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首页> 外文期刊>Cellular Signalling >Activation of muscarinic M-4 receptor augments NGF-induced pro-survival Akt signaling in PC12 cells
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Activation of muscarinic M-4 receptor augments NGF-induced pro-survival Akt signaling in PC12 cells

机译：毒蕈碱M-4受体的激活增强PC12细胞中NGF诱导的生存前Akt信号转导。

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摘要

Survival or death of neurons during development is mediated by the integration of a diverse array of signal transduction cascades that are controlled by the availability and acquisition of neurotrophic factors and agonists acting at G protein-coupled receptors (GPCRs). Recent studies have demonstrated that GPCRs can modulate signals elicited by receptor tyrosine kinases (RTK) and vice versa. Here, we examined the activity of pro-survival Akt kinase, in response to stimulation by muscarinic acetylcholine receptors (mAChRs) and co-activation with the nerve growth factor (NGF) receptor in PC12 cells endogetiously expressing G(i)-coupled M-4 mAChR and G(q)-coupled M-1 and M-5 mAChRs. Western blotting analysis using a phosphospecific anti-Akt antibody revealed a dose- and time-dependent increase in Akt phosphorylation in cells stimulated with mAChR specific agonist carbachol (CCh). Co-stimulation with CCh and NGF resulted in augmentation of Akt activity in a pertussis toxin (PTX)-sensitive manner, suggesting that M4 mAChR, but not M, and M5 mAChRs, was associated with this synergistic Akt activation. The use of transducin as a G beta gamma scavenger indicated that G beta gamma subunits rather than G alpha(i/0). acted as the signal transducer. Additional experiments showed that CCh treatment augmented NGF-induced phosphorylation and degradation of the Akt-regulated translation regulator tuberin. This augmentation was also inhibited by PTX pre-treatment or overexpression of transducin. Finally, costimulation of PC12 cells with CCh and NGF resulted in enhancement of cell survival. This is the first study that demonstrates the augmentation effect between M4 mAChR and NGF receptor, and the regulatory role of mAChR on tuberin. (c) 2005 Elsevier Inc. All rights reserved.
机译：神经元在发育过程中的存活或死亡是由多种信号转导级联的整合介导的，这些信号转导级联受神经营养因子和作用于G蛋白偶联受体（GPCR）的激动剂的可用性和获取的控制。最近的研究表明，GPCR可以调节受体酪氨酸激酶（RTK）引发的信号，反之亦然。在这里，我们检查了毒蕈碱乙酰胆碱受体（mAChRs）的刺激以及内吞表达G（i）偶联M-的PC12细胞与神经生长因子（NGF）受体的共激活反应，促生性Akt激酶的活性。 4个mAChR和G（q）耦合的M-1和M-5 mAChR。使用磷酸特异性抗Akt抗体的蛋白质印迹分析显示，mAChR特异性激动剂卡巴胆碱（CCh）刺激的细胞中Akt磷酸化的剂量和时间依赖性增加。与CCh和NGF共同刺激导致以百日咳毒素（PTX）敏感的方式增强Akt活性，表明M4 mAChR（而非M和M5 mAChR）与这种协同性Akt激活相关。使用转导蛋白作为Gβγ清除剂表明，Gβγ亚基而不是G alpha（i / 0）。充当信号转换器。其他实验表明，CCh处理可增强NGF诱导的Akt调节的翻译调节剂Tuberin的磷酸化和降解。 PTX预处理或转导蛋白的过表达也抑制了这种增加。最后，与CCh和NGF共同刺激PC12细胞可提高细胞存活率。这是第一个证明M4 mAChR和NGF受体之间的增强作用以及mAChR对结核菌素的调节作用的研究。 （c）2005 Elsevier Inc.保留所有权利。

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