Basal Ganglia Pathophysiology Unit, Department Experimental Medical Sciences, Lund University, BMC F11, 221 84 Lund, Sweden, and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
J Neurosci. 2014 Mar 26;34(13):4728-40. doi: 10.1523/JNEUROSCI.2702-13.2014.
In animal models of Parkinson's disease, striatal overactivation of ERK1/2 via dopamine (DA) D1 receptors is the hallmark of a supersensitive molecular response associated with dyskinetic behaviors. Here we investigate the pathways involved in D1 receptor-dependent ERK1/2 activation using acute striatal slices from rodents with unilateral 6-hydroxydopamine (6-OHDA) lesions. Application of the dopamine D1-like receptor agonist SKF38393 induced ERK1/2 phosphorylation and downstream signaling in the DA-denervated but not the intact striatum. This response was mediated through a canonical D1R/PKA/MEK1/2 pathway and independent of ionotropic glutamate receptors but blocked by antagonists of L-type calcium channels. Coapplication of an antagonist of metabotropic glutamate receptor type 5 (mGluR5) or its downstream signaling molecules (PLC, PKC, IP3 receptors) markedly attenuated SKF38393-induced ERK1/2 activation. The role of striatal mGluR5 in D1-dependent ERK1/2 activation was confirmed in vivo in 6-OHDA-lesioned animals treated systemically with SKF38393. In one experiment, local infusion of the mGluR5 antagonist MTEP in the DA-denervated rat striatum attenuated the activation of ERK1/2 signaling by SKF38393. In another experiment, 6-OHDA lesions were applied to transgenic mice with a cell-specific knockdown of mGluR5 in D1 receptor-expressing neurons. These mice showed a blunted striatal ERK1/2 activation in response to SFK38393 treatment. Our results reveal that D1-dependent ERK1/2 activation in the DA-denervated striatum depends on a complex interaction between PKA- and Ca(2+)-dependent signaling pathways that is critically modulated by striatal mGluR5.
在帕金森病的动物模型中，通过多巴胺（DA）D1 受体使 ERK1/2 过度激活是与运动障碍行为相关的超敏分子反应的标志。在这里，我们使用单侧 6-羟多巴胺（6-OHDA）损伤的啮齿动物急性纹状体切片研究了 D1 受体依赖性 ERK1/2 激活所涉及的途径。多巴胺 D1 样受体激动剂 SKF38393 的应用诱导了 DA 去神经但未完整的纹状体中的 ERK1/2 磷酸化和下游信号转导。这种反应是通过典型的 D1R/PKA/MEK1/2 途径介导的，与离子型谷氨酸受体无关，但被 L 型钙通道拮抗剂阻断。代谢型谷氨酸受体 5（mGluR5）拮抗剂或其下游信号分子（PLC、PKC、IP3 受体）的共同应用显著减弱了 SKF38393 诱导的 ERK1/2 激活。在接受全身性 SKF38393 治疗的 6-OHDA 损伤动物体内，证实了纹状体 mGluR5 在 D1 依赖性 ERK1/2 激活中的作用。在一项实验中，在 DA 去神经的大鼠纹状体中局部输注 mGluR5 拮抗剂 MTEP 减弱了 SKF38393 对 ERK1/2 信号的激活。在另一项实验中，将 mGluR5 在表达 D1 受体的神经元中特异性敲低的转基因小鼠应用于 6-OHDA 损伤。这些小鼠对 SFK38393 处理的纹状体 ERK1/2 激活反应迟钝。我们的结果表明，DA 去神经纹状体中的 D1 依赖性 ERK1/2 激活依赖于 PKA 和 Ca2+依赖性信号通路之间的复杂相互作用，而该相互作用受到纹状体 mGluR5 的关键调节。
