The involvement of PKC in NG108-15 cell differentiation was investigated. Differentiation with dBcAMP was associated with a decrease in total cellular phorbol ester binding. The histone-directed PKC activity was decreased in the soluble fraction. Northern and Western blotting revealed the presence of only PKC alpha but not PKC beta and PKC gamma among the calcium-dependent isoforms. Differentiation induced a decrease of cytosolic PKC alpha immunoreactivity, with no changes of mRNA content or appearance of PKC beta and PKC gamma isoforms. The low levels of PKC alpha in the soluble fraction suggest that the mRNA for this species is less efficiently translated in differentiated NG108-15 cells. The data suggest that down-regulation of PKC alpha protein and kinase activity are associated with induction of neuronal morphology in NG108-15 cells.