We investigated the effects of anions on different P2 receptors by measuring ATP-induced increase in intracellular Ca²⁺ concentration ([Ca²⁺]_i) in fura-2-loaded NG108-15 and PC12 cells. In NG108-15 cells, ATP at 100 μM and 1 mM induced a transient and a sustained [Ca²⁺]_i increase, respectively. The former, but not the latter, was inhibited by U-73122, indicating that the former was via the P2Y₂ receptor and the latter via the P2X₇ receptor. When external Cl⁻ was replaced by other anions, the [Ca²⁺]_i increase mediated by the P2Y₂ receptor was not changed, but that mediated by the P2X₇ receptor varied in the order of aspartate⁻ > methanesulfonate⁻ > Cl⁻ > Br ≥ I⁻. In PC12 cells, transient [Ca²⁺]_i increases mediated by the P2Y₂ and P2X₂ receptors were not affected by various anions. These results suggest that modulation by anions s unique to the P2X₇ receptor and does not occur in P2Y₂ and P2X₂ receptors. This may be because the mechanism of ATP binding to the P2X₇ receptor may be different than that to other P2 receptors.