Histamine inhibits ATP-induced [Ca²⁺](i) rise through the activation of protein kinase a in HL-60 cells

We investigated the cross-talk between the histamine and ATP receptors in HL-60 human promyelocytes. While both histamine and extracellular ATP increase intracellular Ca²⁺ concentration ([Ca²⁺](i)), we found that histamine treatment causes a decrease in the subsequent ATP-induced Ca²⁺ release from intracellular stores and Ca²⁺ influx from extracellular space. In addition, histamine also inhibited the subsequent ATP-induced inositol 1,4,5-trisphosphate (IP₃) generation in a manner comparable to the Ca²⁺ release. However, histamine did not inhibit thapsigargin-induced Ca²⁺ release and influx, thus indicating that histamine does not directly inhibit the Ca²⁺ release-activated channel (CRAC). Ca²⁺ elevation induced by 2'- and 3'-O-(4-benzoylbenzoyl) ATP (BzATP), which does not produce IP₃, was also inhibited by treatment with histamine, suggesting the presence of ATP-gated channels that are regulated by histamine. Treatment with dibutyryl cAMP or 8-bromo-cAMP inhibited the subsequent ATP-induced response similar to histamine. Moreover, the incubation of cells with N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide (H89), a protein kinase A inhibitor, abolished histamine's inhibitory effect on the ATP-induced [Ca²⁺](i) rise and IP₃ formation. These results suggest that histamine inhibits both ATP-induced IP₃ production and ATP-activated channel opening, through protein kinase A activation.