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Protein Kinase Inhibitor H‐7 Differentially Affects Early and Delayed Nerve Growth Factor Responses in PC12 Cells
Author(s) -
Kahle Philipp,
Mangold Martine,
Kuwahara Toshikazu,
Schubenel Robert,
Hertel Cornelia
Publication year - 1994
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1994.62020479.x
Subject(s) - nerve growth factor , neurite , choline acetyltransferase , protein kinase c , tyrosine phosphorylation , phosphorylation , protein kinase a , biology , microbiology and biotechnology , endocrinology , chemistry , medicine , cholinergic , biochemistry , receptor , in vitro
The effects of the protein kinase inhibitor H‐7 on early and delayed responses to nerve growth factor (NGF) were investigated in PC12 cells. H‐7 reduced the NGF‐induced expression of c‐Fos in a dose‐dependent manner without affecting the time course of c‐Fos appearance. Conversely, H‐7 potentiated delayed NGF effects, i.e., neurite outgrowth and Ca 2+ /phospholipid‐dependent protein kinase (PKC) induction, but not choline acetyltransferase induction. Long‐term treatment with NGF resulted in an increase of at least four tyrosine‐phosphorylated protein bands with molecular masses between 39 and 48 kDa, which was also potentiated by H‐7. In the absence of NGF, H‐7 had no significant effect on c‐Fos expression, tyrosine phosphorylation of the 45 kDa protein, or choline acetyltransferase activity. However, 4 days of exposure to H‐7 alone induced PKC activity and tyrosine phosphorylation of the 39‐kDa protein. The action of H‐7 derivatives on neurite outgrowth did not correlate with their inhibition profile of cyclic nucleotide‐dependent protein kinases. Down‐regulation of PKC activity by prolonged exposure to phorbol ester did not completely abolish the effects of NGF and H‐7 on induction of c‐Fos, choline acetyltransferase activity, and neurite outgrowth, indicating that PKC‐independent pathways contribute to these actions. These results suggest that additional pathway(s) sensitive to H‐7 may exist, which induce immediate early gene expression and suppress neuronal differentiation of PC12 cells.