Schematic model of intracellular communication between E-selectin receptors and PAF receptor. PAF binds to its G_q/11 protein-coupled receptor resulting in activation of PLC, leading to cleavage of PIP₂ and generation of membrane-retained DAG and cytosolic IP₃. DAG can directly activate TRPC6.³⁴  Soluble InsP₃ activates the IP₃R on the endoplasmic reticulum to release intracellular Ca²⁺. These responses result in the initial rapid increase of [Ca²⁺]_i. E-selectin interacts with E-selectin receptors on the neutrophil surface, permitting PAF-induced Ca²⁺ mobilization to communicate with TRPC6 and allowing permissive SOCE to occur. Modulation of this Ca²⁺ channel involves Src and PI 3-kinase pathways. ROC indicates receptor-operated channel; G, G protein-coupled receptor.