Fig. 2.

Model of receptor-mediated signaling in activating Ca²⁺ release and entry in endothelial cells during inflammation. The signal transduction begins with the binding of the ligand (hormone, cytokine, etc.) to specific G-protein coupled receptor (GPCR) at the surface of endothelial cells. Initial Gα_11/Gα_q-coupled activation of phospholipase C (PLC) β directs cleavage of phosphatidylinositol 4,5-bisphosphate (PIP₂) into the two secondary messengers, diacylglycerol (DAG) and inositol trisphosphate (IP₃). IP₃ induces clustering and activation of IP₃Rs on the ER membrane, whereas DAG instigates Ca²⁺ entry through transient receptor potential cation channels member 6 (TRPC6) located at the plasma membrane. The latter might contribute to increases in cytosolic Ca²⁺ concentration igniting global Ca²⁺ release through IP₃Rs. Depletion of the ER Ca²⁺ stores triggers oligomerization of stromal interaction molecule 1 (STIM1) which is required for activation of TRPC1 channel and Ca²⁺ entry from extracellular space. Lipopolysaccharide (LPS) also can activate Ca²⁺ entry through the TRPC6 channel by binding to toll-like receptor 4 (TLR4)