Critical involvement of cAMP/DARPP-32 and extracellular signal-regulated protein kinase signaling in L-DOPA-induced dyskinesia
Critical involvement of cAMP/DARPP-32 and extracellular signal-regulated protein kinase signaling in L-DOPA-induced dyskinesia
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DOI：
10.1523/jneurosci.0852-07.2007
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发表时间：
2007-06-27
影响因子：
5.3
通讯作者：
Fisone, Gilberto
中科院分区：
文献类型：
--
作者：
Santini, Emanuela;Valjent, Emmanuel;Fisone, Gilberto
L-3，4-二羟基苯丙氨酸（L-DOPA）诱导的运动障碍（LID）是目前帕金森病治疗的主要障碍之一，其分子基础尚不清楚。我们表明，衰减cAMP信号在介质的纹状体多刺神经元，实现遗传失活的多巴胺和cAMP调节的磷蛋白32 kDa（DARPP-32），降低LID。我们还表明，在运动障碍小鼠中，致敏的cAMP/cAMP依赖性蛋白激酶/DARPP-32信号导致细胞外信号调节蛋白激酶1和2（ERK 1/2）的磷酸化/激活。与运动障碍相关的ERK 1/2磷酸化的增加导致促分裂原和应激激活激酶-1（MSK- 1）的激活和组蛋白H3的磷酸化，这两个下游ERK靶点参与转录调节。与这些观察结果一致，我们发现在受LID影响的小鼠的纹状体中c-Fos表达异常升高。ERK信号级联的持续增强与LID的产生有关。因此，在长期L-DOPA治疗期间使用SL 327（α-[氨基[（4-氨基苯基）硫代]亚甲基]-2-（三氟甲基）苯乙腈）（促分裂原活化激酶/ERK激酶MEK的抑制剂）实现的ERK 1/2的药理学失活抵消了诱导运动障碍。总之，这些结果表明，响应于慢性L-DOPA而发展的显著比例的异常不自主运动可归因于纹状体中等多刺神经元的信号传导途径的过度活化，所述信号传导途径包括DARPP-32、ERK 1/2、MSK-1和组蛋白H3的顺序磷酸化。
The molecular basis of L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia (LID), one of the major hindrances in the current therapy for Parkinson's disease, is still unclear. We show that attenuation of cAMP signaling in the medium spiny neurons of the striatum, achieved by genetic inactivation of the dopamine and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32), reduces LID. We also show that, in dyskinetic mice, sensitized cAMP/cAMP-dependent protein kinase/DARPP-32 signaling leads to phosphorylation/activation of the extracellular signal-regulated protein kinases 1 and 2 (ERK1/2). The increase in ERK1/2 phosphorylation associated with dyskinesia results in activation of mitogen- and stress-activated kinase-1 (MSK- 1) and phosphorylation of histone H3, two downstream targets of ERK involved in transcriptional regulation. In line with these observations, we found that c- Fos expression is abnormally elevated in the striata of mice affected by LID. Persistent enhancement of the ERK signaling cascade is implicated in the generation of LID. Thus, pharmacological inactivation of ERK1/2 achieved using SL327 (alpha-[amino[(4-aminophenyl)thio]methylene]-2-(trifluoromethyl) benzeneacetonitrile), an inhibitor of the mitogen-activated kinase/ERK kinase, MEK, during chronic L-DOPA treatment counteracts the induction dyskinesia. Together, these results indicate that a significant proportion of the abnormal involuntary movements developed in response to chronic L-DOPA are attributable to hyperactivation in striatal medium spiny neurons of a signaling pathway including sequential phosphorylation of DARPP-32, ERK1/2, MSK-1, and histone H3.