Extracellular ATP increases intracellular Ca2+ ([Ca2+]i) in HL-60 cells. When cells are stimulated with supramaximal concentrations of ATP, although the initial [Ca2+]i increase is similar over a range of 30, 100, and 300 microM ATP, the rate of the return to basal [Ca2+]i level is faster in cells treated with higher concentrations of ATP. This probably results from differences in Ca2+ influx rather than Ca2+ release, since the influx of the unidirectional Ca2+ surrogates Ba2+ and Mn2+ also exhibit similar responses. Furthermore, while 300 microM ATP had an inhibitory effect on the thapsigargin-induced capacitative Ca2+ entry, 30 microM ATP potentiated the response. However, the inhibitory action of 300 microM ATP was blocked by protein kinase C (PKC) inhibitors, such as GF 109203X and chelerythrine, and the potentiating action of 30 microM ATP was blocked by protein kinase A (PKA) inhibitors H89 and Rp-cAMPS. The PKC inhibitors also slowed the decay rate of the Ca2+ response induced by 300 microM ATP, and the PKA inhibitors increased it when induced by 30 microM ATP. In the measurements of PKA and PKC activity, 30 microM ATP activates only PKA, while 300 microM ATP activates both kinases. Taken together, these data suggest that the changes in the ATP-induced Ca2+ response result from differential modulation of ATP-induced capacitative Ca2+ entry by PKC and PKA in HL-60 cells.