Neuronal activity-dependent nucleocytoplasmic shuttling of HDAC4 and HDAC5
Neuronal activity-dependent nucleocytoplasmic shuttling of HDAC4 and HDAC5
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DOI：
10.1046/j.1471-4159.2003.01648.x
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发表时间：
2003-04-01
影响因子：
4.7
通讯作者：
Bading, H
中科院分区：
文献类型：
--
作者：
Chawla, S;Vanhoutte, P;Bading, H
II类组蛋白脱乙酰酶HDAC 4和HDAC 5直接结合并抑制肌细胞增强因子-2（MEF-2）家族的肌生成转录因子，从而抑制骨骼肌生成。在肌肉分化过程中，MEF-2/HDAC复合物对基因转录的抑制由于钙/钙调蛋白依赖性（CaM）激酶诱导的HDAC 4和HDAC 5易位到细胞质而被解除。MEF-2蛋白和HDAC也在神经系统中高度表达，并与神经元存活和分化有关。在这里，我们调查的可能性，HDACs的亚细胞定位，从而抑制靶基因的能力，是由神经元的突触活动。我们发现，在培养的海马神经元，HDAC 4和HDAC 5的定位是动态的和信号调节。自发性电活动足以使HDAC 4核输出，但HDAC 5核输出不足。HDAC 5易位到细胞质诱导后，通过突触NMDA受体或L-型钙通道的钙流量的刺激;谷氨酸浴应用（刺激突触和突触外NMDA受体）拮抗核输出。活动诱导的核质穿梭的两个HDACs被部分阻断的CaM激酶抑制剂KN-62与HDAC 5核出口更敏感的CaM激酶抑制比HDAC 4。因此，HDACs在神经元中的亚细胞定位由神经元活性指定; HDAC 4和HDAC 5核输出的激活阈值的差异提供了输入特异性基因表达的机制。
The class II histone deacetylases, HDAC4 and HDAC5, directly bind to and repress myogenic transcription factors of the myocyte enhancer factor-2 (MEF-2) family thereby inhibiting skeletal myogenesis. During muscle differentiation, repression of gene transcription by MEF-2/HDAC complexes is relieved due to calcium/calmodulin-dependent (CaM) kinase-induced translocation of HDAC4 and HDAC5 to the cytoplasm. MEF-2 proteins and HDACs are also highly expressed in the nervous system and have been implicated in neuronal survival and differentiation. Here we investigated the possibility that the subcellular localization of HDACs, and thus their ability to repress target genes, is controlled by synaptic activity in neurones. We found that, in cultured hippocampal neurones, the localization of HDAC4 and HDAC5 is dynamic and signal-regulated. Spontaneous electrical activity was sufficient for nuclear export of HDAC4 but not of HDAC5. HDAC5 translocation to the cytoplasm was induced following stimulation of calcium flux through synaptic NMDA receptors or L-type calcium channels; glutamate bath application (stimulating synaptic and extrasynaptic NMDA receptors) antagonized nuclear export. Activity-induced nucleocytoplasmic shuttling of both HDACs was partially blocked by the CaM kinase inhibitor KN-62 with HDAC5 nuclear export being more sensitive to CaM kinase inhibition than that of HDAC4. Thus, the subcellular localization of HDACs in neurones is specified by neuronal activity; differences in the activation thresholds for HDAC4 and HDAC5 nuclear export provides a mechanism for input-specific gene expression.