The relationship between depleting effects of polychlorinated biphenyls (PCBs) on the intracellular calcium store and PCBs-induced cell death in dopaminergic cells has not been fully evaluated. Here, we evaluated the effects of inhibitors of the release of ER-stored calcium on the cytotoxicities induced by 10 microg/ml of Aroclor 1254 (A1254; polychlorinated biphenyl mixture) in a catecholaminergic cell-line, CATH.a cells. Exposure to A1254 produced an elevation in free calcium ([Ca2+]i) in the presence or absence of extracellular calcium and decreased in cell viability. From our results, we deduced that the A1254-induced elevation of [Ca2+]i resulted from the depletion of ER-stored calcium. The [Ca2+)]i elevation was dramatically inhibited by an inositol 1,4,5-triphosphate receptor (IP3R) antagonist, and slightly inhibited by a ryanodine receptor (RyR) blocker. IP3R blockers conferred significant protection against A1254-induced cell death, as did RyR blockers, but calcium chelators or NMDA blockers did not. However, none of these reagents inhibited the depletion of intracellular dopamine by A1254 indicating that the mechanism of PCB-induced dopamine depletion may be independent of calcium alterations. Taken together, these data suggest that agents inhibiting the receptor-mediated depletion of stored calcium can prevent the A1254-induced cell death, but not modulate the A1254-induced intracellular dopamine depletion in CATH.a cells.