Dopamine D1 receptor signalling in dyskinetic Parkinsonian rats revealed by fiber photometry using FRET-based biosensors
Dopamine D1 receptor signalling in dyskinetic Parkinsonian rats revealed by fiber photometry using FRET-based biosensors
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DOI：
10.1038/s41598-020-71121-8
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发表时间：
2020-09-02
影响因子：
4.6
通讯作者：
Hebert, Terence E.
中科院分区：
文献类型：
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作者：
Jones-Tabah, Jace;Mohammad, Hanan;Hebert, Terence E.
与许多G蛋白偶联受体（GPCR）一样，多巴胺D1受体（D1 R）调节的信号通路是动态的，细胞类型特异性的，并且可以在疾病或药物暴露时发生变化。在纹状体神经元中，D1 R激活cAMP/蛋白激酶A（PKA）信号传导。然而，在帕金森氏病（PD）中，该途径的改变导致细胞外调节激酶1/2（ERK 1/2）的功能上调，导致左旋多巴诱导的运动障碍（LID）。为了检测体内D1 R激活和研究PD和LID中D1 R信号传导的进行性失调，我们开发了具有Forster共振能量转移（FRET）生物传感器的比率光纤光度法，并在自由活动的大鼠中光学检测PKA和ERK 1/2信号传导。我们发现，在帕金森病动物，D1 R信号通过PKA和ERK 1/2是敏感的，但长期治疗与左旋多巴，这些途径变得部分脱敏，而同时D1 R激活导致更大的诱导运动障碍。
As with many G protein-coupled receptors (GPCRs), the signalling pathways regulated by the dopamine D1 receptor (D1R) are dynamic, cell type-specific, and can change in the face of disease or drug exposures. In striatal neurons, the D1R activates cAMP/protein kinase A (PKA) signalling. However, in Parkinson's disease (PD), alterations in this pathway lead to functional upregulation of extracellular regulated kinases 1/2 (ERK1/2), contributing to l-DOPA-induced dyskinesia (LID). In order to detect D1R activation in vivo and to study the progressive dysregulation of D1R signalling in PD and LID, we developed ratiometric fiber-photometry with Forster resonance energy transfer (FRET) biosensors and optically detected PKA and ERK1/2 signalling in freely moving rats. We show that in Parkinsonian animals, D1R signalling through PKA and ERK1/2 is sensitized, but that following chronic treatment with l-DOPA, these pathways become partially desensitized while concurrently D1R activation leads to greater induction of dyskinesia.