Sphingosine-1-phosphate (SPP), produced by sphingosine kinase, has recently been reported to act as an intracellular second messenger for Ca 2ϩ and mitogenic responses triggered by membrane receptors and as an extracellular ligand for specific SPP receptors. Here, we investigated the signaling pathway leading to SPP production by the G protein-coupled P2Y 2 receptor and its functional implication in human leukemia (HL-60) cells, which do not respond to extracellular SPP. P2Y 2 receptor activation by UTP or ATP resulted in rapid and transient production of SPP, which was insensitive to pertussis toxin and blocked by the sphingosine kinase inhibitor, DL-threo-dihydrosphingosine. Treatment of HL-60 cells with this inhibitor did not affect activation of mitogen-activated protein kinases, but suppressed Ca 2ϩ mobilization by the P2Y 2 receptor. However, receptor-induced SPP production apparently required an increase in intracellular Ca 2ϩ concentration, but not Ca 2ϩ influx, and was mimicked by exposure of cells to Ca 2ϩ ionophores. Taken together, activation of the P2Y 2 receptor stimulates SPP production in HL-60 cells, a process apparently not required for mitogen-activated protein kinase activation, but most likely representing an amplification system for receptormediated Ca 2ϩ signaling.Recent studies indicate that sphingolipid metabolites function as a new class of intra-and intercellular second messengers, involved in a large variety of cellular processes. Besides ceramide and sphingosine, sphingosine-1-phosphate (SPP), which results from the phosphorylation of sphingosine by sphingosine kinase, has been in the focus of recent interest. Two distinct cellular actions of SPP have been proposed, namely, as agonist ligand for plasma membrane receptors and as intracellular second messenger (Meyer zu Heringdorf et al., 1997).
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