Two enzymes, protein kinase C and microsomal Caz+-ATPase help regulate levels of Ca2' in many types of cells. Since proteins that regulate Ca2+ often influence sensitivity to Pb2+, we determined the possible roles played by protein kinase C and microsomal Ca2+-ATPase for the PbZ+ -evoked release of norepinephrine (NOR) in PC 12 cells. NOR release was observed at 10 pM PbZ+ when PC 12 cells were stimulated with inhibitors of microsomal Caz + -ATPase such as thapsigargin, cyclopiazonic acid, or 2,5-di-(tbutyl)-hydroquinone. At 5 pM, Pb2+ evoked the release of NOR in PC 12 cells stimulated with activators of protein kinase C such as phorbol 12-myristate 13acetate (PMA) or (-)-7-octylindolactam. NOR release was observed at 1 pM PbZ+ in the presence of both PMA and thapsigargin. Ni2+ and Cd2+ blocked NOR release stimulated by Pbz+ in the presence of thapsigargin but not by PMA. NOR released by thapsigargin stimulation was not altered in PC 12 cells depleted of protein kinase C. Two proteins found in vesicles, chromogranin B and secretogranin-I1 were released with NOR. Our results indicate that in PC 12 cells, Pb2+ -evokes the release of neurotransmitters. Furthermore, thapsigargin and PMA increase the cell's sensitivity to PbZ+ by different pathways.