Lysophosphatidic acid triggers calcium entry through a non-store-operated pathway in human neutrophils (original) (raw)

Lysophosphatidic acid (LPA) is a bioactive lipid, which is structurally similar to sphingosine 1-phosphate (S1P) and which can mobilize Ca 2؉ in multiple cell types. We recently showed that S1P induces Ca 2؉ entry directly through store-operated Ca 2؉ entry channels in human polymorphonuclear neutrophils (PMN) [1]. We therefore examined the mechanisms by which LPA induces intracellular Ca 2؉ mobilization in PMN. External application of low micromolar LPA caused dose-dependent Ca 2؉ influx without releasing Ca 2؉ stores, whereas G-protein-coupled (GPC) LPA receptors respond to nanomolar LPA. Additive Ca 2؉ influx by LPA compared with 100 nM ionomycininduced Ca 2؉ influx suggests that LPA-induced Ca 2؉ influx does not pass through store-operated cation (SOC) channels. Ca 2؉ influx was resistant to inhibition of G i/o by pertussis toxin, of phospholipase C by U73122, and of G 12/13 /Rho by Y27632, all demonstrating GPC receptor independence. This Ca 2؉ influx was inhibited by Gd 3؉ , La 3؉ , Zn 2؉ , or MRS1845 but not by Ni 2؉ or the sphingosine kinase inhibitor dimethylsphingosine. In addition, we found that LPA has no effect on neutrophil chemotaxis; however, it has stimulatory effects on neutrophil respiratory burst in a doseresponse manner. These findings suggest that LPAinduced Ca 2؉ influx in PMN occurs through a mechanism other than SOC channels, independent of Ca 2؉ store-depletion and S1P synthesis, and that the characteristics of LPA-induced Ca 2؉ influx are similar to those of S1P-induced influx in terms of sensitivity to inorganic inhibitors. Unlike S1P, LPA has stimulatory effects on neutrophil respiratory burst.