Activation of muscarinic M4 receptor augments NGF-induced pro-survival Akt signaling in PC12 cells

被引:29
作者
Wu, EH [1 ]
Wong, YH [1 ]
机构
[1] Hong Kong Univ Sci & Technol, Dept Biochem, Mol Neurosci Ctr, Biotechnol Res Inst, Kowloon, Hong Kong, Peoples R China
关键词
Akt; carbachol; cell survival; muscarinic; nerve growth factor; tuberin;
D O I
10.1016/j.cellsig.2005.04.009
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
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.
引用
收藏
页码:285 / 293
页数:9
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