responsible for the selective induction of rpS6 phosphorylation at active synapses. In contrast, PI3-kinase/mTOR-dependent signaling induces rpS6 phosphorylation throughout the somatodendritic compartment but plays a minimal role at active synapses. Collectively, these results suggest a potential mechanism by which PI3-kinase/mTOR and MAPK/ERK pathways regulate translation at specific subcellular compartments in response to synaptic activity.
登录
查看更多内容
影响因子：
4.7
作者：
Gobert, Delphine;Topolnik, Lisa;Lacaille, Jean-Claude
通讯作者：
Lacaille, Jean-Claude
影响因子：
4.8
作者：
Jin, Shan-Xue;Arai, Junko;Feig, Larry A.
通讯作者：
Feig, Larry A.
影响因子：
8
作者：
Lee-Fruman, KK;Kuo, CJ;Blenis, J
通讯作者：
Blenis, J
影响因子：
5.3
作者：
Farris, Shannon;Lewandowski, Gail;Steward, Oswald
通讯作者：
Steward, Oswald
影响因子：
4.8
作者：
Kroczynska, Barbara;Joshi, Sonali;Platanias, Leonidas C.
通讯作者：
Platanias, Leonidas C.