Mutations in polycystin-2 (TRPP2) cause polycystic kidney disease (PKD). TRPP2 functions as a Ca²⁺-permeable nonselective cation channel. However, it is disputed whether TRPP2 acts at the plasma or ER membrane. Here we studied the functional role of TRPP2 in the ER. We hypothesized that TRPP2 might affect the Ca²⁺ concentration in the ER ([Ca²⁺]_ER), which is known to be an important factor controlling the apoptosis sensitivity of cells. In fact, bcl-2 has been shown to protect cells from apoptosis by decreasing [Ca²⁺]_ER. Interestingly, bcl-2deficient mice develop PKD. To test whether TRPP2 also decreases [Ca²⁺]_ER we studied Ca²⁺ release from the ER. We found that the cytosolic Ca²⁺ increase after stimulation (GPCRs, ionomycin, thapsigargin) was significantly decreased in different cell types overexpressing TRPP2. We measured [Ca²⁺]_ER directly by using an ER-targeted Cameleon dye (a genetically encoded FRET-based Ca²⁺ sensor) and found that the [Ca²⁺]_ER was significantly reduced in cells overexpressing TRPP2. The sensitivity to ceramide-induced apoptosis was decreased in these cells whereas siRNA-mediated knockdown of endogenous TRPP2 increased apoptosis. This may explain the increased rates of apoptosis in PKD. In conclusion, we propose that bcl-2 and TRPP2 control apoptosis sensitivity by regulating [Ca²⁺]_ER, which may play an important role in the pathogenesis of PKD.