Involvement of NFκB signaling in mediating the effects of GRK5 on neural stem cells.
Nuclear factor κB (NFκB) signaling plays ubiquitous roles in inflammation, immune response and neurogenesis. G protein-coupled receptor kinase 5 (GRK5) can protect neurons from degeneration. GRK5 also mediates tumor necrosis factor-α (TNFα)-induced NFκB signaling through the phosphorylation of IκBα. Here, we show that NFκB signaling is involved in neural stem cell (NSC) differentiation. The IκBα/p65 pathway was activated by phorbol myristate acetate (PMA), a stimulator of protein kinase C (PKC). Once the NFκB was activated, the initial stage of neural differentiation was induced, with an increased level of GRK5 in NSCs. This finding was reversed in response to the NFκB inhibitor N-acetyl cysteine (NAC). To evaluate the effect of GRK5-NFκB signaling crosstalk on NSC neurogenesis and apoptosis, GRK5 was knocked down by siRNAs in cell culture. SiRNAs against GRK5 not only impaired neural differentiation and axogenesis, but also induced apoptosis of NSC. GRK5 knockdown affected the transcription of NFκB, phosphorylation of the liver kinase B1 (LKB1) and the activity of caspase 3, thereby modulated neurogenesis and apoptosis. Taken together, our findings reveal a novel function of GRK5 in neurogenesis and provide insight into the molecular mechanisms underlying neurodevelopmental disorders and neurodegenerative diseases.
Department of Neurology, Beijing Shijitan Hospital, Capital Medical University, 10 TieYi Road, Haidian District, Beijing 100038, PR China.
Yun
Y
Zhang
Department of Neurology, Beijing Shijitan Hospital, Capital Medical University, 10 TieYi Road, Haidian District, Beijing 100038, PR China.
Guang-li
GL
Shen
Department of Neurology, Beijing Shijitan Hospital, Capital Medical University, 10 TieYi Road, Haidian District, Beijing 100038, PR China.
Li-juan
LJ
Shangguan
Department of Neurology, Beijing Shijitan Hospital, Capital Medical University, 10 TieYi Road, Haidian District, Beijing 100038, PR China.
Yang
Y
Yu
Department of Neurology, Beijing Shijitan Hospital, Capital Medical University, 10 TieYi Road, Haidian District, Beijing 100038, PR China. Electronic address: maolinh09@sina.com.
Mao-lin
ML
He
D000091162:AMP-Activated Protein Kinase Kinases; D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D004347:Drug Interactions; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D054774:G-Protein-Coupled Receptor Kinase 5 / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006624:Hippocampus / Q000166:cytology; D016328:NF-kappa B / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism; D064231:Nestin / Q000378:metabolism; D058953:Neural Stem Cells / Q000187:drug effects / Q000378:metabolism*; D029543:Nucleocytoplasmic Transport Proteins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D004791:Enzyme Inhibitors; D016328:NF-kappa B; D009363:Neoplasm Proteins; D064231:Nestin; D029543:Nucleocytoplasmic Transport Proteins; D034741:RNA, Small Interfering; C063447:p65 oncofetal mRNA transport protein, rat; D017346:Protein Serine-Threonine Kinases; C488755:Stk11 protein, rat; D054774:G-Protein-Coupled Receptor Kinase 5; C517897:Grk5 protein, rat; D000091162:AMP-Activated Protein Kinase Kinases; D013755:Tetradecanoylphorbol Acetate; D000111:Acetylcysteine
Apoptosis; G protein-coupled receptor; NFκB; Neurogenesis; Neuron stem cell