M1 muscarinic receptors regulate the phosphorylation of AMPA receptor subunit GluA1 via a signaling pathway linking cAMP-PKA and PI3K-Akt
M1 muscarinic receptors regulate the phosphorylation of AMPA receptor subunit GluA1 via a signaling pathway linking cAMP-PKA and PI3K-Akt
复制标题
M1 毒蕈碱受体通过连接 cAMP-PKA 和 PI3K-Akt 的信号通路调节 AMPA 受体亚基 GluA1 的磷酸化
DOI：
10.1096/fj.201802351r
复制
发表时间：
2019-05-01
期刊：
影响因子：
4.8
通讯作者：
Chen, Hong-Zhuan
中科院分区：
文献类型：
--
作者：
Zhao, Lan-Xue;Ge, Yan-Hui;Chen, Hong-Zhuan
M1毒蕈碱乙酰胆碱受体在控制认知的关键区域高度表达，如皮质和海马，代表了阿尔茨海默病和精神分裂症认知功能障碍的一个潜在治疗靶点。我们报道了M1受体通过在Ser845位点磷酸化，促进-氨基-3-羟基-5-甲基-4-异恶唑油酸受体AMPA受体亚基1 （GluA1）的膜插入，从而促进认知。然而，信号通路尚不清楚。我们发现腺苷酸环化酶抑制剂2′，5′-二脱氧腺苷和PKA抑制剂KT5720抑制M1受体激活诱导的Ser845磷酸化增强和GluA1的膜插入。此外，PI3K抑制剂LY294002和蛋白激酶B （Akt）抑制剂IV也阻断了M1受体的作用。值得注意的是，由M1受体激活引起的PI3K-Akt信号活性的增加可以被cAMP-PKA抑制剂所消除。此外，通过短期应用雷帕霉素抑制哺乳动物PI3K-Akt的重要下游效应物雷帕霉素靶蛋白（mTOR）复合物1，可减弱M1受体对GluA1的作用。此外，这种作用与mTOR可能促进的蛋白质合成无关。综上所述，这些数据表明，M1受体激活通过连接cAMP-PKA和PI3K-Akt-mTOR通路的信号传导诱导GluA1的膜插入，但与蛋白质合成无关。赵,L.-X。， Ge, y - h。Li, j - b。，熊昌辉。，法律，p.y。徐j.r。，邱艳，陈宏志。M1毒蕈碱受体通过连接cAMP-PKA和PI3K-Akt的信号通路调节AMPA受体亚基GluA1的磷酸化。
M1 muscarinic acetylcholine receptors are highly expressed in key areas that control cognition, such as the cortex and hippocampus, representing one potential therapeutic target for cognitive dysfunctions of Alzheimer's disease and schizophrenia. We have reported that M1 receptors facilitate cognition by promoting membrane insertion of -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor AMPA receptor subunit 1 (GluA1) through phosphorylation at Ser845. However, the signaling pathway is still unclear. Here we showed that adenylyl cyclase inhibitor 2',5'-dideoxyadenosine and PKA inhibitor KT5720 inhibited enhancement of phosphorylation of Ser845 and membrane insertion of GluA1 induced by M1 receptor activation. Furthermore, PI3K inhibitor LY294002 and protein kinase B (Akt) inhibitor IV blocked the effects of M1 receptors as well. Remarkably, the increase of the activity of PI3K-Akt signaling induced by M1 receptor activation could be abolished by cAMP-PKA inhibitors. Moreover, inhibiting the mammalian target of rapamycin (mTOR) complex 1, an important downstream effector of PI3K-Akt, by short-term application of rapamycin attenuated the effects of M1 receptors on GluA1. Furthermore, such effect was unrelated to possible protein synthesis promoted by mTOR. Taken together, these data demonstrate that M1 receptor activation induces membrane insertion of GluA1 via a signaling linking cAMP-PKA and PI3K-Akt-mTOR pathways but is irrelevant to protein synthesis.Zhao, L.-X., Ge, Y.-H., Li, J.-B., Xiong, C.-H., Law, P.-Y., Xu, J.-R., Qiu, Y., Chen, H.-Z. M1 muscarinic receptors regulate the phosphorylation of AMPA receptor subunit GluA1 via a signaling pathway linking cAMP-PKA and PI3K-Akt.