We previously showed that extracellular ATP-induced Ca2+ influx is inhibited by self-activated protein kinase C in rat PC12 pheochromocytoma cells. In the present study, we examined whether tyrosine kinase is involved in the ATP-induced Ca2+ influx in PC12 cells. Genistein, an inhibitor of protein tyrosine kinases, which by itself had little effect on 45Ca2+ influx, significantly suppressed the ATP-induced 45Ca2+ influx in a dose-dependent manner in the range between 1 and 30 micrograms/ml. Tyrophostin, another inhibitor of tyrosine kinases chemically distinct from genistein, also inhibited the 45Ca2+ influx. Sodium orthovanadate, an inhibitor of protein tyrosine phosphatases, markedly enhanced the ATP-induced 45Ca2+ influx. These results suggest that tyrosine kinase regulates Ca2+ influx induced by extracellular ATP in PC12 pheochromocytoma cells.