Feedback regulation of ATP-induced Ca2+ signaling in HL-60 cells is mediated by protein kinase A- and C-mediated changes in capacitative Ca2+ entry

Abstract

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 mu M 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 mu M ATP had an inhibitory effect on the thapsigargin-induced capacitative Ca2+ entry, 30 mu M ATP potentiated the response, However, the inhibitory action of 300 mu M ATP was blocked by protein kinase C (PKC) inhibitors, such as GF 109203X and chelerythrine, and the potentiating action of 30 mu M 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 mu M ATP, and the PKA inhibitors increased it when induced by 30 mu M ATP. In the measurements of PKA and PKC activity, 30 mu M ATP activates only PKA, while 300 mu M 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.