BIPHASIC AND DIFFERENTIAL MODULATION OF CA2+ ENTRY BY ATP AND UTP IN PROMYELOCYTIC LEUKEMIA HL-60 CELLS

ATP and UTP cause mobilization of Ca2+ from the intracellular stores with similar potency in several cell types including both undifferentiated and differentiated HL60 cells. We show here that, in HL60 cells with Ca2+ stores that had been fully and irreversibly emptied using the endomembrane Ca2+-ATPase inhibitor thapsigargin, both nucleotides produced a biphasic effect on Ca2+ entry, first rapid inhibition and then delayed (about 15 s) activation. ATP was more effective at producing the initial inhibition of Ca2+ entry, whereas UTP was more effective at activating the delayed Ca2+ entry. Previous incubation with UTP desensitized the Ca2+ mobilization and the delayed activation of Ca2+ entry induced by ATP but not the inhibition of Ca2+ entry. The ATP analogue 2-methylthioATP (2-MeSATP) barely mobilized stored Ca2+ but inhibited Ca2+ entry. These results could be explained by the presence of two receptors: (i) a P-2u receptor sensitive to ATP and UTP, responsible for activation of phospholipase C and Ca2+ mobilization, early inhibition of Ca2+ entry and delayed activation of Ca2+ entry and (ii) a P-2y-like receptor sensitive to ATP and 2-MeSATP which produces only inhibition of Ca2+ entry. The inhibition of Ca2+ entry by nucleotides increased greatly during differentiation. Given that Ca2+ mobilization by nucleotides is not modified by differentiation, this suggests that a component of the mechanism of inhibition of Ca2+ entry is gradually expressed during differ entiation of HL60 cells.