Sphingosine 1-phosphate, a diffusible calcium influx factor mediating store-operated calcium entry.
Store-operated calcium entry (SOCE) is a fundamental mechanism of calcium signaling. The mechanisms linking store depletion to SOCE remain controversial, hypothetically involving both diffusible messengers and conformational coupling of stores to channels. Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid that can signal via cell surface G-protein-coupled receptors, but S1P can also act as a second messenger, mobilizing calcium directly via unknown mechanisms. We show here that S1P opens calcium entry channels in human neutrophils (PMNs) and HL60 cells without prior store depletion, independent of G-proteins and of phospholipase C. S1P-mediated entry has the typical divalent cation permeability profile and inhibitor profile of SOCE in PMNs, is fully inhibited by 1 microm Gd3+, and is independent of [Ca2+]i. Depletion of PMN calcium stores by thapsigargin induces S1P synthesis. Inhibition of S1P synthesis by dimethylsphingosine blocks thapsigargin-, ionomycin-, and platelet-activating factor-mediated SOCE despite normal store depletion. We propose that S1P is a "calcium influx factor," linking calcium store depletion to downstream SOCE.
Department of Surgery, Division of Trauma, New Jersey Medical School, Newark, New Jersey 07103, USA.
Kiyoshi
K
Itagaki
Carl J
CJ
Hauser
D002118:Calcium / Q000378:metabolism*; D002412:Cations; D002460:Cell Line; D002855:Chromatography, Thin Layer; D004721:Endoplasmic Reticulum / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism; D005682:Gadolinium / Q000494:pharmacology; D018922:HL-60 Cells; D006801:Humans; D015759:Ionomycin / Q000494:pharmacology; D008246:Lysophospholipids; D009504:Neutrophils / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D015398:Signal Transduction; D013050:Spectrometry, Fluorescence; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism*; D013997:Time Factors
D002412:Cations; D008246:Lysophospholipids; C060506:sphingosine 1-phosphate; D015759:Ionomycin; D005682:Gadolinium; D019204:GTP-Binding Proteins; D013110:Sphingosine; D002118:Calcium