Mao Li-Min, Wang Henry H, Wang John Q
Department of Basic Medical Science, School of Medicine, University of Missouri-Kansas City, 2411 Holmes Street, Kansas City, MO, 64108, USA.
Department of Anesthesiology, School of Medicine, University of Missouri-Kansas City, Kansas City, MO, 64108, USA.
Neurochem Res. 2017 Apr;42(4):1202-1210. doi: 10.1007/s11064-016-2157-9. Epub 2016 Dec 28.
Acetylcholine (ACh) is a key transmitter in the mesocorticolimbic circuit. By interacting with muscarinic ACh receptors (mAChR) enriched in the circuit, ACh actively regulates various neuronal and synaptic activities. The extracellular signal-regulated kinase (ERK) is one of members of the mitogen-activated protein kinase family and is subject to the regulation by dopamine receptors, although the regulation of ERKs by limbic mAChRs is poorly understood. In this study, we investigated the role of mAChRs in the regulation of ERK phosphorylation (activation) in the mesocorticolimbic system of adult rat brains in vivo. We targeted a sub-pool of ERKs at synaptic sites. We found that a systemic injection of the mAChR antagonist scopolamine increased phosphorylation of synaptic ERKs in the striatum (caudate putamen and nucleus accumbens) and medial prefrontal cortex (mPFC). Increases in ERK phosphorylation in both forebrain regions were rapid and transient. Notably, pretreatment with a dopamine D1 receptor (D1R) antagonist SCH23390 blocked the scopolamine-stimulated ERK phosphorylation in these brain regions, while a dopamine D2 receptor antagonist eticlopride did not. Scopolamine and SCH23390 did not change the amount of total ERK proteins. These results demonstrate that mAChRs inhibit synaptic ERK phosphorylation in striatal and mPFC neurons under normal conditions. Blockade of this inhibitory mAChR tone leads to the upregulation of ERK phosphorylation likely through a mechanism involving the level of D1R activity.
乙酰胆碱（ACh）是中脑皮质边缘回路中的一种关键神经递质。通过与该回路中富集的毒蕈碱型乙酰胆碱受体（mAChR）相互作用，ACh积极调节各种神经元和突触活动。细胞外信号调节激酶（ERK）是丝裂原活化蛋白激酶家族的成员之一，受多巴胺受体的调节，尽管边缘系统mAChR对ERK的调节作用尚不清楚。在本研究中，我们调查了mAChR在成年大鼠脑内中脑皮质边缘系统中ERK磷酸化（激活）调节中的作用。我们将目标锁定在突触部位的ERK亚群上。我们发现，全身注射mAChR拮抗剂东莨菪碱可增加纹状体（尾状壳核和伏隔核）和内侧前额叶皮质（mPFC）中突触ERK的磷酸化。两个前脑区域中ERK磷酸化的增加都是快速且短暂的。值得注意的是，用多巴胺D1受体（D1R）拮抗剂SCH23390预处理可阻断东莨菪碱刺激的这些脑区ERK磷酸化，而多巴胺D2受体拮抗剂依替必利则无此作用。东莨菪碱和SCH23390并未改变ERK总蛋白的量。这些结果表明，在正常情况下，mAChR抑制纹状体和mPFC神经元中突触ERK的磷酸化。阻断这种抑制性mAChR张力可能通过涉及D1R活性水平的机制导致ERK磷酸化上调。
