PKC and Ras are Involved in M1 Muscarinic Receptor-Mediated Modulation of AMPA Receptor GluA1 Subunit
PKC and Ras are Involved in M1 Muscarinic Receptor-Mediated Modulation of AMPA Receptor GluA1 Subunit
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PKC 和 Ras 参与 M1 毒蕈碱受体 — 介导的 AMPA 受体 GluA1 亚基调节
DOI：
10.1007/s10571-019-00752-x
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发表时间：
2019-11-13
影响因子：
4
通讯作者：
Qiu, Yu
中科院分区：
文献类型：
--
作者：
Chen, Mu-Wen;Zhu, Han;Qiu, Yu
M1毒蕈碱乙酰胆碱受体（M1 mAChR）长期以来一直是治疗阿尔茨海默病（AD）的有吸引力的靶点，阿尔茨海默病是老年痴呆症的最常见原因。M1 mAChR激动剂显示出理想的临床前活性;然而，由于无效或副作用，大多数激动剂没有进一步进入后期临床试验。因此，了解参与M1 mAChR介导的记忆改善的信号通路对于设计具有靶向治疗效果的偏向激动剂可能是重要的。M1 mAChR典型地与G α（q）偶联或异位地与G α（s）偶联以激活多种激酶，例如蛋白激酶C（PKC）、Ras和蛋白激酶A（PKA）。本课题组前期研究发现M1 mAChRs通过PKA-PI 3 K-Akt信号通路调节AMPA受体GluA 1亚基，从而改善学习记忆功能。在这里，我们进一步研究是否PKC和Ras参与M1 mAChR介导的GluA 1的调制。我们证明了PKC和Ras在信号通路中的作用，因为PKC抑制剂Ro-31-8425或Go 6983和Ras抑制剂salirasib都消除了体内原代培养的神经元和海马中由M1 mAChRs诱导的GluA 1的膜插入和其Ser 845磷酸化的增强。我们进一步表明，PKC和Ras调节PKA-PI 3 K-Akt信号转导，因为M1 mAChR激活引起的PKA、Akt和mTOR活性的增加被PKC和Ras抑制剂阻断。这些数据证明了M1 mAChR通过G alpha（q/11）偶联介导的GluA 1调节的详细机制，拓宽了M1 mAChR-G alpha（q/11）偶联后下游信号传导的知识。
M1 muscarinic acetylcholine receptors (M1 mAChRs) have long been an attractive target for the treatment of Alzheimer's disease (AD), the most common cause of dementia in the elderly. M1 mAChR agonists show desirably preclinical activities; however, most have not gone further into late clinical trials due to ineffectiveness or side effects. Thus, to understand the signaling pathways involved in M1 mAChR-mediated memory improvement may be important for design of biased agonists with on-target therapeutic effects. M1 mAChRs are classically coupled to G alpha(q) or ectopically to G alpha(s) to activate multiple kinases such as protein kinase C (PKC), Ras and protein kinase A (PKA). Our previous studies have found that M1 mAChRs could improve learning and memory through modulating AMPA receptor GluA1 subunit via PKA-PI3K-Akt signaling. Here, we further investigated whether PKC and Ras were involved in M1 mAChR-mediated modulation of GluA1. We demonstrated the role of PKC and Ras in the signaling pathway, as both PKC inhibitors Ro-31-8425 or Go6983 and Ras inhibitor salirasib abolished the membrane insertion of GluA1 and enhancement of its phosphorylation at Ser845 induced by M1 mAChRs in the primary cultured neurons and hippocampus in vivo. We further showed that PKC and Ras modulated PKA-PI3K-Akt signaling since the increases of PKA, Akt and mTOR activities by M1 mAChR activation were blocked by PKC and Ras inhibitors. These data demonstrated the detailed mechanism underlying M1 mAChR-mediated modulation of GluA1 through G alpha(q/11) coupling, broadening the knowledge of the downstream signaling after M1 mAChR-G alpha(q/11) coupling.