RT Journal Article
SR Electronic
T1 Stimulation of Sphingosine-1-phosphate Formation by the P2Y<sub>2</sub> Receptor in HL-60 Cells: Ca<sup>2+</sup> Requirement and Implication in Receptor-Mediated Ca<sup>2+</sup> Mobilization, but Not MAP Kinase Activation
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 491
OP 497
DO 10.1124/mol.58.3.491
VO 58
IS 3
A1 Alemany, Regina
A1 Sichelschmidt, Britta
A1 zu Heringdorf, Dagmar Meyer
A1 Lass, Holger
A1 van Koppen, Chris J.
A1 Jakobs, Karl H.
YR 2000
UL http://molpharm.aspetjournals.org/content/58/3/491.abstract
AB Sphingosine-1-phosphate (SPP), produced by sphingosine kinase, has recently been reported to act as an intracellular second messenger for Ca2+ 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 P2Y2 receptor and its functional implication in human leukemia (HL-60) cells, which do not respond to extracellular SPP. P2Y2 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 Ca2+ mobilization by the P2Y2 receptor. However, receptor-induced SPP production apparently required an increase in intracellular Ca2+ concentration, but not Ca2+ influx, and was mimicked by exposure of cells to Ca2+ ionophores. Taken together, activation of the P2Y2 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 receptor-mediated Ca2+ signaling.