The regulation of beta-amyloid precursor protein (beta-APP) secretion was compared in differentiated and nondifferentiated PC12 and B104 cells. Phorbol esters stimulated the release of beta-APP in all cells examined. However, differentiated PC12 cells were much more sensitive to phorbol ester treatment than nondifferentiated PC12 cells and their beta-APP release was also induced by the protein phosphatase inhibitor okadaic acid and the Ca(++)-ionophore A23187. In contrast, beta-APP release from B104 cells was strongly stimulated by A23187 and to lesser degree by phorbol esters. This effect was most pronounced in nondifferentiated B104 cells, which might be due to a higher basic release of beta-APP from differentiated B104 cells. Thus, the regulation of beta-APP cleavage and release varies depending on the cell type and differentiation state of the cell.