title: Lysophosphatidic acid triggers calcium entry through a non-store-operated pathway in human neutrophils.
abstract: 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). 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 Gi/o by pertussis toxin, of phospholipase C by U73122, and of G12/13/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.
authors.affiliation: The Department of Surgery, Division of Trauma, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark , NJ 07103, USA. itagakki@umdnj.edu
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Itagaki
authors.forename: Kolenkode B
authors.initials: KB
authors.lastname: Kannan
authors.forename: Carl J
authors.initials: CJ
authors.lastname: Hauser
mesh_terms: D002118:Calcium / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D002633:Chemotaxis / Q000502:physiology; D004963:Estrenes / Q000494:pharmacology; D018922:HL-60 Cells; D006801:Humans; D015759:Ionomycin / Q000494:pharmacology; D008246:Lysophospholipids / Q000378:metabolism* / Q000494:pharmacology; D008954:Models, Biological; D009504:Neutrophils / Q000378:metabolism*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000378:metabolism; D016897:Respiratory Burst / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D000099157:Sphingosine Kinase
chemical_list: D002118:Calcium; D004963:Estrenes; D015759:Ionomycin; D008246:Lysophospholipids; D017853:Phosphotransferases (Alcohol Group Acceptor); D011760:Pyrrolidinones; D043562:Receptors, G-Protein-Coupled; D013110:Sphingosine; D000099157:Sphingosine Kinase; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; C060506:sphingosine 1-phosphate