已知猴头菌属的药用蘑菇产生具有中枢神经系统稳态特性的次级代谢产物。我们和其他人最近证明,在这些代谢物中,氰化烷二萜,特别是赤霉素C在星形细胞中具有有效的神经营养蛋白诱导特性。然而,在神经样肾上腺嗜铬细胞瘤细胞(PC12)细胞中,erinacineC诱导的神经营养蛋白活性下游的信号事件仍然难以捉摸。类似,ErinacineC在星形细胞中激活的信号事件是未知的。使用遗传和药理学抑制剂的组合,我们表明,erinacineC诱导的神经营养活性通过TrkA受体及其相关的PLCγ-介导PC12细胞分化。PI3K-,和MAPK/ERK途径。此外,一个小的转录激活报告基因库显示,赤霉素C诱导由所选保守转录因子家族的DNA共有结合位点介导的转录激活。其中,转录以浓度依赖性方式从ETS共识中激活。有趣的是,诱导的ETS-共有转录平行发生,不依赖于神经营养蛋白的诱导。这一发现有助于解释环烷二萜的许多多效性功能。此外,我们的研究提供了在星形胶质细胞中的环烷二萜功能的遗传途径,并有助于从机械上了解环烷在神经胶质细胞中的作用。
Medicinal mushrooms of the genus Hericium are known to produce secondary metabolites with homeostatic properties for the central nervous system. We and others have recently demonstrated that among these metabolites cyathane diterpenoids and in particular erinacine C possess potent neurotrophin inducing properties in astrocytic cells. Yet, the signaling events downstream of erinacine C induced neurotrophin acitivity in neural-like adrenal phaeochromocytoma cells (PC12) cells have remained elusive. Similar, signaling events activated by erinacine C in astrocytic cells are unknown. Using a combination of genetic and pharmacological inhibitors we show that erinacine C induced neurotrophic activity mediates PC12 cell differentiation via the TrkA receptor and likely its associated PLCγ-, PI3K-, and MAPK/ERK pathways. Furthermore, a small library of transcriptional activation reporters revealed that erinacine C induces transcriptional activation mediated by DNA
consensus binding sites of selected conserved transcription factor families. Among these, transcription is activated from an ETS
consensus in a concentration dependent manner. Interestingly, induced ETS-
consensus transcription occurs in parallel and independent of neurotrophin induction. This finding helps to explain the many pleiotropic functions of cyathane diterpenoids. Moreover, our studies provide genetic access to cyathane diterpenoid functions in astrocytic cells and help to mechanistically understand the action of cyathanes in glial cells.