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J. Biol. Chem., Vol. 278, Issue 30, 27540-27547, July 25, 2003
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Sphingosine 1-Phosphate, a Diffusible Calcium Influx Factor Mediating Store-operated Calcium Entry*
From the Department of Surgery, Division of Trauma, New Jersey Medical School, Newark, New Jersey 07103
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 µM 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.
Received for publication, February 19, 2003 , and in revised form, May 6, 2003.
* This work was supported by a grant from the Foundation for UMDNJ (to K. I.) and by Grant GM-59179 from the National Institutes of Health (to C. J. H.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
To whom correspondence should be addressed: Dept. of Surgery, University of
Medicine and Dentistry/New Jersey Medical School, MSB G-524, 185 South Orange
Ave., Newark, NJ 07103. Tel.: 973-972-2894; Fax: 973-972-6803; E-mail:
hausercj{at}UMDNJ.edu.
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