Studies were undertaken to compare the signal-induced redistribution of conventional protein kinase C (cPKC) to nonclassical protein kinase C (nPKC) family members in response to phorbol 12-myristate 13-acetate (PMA) or nerve growth factor (NGF) treatment of PC12 cells. cPKC-alpha and -beta and nPKC-delta and -epsilon were predominantly cytoplasmic, whereas PKC-zeta displayed approximately equal distribution between the cytoplasm and membrane fraction. Treatment of PC12 cells with PMA induced rapid translocation of both c- and nPKC isoforms to the membrane fraction, although the kinetics varied between isoforms with epsilon being most sensitive, followed by delta > zeta > alpha. Both PKC-epsilon and delta translocated in the presence of minute concentrations of PMA, whereas cPKC was less sensitive, and PKC-zeta was least sensitive. NGF treatment, on the other hand, induced translocation of cPKCs and delta and epsilon nPKC, albeit with differential magnitude, whereas PKC-zeta was found predominantly in the cytoplasm. Chronic treatment of PC12 cells with PMA (1 microM) caused a rapid disappearance of alpha, beta, delta, and epsilon PKC isoforms, whereas the expression of PKC-zeta was unaltered over 4 days. NGF induced an increase in cytoplasmic PKC-zeta in control, or PMA down-regulated PC12 cells. Moreover, the increase in cytoplasmic PKC-zeta was blocked by pretreatment with sphingosine (2.5 microM). Furthermore, PKC-zeta was activated by NGF in PMA down-regulated PC12 cells, as determined by the extent of epsilon-peptide phosphorylation using a permeabilized cell assay. In addition, the zeta-pseudosubstrate peptide inhibited NGF-induced activation of PKC-zeta.(ABSTRACT TRUNCATED AT 250 WORDS)