PDF(Pubmed)
Abstract：
One of the hallmarks of Parkinson\'s disease (PD) is the alteration in the expression and function of NMDA receptor (NMDAR) and cannabinoid receptor 1 (CB1R). The presence of CB1R-NMDAR complexes has been described in neuronal primary cultures. The activation of CB1R in CB1R-NMDAR complexes was suggested to counteract the detrimental NMDAR overactivation in an AD mice model. Thus, we aimed to explore the role of this receptor complex in PD. By using Bioluminescence Resonance Energy Transfer (BRET) assay, it was demonstrated that α-synuclein induces a reorganization of the CB1R-NMDAR complex in transfected HEK-293T cells. Moreover, α-synuclein treatment induced a decrease in the cAMP and MAP kinase (MAPK) signaling of both CB1R and NMDAR not only in transfected cells but also in neuronal primary cultures. Finally, the interaction between CB1R and NMDAR was studied by Proximity Ligation Assay (PLA) in neuronal primary cultures, where it was observed that the expression of CB1R-NMDAR complexes was decreased upon α-synuclein treatment. These results point to a role of CB1R-NMDAR complexes as a new therapeutic target in Parkinson\'s disease.
摘要：
帕金森病(PD)的标志之一是NMDA受体(NMDAR)和大麻素受体1(CB1R)表达和功能的改变。已经在神经元原代培养物中描述了CB1R-NMDAR复合物的存在。提示CB1R-NMDAR复合物中CB1R的激活抵消AD小鼠模型中有害的NMDAR过度激活。因此，我们旨在探讨这种受体复合物在PD中的作用。通过使用生物发光共振能量转移（BRET）测定，已证明α-突触核蛋白诱导转染的HEK-293T细胞中CB1R-NMDAR复合物的重组。此外，α-突触核蛋白处理不仅在转染细胞中而且在神经元原代培养物中诱导CB1R和NMDAR两者的cAMP和MAP激酶(MAPK)信号传导的减少。最后,CB1R和NMDAR之间的相互作用通过邻近连接分析（PLA）在神经元原代培养中进行了研究，其中观察到CB1R-NMDAR复合物的表达在α-突触核蛋白处理后降低。这些结果表明CB1R-NMDAR复合物作为帕金森病新治疗靶点的作用。
