Figure 1. Calcium signaling cascade in neutrophils.

(A) Store operated calcium entry (SOCE) can be initiated either via activation of Fcγ-receptors (FcγRs), β₂-integrins, the engagement of P-selectin glycoprotein ligand 1 (PSGL-1) and L-selectin with E-selectin expressed on inflamed endothelium, or via G-protein coupled receptors (GPCRs). Activation of GPCRs leads to dissociation of the G-protein subunits α and βγ and subsequent activation of phospholipase (PLC) β. FcγRs, β₂-integrins and PSGL-1/L-selectin signaling in turn, activate PLCγ involving spleen tyrosine kinase (Syk). Both, activated PLCβ and PLCγ convert phosphatidylinositol 4,5 bisphosphate (PIP₂) into diacylglycerol (DAG) and inositol-1,4,5 triphosphate (IP₃). IP₃ binds to and opens the IP₃ receptor (IP₃R) in the membrane of the endoplasmic reticulum (ER) which results in Ca²⁺ flux out of the ER into the cytoplasm via IP₃R. Upon store depletion, the Ca²⁺ sensor stromal interaction molecule 1 (STIM1) translocates to PM-ER-junctions and activates Orai1, the predominant Ca²⁺ release activated Ca²⁺ (CRAC) channel in neutrophils. This allows the entry of extracellular Ca²⁺ into the neutrophil, exerting a variety of functions, including (B) phagocytosis, ROS production, secretion and degranulation of vesicles, activation of β₂-integrins and cytoskeletal rearrangement leading to polarization and migration.