Dopamine receptor D1 modulates glutamatergic transmission in cortico-basal ganglia circuits and represents a major target of L-DOPA therapy in Parkinson's disease. Here we show that D1 and metabotropic glutamate type 5 (mGlu5) receptors can form previously unknown heteromeric entities with distinctive functional properties. Interacting with Gq proteins, cell-surface D1-mGlu5 heteromers exacerbated PLC signaling and intracellular calcium release in response to either glutamate or dopamine. In rodent models of Parkinson's disease, D1-mGlu5 nanocomplexes were strongly upregulated in the dopamine-denervated striatum, resulting in a synergistic activation of PLC signaling by D1 and mGlu5 receptor agonists. In turn, D1-mGlu5-dependent PLC signaling was causally linked with excessive activation of extracellular signal-regulated kinases in striatal neurons, leading to dyskinesia in animals treated with L-DOPA or D1 receptor agonists. The discovery of D1-mGlu5 functional heteromers mediating maladaptive molecular and motor responses in the dopamine-denervated striatum may prompt the development of new therapeutic principles for Parkinson's disease.

中文翻译：

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D1-mGlu5异聚体介导帕金森氏病中的非典型多巴胺信号传导。

多巴胺受体D1调节皮质基底神经节回路中的谷氨酸能传递，并代表帕金森氏病L-DOPA治疗的主要目标。在这里，我们显示D1和5型代谢型谷氨酸（mGlu5）受体可以形成具有独特功能特性的未知杂物。与Gq蛋白相互作用，细胞表面D1-mGlu5异聚体加剧了谷氨酸或多巴胺的PLC信号传导和细胞内钙的释放。在帕金森氏病的啮齿动物模型中，D1-mGlu5纳米复合物在多巴胺去神经纹状体中强烈上调，导致D1和mGlu5受体激动剂对PLC信号的协同激活。反过来，D1-mGlu5依赖的PLC信号与纹状体神经元中细胞外信号调节激酶的过度激活有因果关系，导致用L-DOPA或D1受体激动剂治疗的动物运动障碍。在多巴胺去神经纹状体中介导适应不良的分子和运动反应的D1-mGlu5功能性杂合体的发现可能促进帕金森氏病的新治疗原理的发展。