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.
Miñana
M D
MD
Instituto de Investigaciones Citológicas de la Caja de Ahorros de Valencia, Centro Asociado del Consejo Superior de Investigaciones Cientificas, Spain.
Felipo
V
V
Grisolía
S
S
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