Importin-mediated retrograde transport of CREB2 from distal processes to the nucleus in neurons
Importin-mediated retrograde transport of CREB2 from distal processes to the nucleus in neurons
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DOI：
10.1073/pnas.0803906105
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发表时间：
2008-11-04
影响因子：
11.1
通讯作者：
Martin, Kelsey C.
中科院分区：
文献类型：
--
作者：
Lai, Kwok-On;Zhao, Yali;Martin, Kelsey C.
在神经元的远端突触处接收的信号必须被传递到核以启动作为持久突触可塑性的基础的转录变化。importin核转运蛋白和选择性转录因子在突触的存在提高了imporins直接将转录因子从突触转运到细胞核以调节基因表达的可能性。在这里，我们表明，环磷酸腺苷反应元件结合蛋白2（CREB 2）/转录激活因子4（ATF 4），转录抑制剂，调节长期突触可塑性和记忆，定位于远端树突的啮齿动物海马神经元和轴突的感觉神经元（SN）和特定的importin a亚型结合。CREB 2与输入蛋白a的结合是其从远端树突转运到索马和其易位到核中所必需的。CREB 2在啮齿类动物海马突触的长时程抑制（LTD）而非长时程增强过程中以及在失智症感觉-运动突触的LTD而非长时程易化（LTF）过程中在核中积累。延时显微镜CREB 2标记的光转换荧光蛋白进一步揭示了CREB 2从远端神经突逆行运输到细胞核的Aaplasia SIN在苯丙氨酸-甲硫氨酸-精氨酸-苯丙氨酸-酰胺（FMRFamide）诱导的LTD。总之，我们的研究结果表明，CREB 2是一种新的货物的importin一个易位从远端突触位点的神经元突触的LTD刺激后的细胞核。
Signals received at distal synapses of neurons must be conveyed to the nucleus to initiate the changes in transcription that underlie long-lasting synaptic plasticity. The presence of importin nuclear transporters and of select transcription factors at synapses raises the possibility that importins directly transport transcription factors from synapse to nucleus to modulate gene expression. Here, we show that cyclic AMP response element binding protein 2 (CREB2)/activating transcription factor 4 (ATF4), a transcriptional repressor that modulates long-term synaptic plasticity and memory, localizes to distal dendrites of rodent hippocampal neurons and neurites of Aplysia sensory neurons (SNs) and binds to specific importin a isoforms. Binding of CREB2 to importin a is required for its transport from distal dendrites to the soma and for its translocation into the nucleus. CREB2 accumulates in the nucleus during long-term depression (LTD) but not long-term potentiation of rodent hippocampal synapses, and during LTD but not long-term facilitation (LTF) of Aplysia sensory-motor synapses. Time-lapse microscopy of CREB2 tagged with a photoconvertible fluorescent protein further reveals retrograde transport of CREB2 from distal neurites to the nucleus of Aplysia SIN during phenylalanine-methionine-arginine-phenylalanine-amide (FMRFamide)-induced LTD. Together, our findings indicate that CREB2 is a novel cargo of importin a that translocates from distal synaptic sites to the nucleus after stimuli that induce LTD of neuronal synapses.