Histone H3 Phosphorylation is Under the Opposite Tonic Control of Dopamine D2 and Adenosine A2A Receptors in Striatopallidal Neurons
Histone H3 Phosphorylation is Under the Opposite Tonic Control of Dopamine D2 and Adenosine A2A Receptors in Striatopallidal Neurons
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DOI：
10.1038/npp.2008.228
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发表时间：
2009-06-01
影响因子：
7.6
通讯作者：
Fisone, Gilberto
中科院分区：
文献类型：
--
作者：
Bertran-Gonzalez, Jesus;Hakansson, Kerstin;Fisone, Gilberto
氟哌啶醇通过阻断多巴胺D2受体（D2Rs）调节纹状体中棘神经元（MSNs）的基因转录。我们研究了氟哌啶醇增加组蛋白H3磷酸化的机制，这是核小体反应的关键步骤。利用在多巴胺D1受体（D1R）或D2R启动子控制下表达EGFP的细菌人工染色体（BAC）转基因小鼠，我们发现氟哌啶醇诱导背纹状体纹状体msn中组蛋白H3的磷酸化快速持续增加，而其乙酰化没有变化。这种作用被选择性D2R拮抗剂raclopride模仿，并被腺苷A2A受体（A2ARs）的阻断或a2ar相关G蛋白G α (olf)的遗传衰减所阻止。32 kda多巴胺cAMP依赖磷酸化位点（Thr34）和cAMP调节磷酸化蛋白（DARPP-32）的突变降低了氟哌啶醇诱导的H3磷酸化，支持cAMP在H3磷酸化中的作用。氟哌啶醇还能诱导纹状体单胞细胞外信号调节激酶（ERK）磷酸化，但这种作用与H3磷酸化无关。据报道，丝裂原和应激激活激酶1 （MSK1）介导erk诱导的H3磷酸化，在纹状体状细胞中比在纹状体状细胞中水平更低。此外，氟哌啶醇诱导的H3磷酸化在msk1敲除小鼠中没有改变。这些数据表明，在纹状体msn中，H3磷酸化是由D2Rs和A2ARs的相反作用控制的。因此，阻断D2Rs可通过a2ar介导的G α (olf)活化和pka依赖的DARPP-32磷酸化抑制蛋白磷酸酶-1 (PP-1)，从而促进组蛋白H3磷酸化。神经精神药理学（2009）34,1710-1720；doi: 10.1038 / npp.2008.228;2009年1月21日在线发布
The antipsychotic agent haloperidol regulates gene transcription in striatal medium spiny neurons (MSNs) by blocking dopamine D2 receptors (D2Rs). We examined the mechanisms by which haloperidol increases the phosphorylation of histone H3, a key step in the nucleosomal response. Using bacterial artificial chromosome (BAC)-transgenic mice that express EGFP under the control of the promoter of the dopamine D1 receptor (D1R) or the D2R, we found that haloperidol induced a rapid and sustained increase in the phosphorylation of histone H3 in the striatopallidal MSNs of the dorsal striatum, with no change in its acetylation. This effect was mimicked by raclopride, a selective D2R antagonist, and prevented by the blockade of adenosine A2A receptors (A2ARs), or genetic attenuation of the A2AR-associated G protein, G alpha(olf). Mutation of the cAMP-dependent phosphorylation site (Thr34) of the 32-kDa dopamine and cAMP-regulated phosphoprotein (DARPP-32) decreased the haloperidol-induced H3 phosphorylation, supporting the role of cAMP in H3 phosphorylation. Haloperidol also induced extracellular signal-regulated kinase (ERK) phosphorylation in striatopallidal MSNs, but this effect was not implicated in H3 phosphorylation. The levels of mitogen-and stress-activated kinase 1 (MSK1), which has been reported to mediate ERK-induced H3 phosphorylation, were lower in striatopallidal than in striatonigral MSNs. Moreover, haloperidol-induced H3 phosphorylation was unaltered in MSK1-knockout mice. These data indicate that, in striatopallidal MSNs, H3 phosphorylation is controlled by the opposing actions of D2Rs and A2ARs. Thus, blockade of D2Rs promotes histone H3 phosphorylation through the A2AR-mediated activation of G alpha(olf) and inhibition of protein phosphatase-1 (PP-1) through the PKA-dependent phosphorylation of DARPP-32. Neuropsychopharmacology (2009) 34, 1710-1720; doi:10.1038/npp.2008.228; published online 21 January 2009