Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Genoa, Italy.
Sci Rep. 2012;2:301. doi: 10.1038/srep00301. Epub 2012 Mar 5.
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 D(2) 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.
G 蛋白偶联受体激酶 6（GRK6）属于一组使 GPCR 磷酸化的激酶。在帕金森病（PD）中发现 GRK6 水平发生改变，并且缺乏 GRK6（GRK6-KO 小鼠）的小鼠中的 D2 多巴胺受体超敏。为了了解 GRK6 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 GRK6-KO 小鼠中模拟 PD：1）氟哌啶醇的僵住反应；2）将 GRK6 突变引入绝对多巴胺缺乏的急性模型 DDD 小鼠中；3）半帕金森 6-OHDA 模型。此外，通过评估 AKT/GSK3β 和 ERK1/2 的磷酸化来分析与多巴胺相关的纹状体信号。GRK6 缺乏减少僵住行为，增强 DDD 小鼠中 L-DOPA 的急性作用，减少半帕金森小鼠的旋转行为，并减少慢性 L-DOPA 诱导的异常不自主运动。这些数据表明，调节 GRK6 活性的方法可能有助于调节 L-DOPA 的治疗效果和副作用。
