Sphingosine 1-phosphate (S1P) induces shape change in rat C6 glioma cells through the S1P2 receptor:: development of an agonist for S1P receptors

초록

Treatment with isoprenaline led to a change in the cell morphology of rat C6 glioma cells. This morphological change was reverted by the addition of sphingosine 1-phosphate (S1P). Using this morphological change as a response marker we determined that DS-SG-44 ((2.5,3R)-2-amino-3hydroxy-4-(4-octylphenyl)butyl phosphoric acid) was an agonist of SlP receptors. The DS-SG-44-induced morphological reversion was not observed with such structurally related molecules as DS-SG-45 ((2S,3R)-2-amino-3-hydroxy-4-(3-octylphenyl)butyl phosphoric acid) and DS-SG-12 ((2S,3R)2-amino-4-(4-octylphenyl)butane-1,3-diol). The S1P- and DS-SG-44-induced shape changes were nseither reproduced with the S1P(1)/S1P(3) receptor agonist VPC24191 nor inhibited by the S1P(1)/S1P(3) receptor antagonist, VPC230119. Transfection with small interfering RNA (siRNA) for the S1P(2) receptor greatly inhibited the DS-SG-44-induced shape change, and in part an SlP-induced response. In the presence of VPC23019, siRNA transfection for the S1P(2) receptor almost completely blocked the S1P- and DS-SG-44-induced shape changes. Our results suggested that DS-SG-44, a newly-synthesized S1P analogue, acted as an S1 P receptor agonist and that the S1P-induced shape change in rat C6 glioma cells was mediated mainly through the S1P(2) receptor, and cooperatively through the S1P(1)/S1P(3) receptors.

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