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首页> 外文期刊>BMC Neuroscience >Nerve growth factor induces neurite outgrowth of PC12 cells by promoting Gβγ-microtubule interaction
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Nerve growth factor induces neurite outgrowth of PC12 cells by promoting Gβγ-microtubule interaction

机译：神经生长因子通过促进Gβγ-微管相互作用诱导PC12细胞的神经突生长

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Background Assembly and disassembly of microtubules (MTs) is critical for neurite outgrowth and differentiation. Evidence suggests that nerve growth factor (NGF) induces neurite outgrowth from PC12 cells by activating the receptor tyrosine kinase, TrkA. G protein-coupled receptors (GPCRs) as well as heterotrimeric G proteins are also involved in regulating neurite outgrowth. However, the possible connection between these pathways and how they might ultimately converge to regulate the assembly and organization of MTs during neurite outgrowth is not well understood. Results Here, we report that Gβγ, an important component of the GPCR pathway, is critical for NGF-induced neuronal differentiation of PC12 cells. We have found that NGF promoted the interaction of Gβγ with MTs and stimulated MT assembly. While Gβγ-sequestering peptide GRK2i inhibited neurite formation, disrupted MTs, and induced neurite damage, the Gβγ activator mSIRK stimulated neurite outgrowth, which indicates the involvement of Gβγ in this process. Because we have shown earlier that prenylation and subsequent methylation/demethylation of γ subunits are required for the Gβγ-MTs interaction in vitro , small-molecule inhibitors (L-28 and L-23) targeting prenylated methylated protein methyl esterase (PMPMEase) were tested in the current study. We found that these inhibitors disrupted Gβγ and ΜΤ organization and affected cellular morphology and neurite outgrowth. In further support of a role of Gβγ-MT interaction in neuronal differentiation, it was observed that overexpression of Gβγ in PC12 cells induced neurite outgrowth in the absence of added NGF. Moreover, overexpressed Gβγ exhibited a pattern of association with MTs similar to that observed in NGF-differentiated cells. Conclusions Altogether, our results demonstrate that βγ subunit of heterotrimeric G proteins play a critical role in neurite outgrowth and differentiation by interacting with MTs and modulating MT rearrangement.
机译：背景技术微管（MTs）的组装和拆卸对于神经突生长和分化至关重要。有证据表明神经生长因子（NGF）通过激活受体酪氨酸激酶TrkA诱导PC12细胞的神经突生长。 G蛋白偶联受体（GPCR）以及异三聚体G蛋白也参与调节神经突的生长。然而，人们对这些通路之间的可能联系以及它们最终如何收敛以调控神经突生长过程中MT的组装和组织的了解还不清楚。结果在这里，我们报道GPCR通路的重要组成部分Gβγ对NGF诱导的PC12细胞神经元分化至关重要。我们发现NGF促进了Gβγ与MT的相互作用并刺激了MT的装配。 Gβγ异位肽GRK2i抑制神经突的形成，破坏MTs并诱导神经突损伤，而Gβγ活化剂mSIRK刺激神经突生长，这表明Gβγ参与了这一过程。因为我们先前已经证明了γ亚基的异戊二烯化和随后的甲基化/去甲基化是体外Gβγ-MT相互作用所必需的，所以测试了针对异戊二烯化甲基化蛋白甲基酯酶（PMPMEase）的小分子抑制剂（L-28和L-23）在当前的研究中。我们发现这些抑制剂破坏了Gβγ和ΜΤ的组织并影响了细胞形态和神经突生长。为进一步支持Gβγ-MT相互作用在神经元分化中的作用，已观察到在不添加NGF的情况下，PC12细胞中Gβγ的过表达诱导神经突生长。而且，过表达的Gβγ表现出与MTs缔合的模式，类似于在NGF分化的细胞中观察到的模式。结论总之，我们的结果表明，异三聚体G蛋白的βγ亚基通过与MT相互作用和调节MT重排在神经突生长和分化中起关键作用。

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