1. It is well known that extracellular ATP (ATP(o)) elevates the intracellular Ca2- concentration ([Ca2+](i)) by inducing Ca2+ influx or mobilizing Ca2+ from internal stores via activation of purinoceptors in the plasma membrane. This study shows that ATP(o) also activates the plasma membrane Ca2+ pumps (PMCPs) to bring the elevated [Ca2+](i) back to the resting level in human embryonic kidney-293 (HEK-293) cells. 2. The duration of ATP(o)-induced intracellular Ca2+ transients was significantly increased by PMCP blockers, La3+ or orthovanadate. In contrast, replacement of extracellular Na+ with NMDG+, a membrane-impermeable cation, had no significant effect on duration, thus suggesting that Na+/Ca2+ exchangers do not participate in the ATP(o)-induced Ca2+ transient. 3. A rapid and significant decrease in [Ca2+](i), which was not dependent on extracellular Na+, was induced by ATP(o) in cells pretreated with thapsigargin (TG). This decrease was blocked by orthovanadate, indicating that it was caused by PMCPs rather than sarco/endoplasmic reticulum Ca2+ pumps (SERCPs). 4. UTP and ATPγS also caused a decrease in [Ca2+](i) in cells pretreated with TG, although they were less effective than ATP. The effect of UTP implies the involvement of both P2Y1 anti P2Y2 receptors, while the effect of ATPγS implies no significant role of ectophosphorylation and agonist hydrolysis in the agonist-induced [Ca2+](i) decreases. 5. These results point to a role of PMCPs in shaping the Ca2+ signal and in restoring the resting [Ca2+](i) level to maintain intracellular Ca2+ homeostasis after agonist stimulation.
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