The role of GRK6 in animal models of Parkinson's disease and L-DOPA treatment.
The role of GRK6 in animal models of Parkinson's disease and L-DOPA treatment.
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DOI：
10.1038/srep00301
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发表时间：
2012
影响因子：
4.6
通讯作者：
Gainetdinov, Raul R.
中科院分区：
文献类型：
--
作者：
Manago, Francesca;Espinoza, Stefano;Salahpour, Ali;Sotnikova, Tatyana D.;Caron, Marc G.;Premont, Richard T.;Gainetdinov, Raul R.
G蛋白偶联受体激酶6（GRK 6）属于磷酸化GPCR的激酶家族。发现GRK 6水平在帕金森病（PD）中改变，并且D2多巴胺受体在缺乏GRK 6的小鼠（GRK 6-KO小鼠）中超敏感。为了理解GRK 6如何调节多巴胺缺乏的行为表现和对L-DOPA的反应，我们使用三种方法在GRK 6-KO小鼠中建立PD模型：1）对氟哌啶醇的僵硬反应; 2）将GRK 6突变引入绝对多巴胺缺乏的急性模型，DDD小鼠; 3）偏侧帕金森病6-OHDA模型。此外，通过评估AKT/GSK 3 β和ERK 1/2的磷酸化来分析多巴胺相关的纹状体信号传导。GRK 6缺乏减少了僵住行为，增强了DDD小鼠中L-DOPA的急性作用，减少了偏侧帕金森病小鼠的旋转行为，并减少了由慢性L-DOPA诱导的异常不自主运动。这些数据表明，调节GRK 6活性的方法可用于调节L-DOPA的治疗和副作用。
G protein-coupled Receptor Kinase 6 (GRK6) belongs to a family of kinases that phosphorylate GPCRs. GRK6 levels were found to be altered in Parkinson's Disease (PD) and D2 dopamine receptors are supersensitive in mice lacking GRK6 (GRK6-KO mice). To understand how GRK6 modulates the behavioral manifestations of dopamine deficiency and responses to L-DOPA, we used three approaches to model PD in GRK6-KO mice: 1) the cataleptic response to haloperidol; 2) introducing GRK6 mutation to an acute model of absolute dopamine deficiency, DDD mice; 3) hemiparkinsonian 6-OHDA model. Furthermore, dopamine-related striatal signaling was analyzed by assessing the phosphorylation of AKT/GSK3β and ERK1/2. GRK6 deficiency reduced cataleptic behavior, potentiated the acute effect of L-DOPA in DDD mice, reduced rotational behavior in hemi-parkinsonian mice, and reduced abnormal involuntary movements induced by chronic L-DOPA. These data indicate that approaches to regulate GRK6 activity could be useful in modulating both therapeutic and side-effects of L-DOPA.
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