Sphingosine-1-phosphate: a platelet-activating sphingolipid released from agonist-stimulated human platelets.
Sphingosine-1-phosphate (Sph-1-P) is the initial product of catabolism of sphingosine by sphingosine kinase and is cleaved by Sph-1-P lyase to a fatty aldehyde and ethanolamine phosphate. This phosphorylated sphingoid base is not only an intermediary catabolite, but also a bioactive lipid with important functions, including stimulation of cell proliferation in Swiss 3T3 fibroblasts and inhibition of tumor cell motility. In the present study, we examined functional roles of Sph-1-P in human platelets. Sph-1-P induced platelet shape change and aggregation reactions, although it failed to elicit secretion. Sphingosine, ceramide, sphingomyelin, and N,N-dimethylsphingosine did not mimic the positive effects of Sph-1-P on platelets. Subthreshold concentrations of Sph-1-P and weak platelet agonists such as adenosine diphosphate (ADP) and epinephrine synergistically elicited aggregation, which may be important for efficient amplification of platelet activation. Sph-1-P induced intracellular Ca2+ mobilization and the dose-response for Ca2+ release correlated closely with the concentration required for induction of shape change. On addition of [3H]sphingosine to intact platelets, the label was rapidly converted to Sph-1-P, and subsequently to ceramide and sphingomyelin. Interestingly, the Sph-1-P formed was specifically released into medium on stimulation of platelets with physiologic agonists. The amount of Sph-1-P in platelets, as measured by its conversion into radiolabeled N-acetyl-Sph-1-P, was 1.4 nmol/10(9) cells and was about four times higher than the mass of Sph present. When compared by mole percent Sph-1-P/phospholipid, the value for platelets is over 10 times higher than that for neutrophils. Our results suggest that Sph-1-P, rapidly converted from sphingosine, abundantly stored in platelets, and released on the cell activation, may play a physiologic role in thrombosis, hemostasis, and the natural wound-healing processes.
Yatomi
Y
Y
Biomembrane Institute, University of Washington, Seattle 98119, USA.
Ruan
F
F
Hakomori
S
S
Igarashi
Y
Y
D000244:Adenosine Diphosphate / Q000494:pharmacology; D001792:Blood Platelets / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D004357:Drug Synergism; D004837:Epinephrine / Q000494:pharmacology; D006801:Humans; D008246:Lysophospholipids; D015539:Platelet Activation / Q000187:drug effects*; D010974:Platelet Aggregation / Q000187:drug effects; D012701:Serotonin / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology
D008246:Lysophospholipids; C060506:sphingosine 1-phosphate; D012701:Serotonin; D000244:Adenosine Diphosphate; D013110:Sphingosine; D004837:Epinephrine