Activation of ERK cascade promotes accumulation of Vesl-1S/Homer-1a immunoreactivity at synapses
Activation of ERK cascade promotes accumulation of Vesl-1S/Homer-1a immunoreactivity at synapses
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DOI：
10.1016/j.molbrainres.2003.07.005
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发表时间：
2003-10-21
期刊：
影响因子：
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通讯作者：
Sugiyama, H
中科院分区：
文献类型：
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作者：
Kato, A;Fukazawa, Y;Sugiyama, H
Vesl-1 S/Homer-1a蛋白在长时程增强（LTP）过程中被诱导，并含有结合突触后蛋白的基序。我们以前曾报道过，Vesl-1 S/Homer-1a免疫反应性（IR）在神经元胞体轮廓上的突触处的突触积累通过用佛波醇酯、90 mM KCl或蛋白酶体抑制剂刺激细胞来促进。在本研究中，我们研究了导致这种蛋白质在突触处的突触积累的细胞内机制。MEK抑制剂完全阻断佛波醇酯和KCl对Vesl-1 S/Homer-1a积累的影响，部分阻断蛋白酶体抑制剂的作用。相反，脑源性神经营养因子（BDNF）和NT 3促进Vesl-1 S/Homer-1a IR在突触处的积累。这种积累的程度与BDNF处理后细胞外信号调节激酶ERK的活化水平相关。BDNF还引起Vesl-1 S/Homer-1a蛋白量的增加，但这发生在Vesl-IS/Homer-1a在突触处积累之后。此外，从头抑制蛋白质合成不影响佛波酯介导的Vest-1 S/Homer-1a IR在突触处的积累。这些结果表明，ERK级联的激活在Vesl-1 S/Homer-1a IR的突触积聚中起着至关重要的作用，并表明这种积聚主要通过Vesl-IS/Homer-la蛋白的重新定位而发生，而不是通过Vesl-1 S/Homer-1a水平的增加。神经营养因子的活性依赖性释放或去极化可引起ERK级联的局部激活以产生Vesl-IS/Homer-la的突触特异性定位。(C)2003 Elsevier B. V.保留所有权利。
The Vesl-1S/Homer-1a protein is induced during long-term potentiation (LTP), and contains a motif that binds postsynaptic proteins. We have previously reported that synaptic accumulation of Vesl-1S/Homer-1a immunoreactivity (IR) at synapses on the contour of neuronal somata is promoted by stimulation of cells with phorbol esters, 90 mM KCl or proteasome inhibitors. In the present study, we investigated the intracellular mechanism that results in the synaptic accumulation of this protein at synapses. MEK inhibitors completely blocked the effects of phorbol esters and KCl on the accumulation of Vesl-1S/Homer-1a and partially blocked the effect of proteasome inhibitors. Conversely, brain-derived neurotrophic factor (BDNF) and NT3 promoted the accumulation of Vesl-1S/Homer-1a IR at synapses. The extent of this accumulation is correlated with the level of activation of extracellular signal-regulated kinases, ERK following treatment with BDNF. BDNF also caused an increase in the amount of Vesl-1S/Homer-1a protein, but this occurred after Vesl-IS/Homer-la had accumulated at the synapses. In addition, inhibition of de novo, protein synthesis did not affect the phorbol ester-mediated accumulation of Vest-1S/Homer-1a IR at synapses. These results indicate that activation of the ERK cascade plays a crucial role in the synaptic accumulation of Vesl-1S/Homer-1a IR, and suggest that this accumulation occurs mainly by re-localization of Vesl-IS/Homer-la protein, and not through an increase in the level of Vesl-1S/Homer-1a. Activity-dependent release of neurotrophins or depolarization may cause local activation of the ERK cascade to produce the synapse-specific localization of Vesl-IS/Homer-la. (C) 2003 Elsevier B.V. All rights reserved.