Amplification of Ca²⁺ signaling by diacylglycerol-mediated inositol 1,4,5-trisphosphate production

Stimulation of various cell surface receptors leads to the production of inositol 1,4,5-trisphosphate (IP₃) and diacylglycerol (DAG) through phospholipase C (PLC) activation, and the IP₃ and DAG in turn trigger Ca²⁺ release through IP₃ receptors and protein kinase C activation, respectively. The amount of IP₃ produced is particularly critical to determining the spatio-temporally coordinated Ca²⁺- signaling patterns. In this paper, we report a novel signal cross-talk between DAG and the IP₃-mediated Ca²⁺-signaling pathway. We found that a DAG derivative, 1-oleoyl-2-acyl-sn-glycerol (OAG), induces Ca ²⁺ oscillation in various types of cells independently of protein kinase C activity and extracellular Ca²⁺. The OAG-induced Ca ²⁺ oscillation was completely abolished by depletion of Ca ²⁺ scores or inhibition of PLC and IP₃ receptors, indicating that OAG stimulates IP₃ production through PLC activation and thereby induces IP₃-induced Ca²⁺ release. Furthermore, intracellular accumulation of endogenous DAG by a DAG-lipase inhibitor greatly increased the number of cells responding to agonist stimulation at low doses. These results suggest a novel physiological function of DAG, i.e. amplification of Ca²⁺ signaling by enhancing [P₃ production via its positive feedback effect on PLC activity.