Caldendrin-Jacob: a protein liaison that couples NMDA receptor signalling to the nucleus.
Caldendrin-Jacob: a protein liaison that couples NMDA receptor signalling to the nucleus.
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DOI：
10.1371/journal.pbio.0060034
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发表时间：
2008-02
期刊：
影响因子：
9.8
通讯作者：
Kreutz, Michael R.
中科院分区：
文献类型：
--
作者：
Dieterich, Daniela C.;Karpova, Anna;Mikhaylova, Marina;Zdobnova, Irina;Koenig, Imbritt;Landwehr, Marco;Kreutz, Martin;Smalla, Karl-Heinz;Richter, Karin;Landgraf, Peter;Reissner, Carsten;Boeckers, Tobias M.;Zuschratter, Werner;Spilker, Christina;Seidenbecher, Constanze I.;Garner, Craig C.;Gundelfinger, Eckart D.;Kreutz, Michael R.
NMDA（N-甲基-D-天冬氨酸）受体和钙可以在神经元细胞内发挥多种和非常不同的作用，从而影响相反的发生，如突触可塑性和神经元变性。神经元Ca 2+传感器Caldendrin是与钙调素高度相似的突触后密度组分。Jacob是最近发现的钙调素结合蛋白，是一种在大脑边缘系统和大脑皮层中大量表达的新蛋白。严格依赖于NMDA型谷氨酸受体的激活，雅各布被招募到神经元细胞核，导致突触接触的快速剥离和树突树的形态急剧改变。Jacob的核从远端树突的运输至关重要地需要经典的Importin途径。Caldendrin以Ca 2+依赖性方式结合Jacob核定位信号，从而通过与Importin-α竞争结合Jacob核定位信号来控制Jacob核定位。这种竞争需要持续的突触树突状细胞的Ca 2+水平，这大概不能通过激活突触外NMDA受体来实现，但仅限于Ca 2+微域，如突触后棘。突触外NMDA受体与其突触对应物相反，触发cAMP反应元件结合蛋白（CREB）关闭途径和细胞死亡。我们发现，核敲低雅各布防止CREB关闭突触外NMDA受体激活后，而其核过表达诱导CREB关闭没有NMDA受体刺激。重要的是，Jacob的核敲低减弱了NMDA诱导的突触接触的丧失和神经元变性。这定义了一种新的机制，通过突触的钙离子传感器蛋白，其链接的活动，NMDA受体参与建模突触树突输入和NMDA受体诱导的细胞变性的核信号转导事件的突触到核通信。神经细胞之间通讯的长期变化需要基因表达的调节。钙离子流入细胞，特别是通过称为NMDA受体的膜蛋白，通过确定诱导的基因表达类型在这一过程中起着至关重要的作用。NMDA受体可以通过影响相反的现象，如突触可塑性和神经元变性，在神经元细胞内发挥多种和非常不同的作用。我们发现了一种名为Jacob的蛋白质，它似乎在这些过程中发挥着关键作用，通过响应NMDA受体激活进入细胞核并控制基因表达，从而控制细胞存活和突触细胞接触的稳定性。将Jacob从细胞核中去除可以保护神经元免受NMDA受体诱导的细胞死亡，并增加转录因子CREB的磷酸化，而将Jacob专门靶向细胞核后则发生相反的情况。这项工作定义了一种新的突触到细胞核的通信途径，涉及建模突触树突输入和NMDA受体诱导的细胞变性。从NMDA受体到细胞核的新的信号传导机制在转录因子CREB的磷酸化和神经细胞存活中起重要作用。
NMDA (N-methyl-D-aspartate) receptors and calcium can exert multiple and very divergent effects within neuronal cells, thereby impacting opposing occurrences such as synaptic plasticity and neuronal degeneration. The neuronal Ca2+ sensor Caldendrin is a postsynaptic density component with high similarity to calmodulin. Jacob, a recently identified Caldendrin binding partner, is a novel protein abundantly expressed in limbic brain and cerebral cortex. Strictly depending upon activation of NMDA-type glutamate receptors, Jacob is recruited to neuronal nuclei, resulting in a rapid stripping of synaptic contacts and in a drastically altered morphology of the dendritic tree. Jacob's nuclear trafficking from distal dendrites crucially requires the classical Importin pathway. Caldendrin binds to Jacob's nuclear localization signal in a Ca2+-dependent manner, thereby controlling Jacob's extranuclear localization by competing with the binding of Importin-α to Jacob's nuclear localization signal. This competition requires sustained synapto-dendritic Ca2+ levels, which presumably cannot be achieved by activation of extrasynaptic NMDA receptors, but are confined to Ca2+ microdomains such as postsynaptic spines. Extrasynaptic NMDA receptors, as opposed to their synaptic counterparts, trigger the cAMP response element-binding protein (CREB) shut-off pathway, and cell death. We found that nuclear knockdown of Jacob prevents CREB shut-off after extrasynaptic NMDA receptor activation, whereas its nuclear overexpression induces CREB shut-off without NMDA receptor stimulation. Importantly, nuclear knockdown of Jacob attenuates NMDA-induced loss of synaptic contacts, and neuronal degeneration. This defines a novel mechanism of synapse-to-nucleus communication via a synaptic Ca2+-sensor protein, which links the activity of NMDA receptors to nuclear signalling events involved in modelling synapto-dendritic input and NMDA receptor–induced cellular degeneration. Long-lasting changes in communication between nerve cells require the regulation of gene expression. The influx of calcium ions into the cell, particularly through membrane protein called NMDA receptors, plays a crucial role in this process by determining the type of gene expression induced. NMDA receptors can exert multiple and very divergent effects within neuronal cells by impacting opposing phenomena such as synaptic plasticity and neuronal degeneration. We identified a protein termed Jacob that appears to play a pivotal role in such processes by entering the nucleus in response to NMDA receptor activation and controlling gene expression that governs cell survival and the stability of synaptic cell contacts. Removal of Jacob from the nucleus protects neurons from NMDA receptor–induced cell death and increases phosphorylation of the transcription factor CREB, whereas the opposite occurs after targeting Jacob exclusively to the nucleus. The work defines a novel pathway of synapse-to-nucleus communication involved in modelling synapto-dendritic input and NMDA receptor–induced cellular degeneration. A new signaling mechanism from NMDA receptors to the nucleus plays an important role in the phosphorylation of the transcription factor CREB and neuronal cell survival.
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