Inhibition of protein kinase C induces differentiation in Neuro-2a cells.
1-(5-Isoquinolinylsulfonyl)-2-methylpiperazine (H7), a potent inhibitor of protein kinase C, induced neuritogenesis in Neuro-2a cells, whereas N-(2-guanidinoethyl)-5-isoquinolinesulfonamide (HA 1004), which inhibits more efficiently cAMP- and cGMP-dependent protein kinases, did not. The effect, noticeable after 3 hr, was maximum (13-fold increase at 500 microM H7) between 1 and 3 days and was maintained over 2 months. In controls, 90% of the cells were undifferentiated, whereas after 3 hr with 500 microM H7 only 25% of the cells remained undifferentiated. DNA synthesis decreased as the number of differentiated cells increased. Differentiation is also functional since acetylcholinesterase activity increased approximately 7-fold after 48 hr with 500 microM H7. Phorbol 12-myristate 13-acetate, a specific activator of protein kinase C, prevented or reversed the induction of neuritogenesis and the inhibition of DNA synthesis by H7. There is a good correlation between the level of protein kinase C and the percentage of differentiated cells. The results indicate that protein kinase C may play a key role in the control of differentiation of neural cells. Some possible clinical implications are briefly discussed.
Instituto de Investigaciones Citológicas de la Caja de Ahorros de Valencia, Centro Asociado del Consejo Superior de Investigaciones Cientificas, Spain.
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D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000110:Acetylcholinesterase / Q000096:biosynthesis; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D004247:DNA / Q000096:biosynthesis; D007546:Isoquinolines / Q000494:pharmacology*; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000096:biosynthesis; D009447:Neuroblastoma / Q000473:pathology*; D010879:Piperazines / Q000494:pharmacology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000502:physiology; D012313:RNA / Q000096:biosynthesis; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013997:Time Factors; D014404:Tubulin / Q000378:metabolism; D014407:Tumor Cells, Cultured
D007546:Isoquinolines; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; D010879:Piperazines; D014404:Tubulin; D012313:RNA; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D004247:DNA; D011493:Protein Kinase C; D000110:Acetylcholinesterase; D013755:Tetradecanoylphorbol Acetate