Differential roles of STIM1 and STIM2 in calcium-dependent signaling pathways in neutrophils. Following the engagement of surface receptors, the second messenger IP₃ is produced. Following binding of IP₃ to its receptors, Ca²⁺ is released into the cytoplasm, leading to ER-store depletion. STIM1 and STIM2 sense changes in ER-Ca²⁺ concentration and induce SOCE via the interaction with calcium-release activated channels (CRAC) in the plasma membrane. Additionally, STIM1 induces production of ROS, which in turn inhibit the activation of the transcription factor NF-κB and cytokine synthesis. In contrast, STIM2 activates the calcium-dependent translocation of NF-κB, leading to increased cytokine synthesis. IP₃R, IP₃ receptor.