Antagonism of Muscarinic Acetylcholine Receptors Alters Synaptic ERK Phosphorylation in the Rat Forebrain.
Antagonism of Muscarinic Acetylcholine Receptors Alters Synaptic ERK Phosphorylation in the Rat Forebrain.
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DOI：
10.1007/s11064-016-2157-9
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发表时间：
2017-04
影响因子：
4.4
通讯作者：
Wang JQ
中科院分区：
文献类型：
--
作者：
Mao LM;Wang HH;Wang JQ
乙酰胆碱（Acetylcholine，ACh）是中皮质边缘回路的重要递质。通过与回路中富集的毒蕈碱型ACh受体（mAChR）相互作用，ACh积极地调节各种神经元和突触活动。细胞外信号调节激酶（extracellular signal-regulated kinase，ERK）是有丝分裂原活化蛋白激酶家族的成员之一，受多巴胺受体的调节，但人们对边缘系统mAChR对ERK的调节知之甚少。在这项研究中，我们调查的作用mAChRs在调节ERK磷酸化（激活）在成年大鼠大脑中皮质边缘系统在体内。我们将ERK的一个子库定位在突触部位。我们发现，全身注射mAChR拮抗剂东莨菪碱增加了纹状体（尾壳核和丘脑核）和内侧前额叶皮质（mPFC）中突触ERK的磷酸化。在两个前脑区域ERK磷酸化的增加是快速和短暂的。值得注意的是，多巴胺D1受体（D1 R）拮抗剂SCH 23390预处理阻断东莨菪碱刺激的ERK磷酸化在这些脑区，而多巴胺D2受体拮抗剂依替氯必利没有。东莨菪碱和SCH 23390不改变总ERK蛋白的量。这些结果表明，在正常条件下，mAChR抑制纹状体和mPFC神经元中的突触ERK磷酸化。这种抑制性mAChR张力的阻断可能通过涉及D1 R活性水平的机制导致ERK磷酸化的上调。
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.