title: KCl potentiates forskolin-induced PC12 cell neurite outgrowth via protein kinase A and extracellular signal-regulated kinase signaling pathways.
abstract: In the present study, the effect of KCl-induced calcium influx on PC12 cell differentiation was examined. We show that KCl depolarization potentiates the effect of forskolin-induced neurite outgrowth of PC12 cells. The effects of KCl and forskolin were mediated via the protein kinase A (PKA) and the extracellular signal-regulated kinase (ERK) signaling pathways, since addition of the ERK kinase (MEK1) inhibitor PD98059 and the PKA inhibitor H89 inhibits neurite outgrowth. KCl depolarization and forskolin synergistically activate the ERK signaling pathway, but whereas KCl-mediated ERK activation depends on both PKA and MEK1, forskolin activates ERK in a PKA-independent manner. Finally, we find that KCl depolarization and forskolin both induce nuclear ERK2 translocation via a PKA- and MEK1-dependent pathway. The results demonstrate that PKA and ERK play a key role in KCl- and forskolin-induced neuronal differentiation by integration of signals from both pathways.
authors.affiliation: Department of Clinical Biochemistry, Rigshospitalet, University of Copenhagen, DK-2100, Copenhagen, Denmark.
authors.forename: Thomas v O
authors.initials: Tv
authors.lastname: Hansen
authors.forename: Jens F
authors.initials: JF
authors.lastname: Rehfeld
authors.forename: Finn C
authors.initials: FC
authors.lastname: Nielsen
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D005576:Colforsin / Q000494:pharmacology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005419:Flavonoids / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D048369:MAP Kinase Kinase 1; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D016501:Neurites / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D016716:PC12 Cells; D010766:Phosphorylation; D011189:Potassium Chloride / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D013449:Sulfonamides
chemical_list: D005419:Flavonoids; D007546:Isoquinolines; D013449:Sulfonamides; D005576:Colforsin; D011189:Potassium Chloride; D017346:Protein Serine-Threonine Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D002118:Calcium