The sphingosine-1-phosphate type 1 (S1P1) receptor is a lipid receptor which belongs to the family of G protein-coupled receptors and predominantly couples to and activates Gi/o proteins. Genetic deletion and pharmacological intervention studies revealed a crucial role for this receptor in the vascular and immune system. Probably because of its important role in these systems S1P1 receptor expression has been conserved from non-mammalian vertebrates including the zebrafish to mammalian species. Although the zebrafish S1P1 receptor has already been identified in 2000 it has not been extensively characterized yet. In this study we characterized the zebrafish S1P1 receptor using various pharmacological tools that recently have become available and compared the signalling properties directly to those of the human S1P1 receptor. N-terminally HisG-tagged zebrafish and human S1P1 receptors were stably expressed in CHO-FlpIn cells and signal transduction was measured by determining the effect of various selective and non-selective S1P1 ligands on the forskolin-induced cAMP accumulation. Alignment of the zebrafish and human S1P1 sequence reveals a relatively low overall amino acid homology of about 70%. However, the signalling properties between the zebrafish and human S1P1 receptor seem to be well conserved. As found for the human receptor the zebrafish S1P1 receptor also mediates the S1P-induced inhibition of adenylyl cyclase which is pertussis toxin-dependent indicating the involvement of Gi/o proteins. Overall, the potency profiles of the S1P1 selective (SEW2871, CYM5442) and unselective (S1P, FTY720-P, dihydroS1P) ligands was comparable at both receptor species although the potency at the human receptor generally was a bit higher. The S1P1 antagonist W146 also behaved as a competitive antagonist at the zebrafish S1P1 receptor.

In conclusion, despite a relatively low amino acid homology between the zebrafish and human S1P1 receptor the signalling properties between these two species are well conserved.