Department of Molecular, Cellular & Biomedical Sciences, CUNY School of Medicine, New York, NY, USA.
Ph.D. Programs in Biochemistry and Biology, The Graduate Center, CUNY, New York, USA.
Sci Rep. 2020 Feb 13;10(1):2542. doi: 10.1038/s41598-020-59011-5.
The dopamine D5 receptor (D5R) is a Gα-coupled dopamine receptor belonging to the dopamine D1-like receptor family. Together with the dopamine D2 receptor it is highly expressed in striatal cholinergic interneurons and therefore is poised to be a positive regulator of cholinergic activity in response to L-DOPA in the dopamine-depleted parkinsonian brain. Tonically active cholinergic interneurons become dysregulated during chronic L-DOPA administration and participate in the expression of L-DOPA induced dyskinesia. The molecular mechanisms involved in this process have not been elucidated, however a correlation between dyskinesia severity and pERK expression in cholinergic cells has been described. To better understand the function of the D5 receptor and how it affects cholinergic interneurons in L-DOPA induced dyskinesia, we used D5R knockout mice that were rendered parkinsonian by unilateral 6-OHDA injection. In the KO mice, expression of pERK was strongly reduced indicating that activation of these cells is at least in part driven by the D5 receptor. Similarly, pS6, another marker for the activity status of cholinergic interneurons was also reduced. However, mice lacking D5R exhibited slightly worsened locomotor performance in response to L-DOPA and enhanced LID scores. Our findings suggest that D5R can modulate L-DOPA induced dyskinesia and is a critical activator of CINs via pERK and pS6.
多巴胺 D5 受体（D5R）是一种 Gα 偶联多巴胺受体，属于多巴胺 D1 样受体家族。与多巴胺 D2 受体一起，它在纹状体胆碱能中间神经元中高度表达，因此有望成为多巴胺耗竭性帕金森病大脑中 L-DOPA 反应性胆碱能活动的正调节剂。在慢性 L-DOPA 给药期间，紧张性活动的胆碱能中间神经元变得失调，并参与 L-DOPA 诱导的运动障碍的表达。然而，这个过程中涉及的分子机制尚未阐明，但是已经描述了运动障碍严重程度与胆碱能细胞中 pERK 表达之间的相关性。为了更好地理解 D5 受体的功能以及它如何影响 L-DOPA 诱导的运动障碍中的胆碱能中间神经元，我们使用了单侧 6-OHDA 注射致帕金森病的 D5R 敲除小鼠。在 KO 小鼠中，pERK 的表达强烈减少，表明这些细胞的激活至少部分是由 D5 受体驱动的。同样，pS6，另一种胆碱能中间神经元活性状态的标志物，也减少了。然而，缺乏 D5R 的小鼠在 L-DOPA 反应中表现出稍微恶化的运动性能和增强的 LID 评分。我们的发现表明，D5R 可以调节 L-DOPA 诱导的运动障碍，并且通过 pERK 和 pS6 是 CINs 的关键激活剂。
