STIM1, but not STIM2, is required for proper agonist-induced Ca²⁺ signaling

The stromal interaction molecules STIM1 and STIM2 sense a decreasing Ca²⁺ concentration in the lumen of the endoplasmic reticulum and activate Ca²⁺ channels in the plasma membrane. In addition, at least 2 reports suggested that STIM1 may also interact with the inositol 1,4,5-trisphosphate (IP₃) receptor. Using embryonic fibroblasts from Stim1^-/-, Stim2^-/- and wild-type mice, we now tested the hypothesis that STIM1 and STIM2 would also regulate the IP₃ receptor. We investigated whether STIM1 or STIM2 would be the luminal Ca²⁺ sensor that controls the loading dependence of the IP₃-induced Ca²⁺ release. Partial emptying of the stores in plasma-membrane permeabilized cells resulted in an increased EC₅₀ and a decreased Hill coefficient for IP₃-induced Ca²⁺ release. This effect occurred both in the presence and absence of STIM proteins, indicating that these proteins were not the luminal Ca²⁺ sensor for the IP₃ receptor. Although Stim1^-/- cells displayed a normal IP₃-receptor function, agonist-induced Ca²⁺ release was reduced. This finding suggests that the presence of STIM1 is required for proper agonist-induced Ca²⁺ signaling. Our data do not provide experimental evidence for the suggestion that STIM proteins would directly control the function of the IP₃ receptor.