Haloperidol promotes mTORC1-dependent phosphorylation of ribosomal protein S6 via dopamine- and cAMP-regulated phosphoprotein of 32 kDa and inhibition of protein phosphatase-1
Haloperidol promotes mTORC1-dependent phosphorylation of ribosomal protein S6 via dopamine- and cAMP-regulated phosphoprotein of 32 kDa and inhibition of protein phosphatase-1
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DOI：
10.1016/j.neuropharm.2013.04.043
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发表时间：
2013-09-01
影响因子：
4.7
通讯作者：
Fisone, Gilberto
中科院分区：
文献类型：
--
作者：
Bonito-Oliva, Alessandra;Pallottino, Simone;Fisone, Gilberto
核糖体蛋白S6（rpS 6）是核糖体40 S小亚基的组成部分，参与多种生理功能。在这里，我们研究了氟哌啶醇，一种典型的抗精神病药物，对磷酸化的rpS 6在Ser 240/244在纹状体，大脑区域参与神经退行性疾病和神经精神疾病。我们发现，氟哌啶醇的管理增加了丝氨酸240/244磷酸化的GABA能中型棘神经元（MSN），优先表达多巴胺D2受体（D2 R5）的亚群。这种作用被雷帕霉素（一种哺乳动物雷帕霉素靶蛋白复合物1（mTORC 1）的抑制剂）或PF 470867（一种p70核糖体S6激酶1（S6 K1）的选择性抑制剂）消除。我们还发现，氟哌啶醇对Ser 240/244磷酸化的影响是通过多巴胺和cAMP调节的32 kDa磷蛋白（DARPP-32）的功能失活来阻止的，DARPP-32是蛋白磷酸酶-1（PP-1）的内源性抑制剂。与这一观察结果一致，用两种PP-1抑制剂冈田酸和calyculin A孵育纹状体切片，增加了Ser 240/244磷酸化。这些结果表明，氟哌啶醇促进表达D2 R的纹状体MSN亚群中rpS 6在Ser 240/244处的mTORC 1和S6 K1依赖性磷酸化。他们还表明，这种作用是通过抑制Ser 240/244的去磷酸化，通过PICA依赖性激活DARPP-32和抑制PP-1来发挥的。(C)2013爱思唯尔有限公司保留所有权利。
The ribosomal protein S6 (rpS6) is a component of the small 40S ribosomal subunit, involved in multiple physiological functions. Here, we examined the effects produced by haloperidol, a typical antipsychotic drug, on the phosphorylation of rpS6 at Ser240/244 in the striatum, a brain region involved in neuro-degenerative and neuropsychiatric disorders. We found that administration of haloperidol increased Ser240/244 phosphorylation in a subpopulation of GABA-ergic medium spiny neurons (MSNs), which preferentially express dopamine D2 receptors (D2R5). This effect was abolished by rapamycin, an inhibitor of the mammalian target of rapamycin complex 1 (mTORC1), or by PF470867, a selective inhibitor of the p70 ribosomal S6 kinase 1 (S6K1). We also found that the effect of haloperidol on Ser240/244 phosphorylation was prevented by functional inactivation of dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32), an endogenous inhibitor of protein phosphatase-1 (PP-1). In line with this observation, incubation of striatal slices With okadaic acid and calyculin A, two inhibitors of PP-1, increased Ser240/244 phosphorylation. These results show that haloperidol promotes mTORC1- and S6K1-dependent phosphorylation of rpS6 at Ser240/244, in a subpopulation of striatal MSNs expressing D2Rs. They also indicate that this effect is exerted by suppressing dephosphorylation at Ser240/244, through PICA-dependent activation of DARPP-32 and inhibition of PP-1. (C) 2013 Elsevier Ltd. All rights reserved.