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Published online before print November 2, 2004

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(Journal of Leukocyte Biology. 2005;77:181-189.)
© 2005 by Society for Leukocyte Biology

Lysophosphatidic acid triggers calcium entry through a non-store-operated pathway in human neutrophils

The Department of Surgery, Division of Trauma, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark

¹ Correspondence: Department of Surgery, UMDNJ-New Jersey Medical School, MSB G-523, 185 South Orange Avenue, Newark, NJ 07103. E-mail: itagakki{at}umdnj.edu

Lysophosphatidic acid (LPA) is a bioactive lipid, which is structurally similar to sphingosine 1-phosphate (S1P) and which can mobilize Ca²⁺ in multiple cell types. We recently showed that S1P induces Ca²⁺ entry directly through store-operated Ca²⁺ entry (SOCE) channels in human polymorphonuclear neutrophils (PMN) [¹ ]. We therefore examined the mechanisms by which LPA induces intracellular Ca²⁺ mobilization in PMN. External application of low micromolar LPA caused dose-dependent Ca²⁺ influx without releasing Ca²⁺ stores, whereas G-protein-coupled (GPC) LPA receptors respond to nanomolar LPA. Additive Ca²⁺ influx by LPA compared with 100 nM ionomycin-induced Ca²⁺ influx suggests that LPA-induced Ca²⁺ influx does not pass through SOCE channels. Ca²⁺ 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 Ca²⁺ influx was inhibited by Gd³⁺, La³⁺, Zn²⁺, or MRS1845 but not by Ni²⁺ 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 dose-response manner. These findings suggest that LPA-induced Ca²⁺ influx in PMN occurs through a mechanism other than SOCE channels, independent of Ca²⁺ store-depletion and S1P synthesis, and that the characteristics of LPA-induced Ca²⁺ 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.

Key Words: bioactive lipid • calcium influx • G-protein-coupled receptors

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