Both nerve growth factor (NGF) and K-252a stimulate the uptake of calcium into PC12 cells. Stimulation by either is prevented by pretreatment of the cells with the tumor promoter phorbol 12-myristate 13-acetate (PMA), suggesting an involvement of protein kinase C in the stimulation. The effect of PMA is specific in that the calcium uptake stimulated by either the L- type channel agonist BAY K 8644 or by ATP is not altered in PMA-pretreated cells. An involvement of kinase C is also suggested by the inhibition of NGF- or K-252a-stimulated calcium uptake by the kinase C inhibitors staurosporine and calphostin C. Inhibition by the isoform-specific agents GO 6976 and thymeleatoxin implicates one of the classic calcium-sensitive isoforms of kinase C. The close similarity in the profiles of inhibition of NGF- stimulated and K-252a-stimulated calcium uptake by the various effectors suggests that NGF and K-252a act on calcium uptake through some of the same signaling elements.