Mechanisms of sphingosine and sphingosine 1-phosphate generation in human platelets

Motohiro Tani, Takamitsu Sano, Makoto Ito, and Yasuyuki Igarashi

Department of Biomembrane and Biofunctional Chemistry, Hokkaido University, Sapporo, Hokkaido Pref. 060-0812

Corresponding Author: yigarash{at}pharm.hokudai.ac.jp

The bioactive molecule sphingosine 1-phosphate (S1P) is abundantly stored in platelets and can be released extracellularly. However, although they have high sphingosine kinase activity, platelets lack the de novo sphingolipid biosynthesis necessary to provide the substrates. Here, we reveal a generation pathway for sphingosine, the precursor of S1P, in human platelets. Platelets incorporated extracellular [³H]-labeled sphingosine much faster than human megakaryoblastic cells and rapidly converted it to S1P. Furthermore, sphingosine formed from plasma sphingomyelin by bacterial sphingomyelinase and neutral ceramidase was rapidly incorporated into platelets and converted to S1P, suggesting that platelets utilize extracellular sphingosine as a source of S1P. Platelets abundantly express sphingomyelin, possibly supplied from plasma lipoproteins, at the cell surface. Treating platelets with bacterial sphingomyelinase resulted in sphingosine generation at the cell surface, conceivably by the action of membrane-bound neutral ceramidase. As simultaneous, a time-dependent increase in S1P levels was observed. Finally, we demonstrated that secretory acid sphingomyelinase also induces S1P elevation in platelets. In conclusion, our results suggest that in platelets sphingosine is supplied from at least two sources; generation in the plasma followed by incorporation, and generation at the outer leaflet of the plasma membrane, initiated by cell surface sphingomyelin degradation.

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