Reduced D2-mediated signaling activity and trans-synaptic upregulation of D1 and D2 dopamine receptors in mice overexpressing the dopamine transporter
Reduced D2-mediated signaling activity and trans-synaptic upregulation of D1 and D2 dopamine receptors in mice overexpressing the dopamine transporter
复制标题
DOI：
10.1016/j.cellsig.2008.09.011
复制
发表时间：
2009-01-01
影响因子：
4.8
通讯作者：
Salahpour, Ali
中科院分区：
文献类型：
--
作者：
Ghisi, Valentina;Ramsey, Amy J.;Salahpour, Ali
多巴胺转运体(DAT)通过将多巴胺的神经递质重新摄取到突触前神经元来调节多巴胺的时空行为。我们最近培育出了过量表达DAT的转基因小鼠(DAT-TG)，其DAT蛋白水平增加了3倍，导致纹状体细胞外DA浓度降低了40%。本研究的目的是研究多巴胺能张力降低对多巴胺受体介导的突触后反应的影响。我们在此报告，DAT-TG小鼠纹状体多巴胺受体的水平增加了30%和D2(类似于60%)，而D1受体的信号成分没有明显的变化，这一点从基础或刺激的磷酸化GluR1(Ser845)和磷酸化ERK2的水平上得到了证明。然而，新的D2介导的Akt信号在DAT-TG动物中显著改变。特别是，DAT-TG纹状体内磷酸化Akt的基础水平增加了300%，反映了这些动物细胞外多巴胺张力的降低。在用选择性酪氨酸羟化酶抑制剂α-甲基对酪氨酸(α-MPT)治疗的WT小鼠中，这种基础PACT水平的增加可以通过部分多巴胺耗竭得到药理学上的重现。在行为上，DAT-TG动物表现出上调的D1和D2受体之间的增强的协同相互作用，这导致转基因小鼠在受到阿朴吗啡或选择性D1和D2受体激动剂的刺激后攀爬行为增加。综上所述，我们的研究表明，DAT上调引起的多巴胺减少会导致突触后受体功能的显著改变，其中最显著的是D2受体信号水平的失调。(C)2008 Elsevier Inc.保留所有权利。
The dopamine transporter (DAT) regulates the temporal and spatial actions of dopamine by reuptaking this neurotransmitter into the presynaptic neurons. We recently generated transgenic mice overexpressing DAT (DAT-tg) that have a 3-fold increase in DAT protein levels which results in a 40% reduction of the extracellular DA concentration in the striatum. The aim of this study was to examine the effect of this reduction in dopaminergic tone on postsynaptic responses mediated by dopamine receptors. We report here that DAT-tg mice have increased levels of striatal D1 (30%) and D2 (similar to 60%) dopamine receptors with D1 receptor signaling components not significantly altered, as evidenced by unaffected basal or stimulated levels of phospho-GluR1 (Ser845) and phospho-ERK2. However, the novel D2 mediated Akt signaling is markedly altered in DAT-tg animals. In particular, there is a 300% increase in the basal levels of phospho-Akt in the striatum of DAT-tg, reflecting the reduced extracellular dopamine tone in these animals. This increase in basal pAkt levels can be pharmacologically recapitulated by partial dopamine depletion in WT mice treated with the selective tyrosine hydroxylase inhibitor alpha-methyl-para-tyrosine (alpha-MPT). Behaviorally, DAT-tg animals demonstrate an augmented synergistic interaction between up-regulated D1 and D2 receptors, which results in increased climbing behavior in transgenic mice after stimulation with either apomorphine or a co-administration of selective D1 and D2 receptor agonists. In sum, our study reveals that hypodopaminegia caused by up-regulation of DAT results in significant alterations at postsynaptic receptor function with most notable dysregulation at the level of D2 receptor signaling. (C) 2008 Elsevier Inc. All rights reserved.