Cocaine Induces the Expression of MEF2C Transcription Factor in Rat Striatum Through Activation of SIK1 and Phosphorylation of the Histone Deacetylase HDAC5
Cocaine Induces the Expression of MEF2C Transcription Factor in Rat Striatum Through Activation of SIK1 and Phosphorylation of the Histone Deacetylase HDAC5
复制标题
DOI：
10.1002/syn.20988
复制
发表时间：
2012-01-01
期刊：
影响因子：
2.3
通讯作者：
Zwiller, Jean
中科院分区：
文献类型：
--
作者：
Dietrich, Jean-Bernard;Takemori, Hiroshi;Zwiller, Jean
不同形式的MEF 2转录因子作为树突棘形成的正或负调节因子，MEF 2C在突触可塑性中起关键调节作用。我们在这里报告，急性可卡因治疗大鼠诱导MEF 2C的表达在纹状体通过最近发现的转导途径。发现重复注射在较小程度上诱导MEF 2C。MEF 2C被诱导的机制涉及盐诱导激酶SIK 1的随后激活和HDAC 5的磷酸化，HDAC 5是HDACs的IIa类成员。辅酶Ⅱ通过Thr-182残基的磷酸化激活SIK 1，这伴随着激酶的核输入。在核区室中，SIK 1然后磷酸化HDAC 5，导致其磷酸化形式从纹状体细胞的细胞核穿梭到细胞质。通过TORC 1/3的磷酸化进一步验证可卡因对SIK 1的激活，随后TORC蛋白从细胞核穿梭到细胞质。通过测量MEF 2C基因本身的表达来评估MEF 2C的活化，因为已知该基因受其自身产物的控制。由于MEF 2C在记忆/学习过程中起着关键作用，可卡因对该途径的激活可能涉及可塑性机制，从而药物建立其长期效应，如药物依赖性。Synapse 66：61-70，2012. (C)2011 Wiley Periodicals，Inc.
Distinct forms of MEF2 transcription factor act as positive or negative regulators of dendritic spine formation, with MEF2C playing a key regulator role in synapse plasticity. We report here that acute cocaine treatment of rats induced the expression of MEF2C in the striatum through a recently discovered transduction pathway. Repeated injections were found to induce MEF2C to a lesser extent. The mechanism by which MEF2C was induced involves the subsequent activation of the salt-inducible kinase SIK1 and the phosphorylation of HDAC5, a member of the class IIa of HDACs. Cocaine activated SIK1 by phosphorylation on Thr-182 residue, which was accompanied by the nuclear import of the kinase. In the nuclear compartment, SIK1 then phosphorylated HDAC5 causing the shuttling of its phospho-form from the nucleus to the cytoplasm of striatal cells. Activation of SIK1 by cocaine was further validated by the phosphorylation of TORC1/3, which was followed by the shuttling of TORC proteins from the nucleus to the cytoplasm. Activation of MEF2C was assessed by measuring the expression of the MEF2C gene itself, since the gene is known to be under the control of its own product. Since MEF2C plays a key role in memory/learning processes, activation of this pathway by cocaine is probably involved in plasticity mechanisms whereby the drug establishes its long-term effects such as drug dependence. Synapse 66:61-70, 2012. (C) 2011 Wiley Periodicals, Inc.