Reactive Blue 2 (RB), which is used as an ATP receptor antagonist, induced Ca(2+) oscillations in HeLa cells. RB-induced Ca(2+) oscillations were abolished in Ca(2+)-free solution. RB, however, did not affect Ca(2+) influx measured by Mn(2+) quenching. The PLC cascade and intracellular Ca(2+) release were involved as U73122 and thapsigargin inhibited RB-induced Ca(2+) oscillations. RB enhanced a Ca(2+) response to histamine that is linked to the PLC cascade. RB may activate the PLC cascade in an extracellular Ca(2+)-dependent manner and induce Ca(2+) oscillations.