Differential effects of Ca2+ and cAMP on transcription mediated by MEF2D and cAMP-response element-binding protein in hippocampal neurons
Differential effects of Ca2+ and cAMP on transcription mediated by MEF2D and cAMP-response element-binding protein in hippocampal neurons
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DOI：
10.1074/jbc.m601485200
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发表时间：
2006-09-22
影响因子：
4.8
通讯作者：
Chawla, Sangeeta
中科院分区：
文献类型：
--
作者：
Belfield, Johanna L.;Whittaker, Chris;Chawla, Sangeeta
在神经元中，第二信使Ca 2+和cAMP是转录反应的介质，对神经系统的发育和功能很重要。促存活神经元转录因子cAMP-反应元件结合蛋白（CREB）和肌细胞增强因子-2（MEF2）均刺激基因表达，以响应细胞内Ca 2+离子浓度的活性依赖性增加。CREB也被细胞内cAMP的增加激活。在这里，我们研究了MEF2家族成员MEF2D，类似于CREB，是否也被海马神经元中的cAMP激活。我们已经表明，与CREB不同，MEF2D不被增加细胞内cAMP的试剂激活。此外，cAMP的增加抑制Ca2+激活的MEF2D介导的基因表达。我们还表明，cAMP抑制Ca2+诱导的MEF2共阻遏物HDAC 5的核输出，并阻止Ca2+刺激的MEF2共激活剂NFAT 3/c4的核输入。我们的研究结果表明，cAMP干扰MEF2D介导的基因表达在多个水平上通过拮抗HDAC5的MEF2D的去阻遏和抑制募集的辅激活剂NFAT。
In neurons, the second messengers Ca2+ and cAMP are mediators of transcriptional responses that are important for the development and function of the nervous system. The pro-survival neuronal transcription factors cAMP-response elementbinding protein (CREB) and myocyte enhancer factor-2 (MEF2) both stimulate gene expression in response to activity-dependent increases in the concentration of intracellular Ca2+ ions. CREB is also activated by increases in intracellular cAMP. Here we have investigated whether the MEF2 family member MEF2D, similar to CREB, is also activated by cAMP in hippocampal neurons. We have shown that, unlike CREB, MEF2D is not activated by agents that increase intracellular cAMP. Moreover, increases in cAMP inhibit Ca2+-activated MEF2D-mediated gene expression. We have also shown that cAMP inhibits Ca2+-induced nuclear export of the MEF2 co-repressor HDAC5 and prevents Ca2+-stimulated nuclear import of the MEF2 co-activator NFAT3/c4. Our results suggest that cAMP interferes with MEF2D-mediated gene expression at multiple levels by antagonizing the derepression of MEF2D by HDAC5 and by inhibiting recruitment of the co-activator NFAT.