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J. Biol. Chem., Vol. 275, Issue 49, 38532-38539, December 8, 2000

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Lysophosphatidic Acid-induced Ca²⁺ Mobilization Requires Intracellular Sphingosine 1-Phosphate Production
POTENTIAL INVOLVEMENT OF ENDOGENOUS EDG-4 RECEPTORS^*

Kenneth W. Young^§, Martin D. Bootman^¶, Deborah R. Channing, Peter Lipp^¶, Peter R. Maycox, Jackie Meakin, R. A. John Challiss, and Stefan R. Nahorski

From the  Department of Cell Physiology and Pharmacology, Medical Sciences Building, University of Leicester, University Road, Leicester, LE1 9HN United Kingdom, the ^¶ Laboratory of Molecular Signalling, The Babraham Institute, Babraham, Cambridge, CB2 4AT United Kingdom, and  SmithKline Beecham Pharmaceuticals, Harlow, Essex, CM19 5AW United Kingdom

Lysophosphatidic acid (LPA)-mediated Ca²⁺ mobilization in human SH-SY5Y neuroblastoma cells does not involve either inositol 1,4,5-trisphosphate (Ins(1,4,5)P₃)- or ryanodine-receptor pathways, but is sensitive to inhibitors of sphingosine kinase. This present study identifies Edg-4 as the receptor subtype involved and investigates the presence of a Ca²⁺ signaling cascade based upon the lipid second messenger molecule, sphingosine 1-phosphate. Both LPA and direct G-protein activation increase [³H]sphingosine 1-phosphate levels in SH-SY5Y cells. Measurements of ⁴⁵Ca²⁺ release in premeabilized SH-SY5Y cells indicates that sphingosine 1-phosphate, sphingosine, and sphingosylphosphorylcholine, but not N-acetylsphingosine are capable of mobilizing intracellular Ca²⁺. Furthermore, the effect of sphingosine was attenuated by the sphingosine kinase inhibitor dimethylsphingosine, or removal of ATP. Confocal microscopy demonstrated that LPA stimulated intracellular Ca²⁺ "puffs," which resulted from an interaction between the sphingolipid Ca²⁺ release pathway and Ins(1,4,5)P₃ receptors. Down-regulation of Ins(1,4,5)P₃ receptors uncovered a Ca²⁺ response to LPA, which was manifest as a progressive increase in global cellular Ca²⁺ with no discernible foci. We suggest that activation of an LPA-sensitive Edg-4 receptor solely utilizes the production of intracellular sphingosine 1-phosphate to stimulate Ca²⁺ mobilization in SH-SY5Y cells. Unlike traditional Ca²⁺ release processes, this novel pathway does not require the progressive recruitment of elementary Ca²⁺ events.

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