Different response patterns of several ligands at the sphingosine‐1‐phosphate receptor subtype 3 (S1P3)

Background and purpose: Recently, some ligands targeting the sphingosine‐1‐phosphate receptor subtype 3 (S1P3) have become available. The characterization of these compounds was mainly based on one functional read‐out system, although S1P3 receptors are known to activate different signal transduction pathways. Therefore, this study pharmacologically characterizes these compounds using different assays. Experimental approach: Using CHO‐FlpIn cells expressing the human S1P3 receptor the potencies and maximal effects of S1P, FTY720‐P, VPC23019, VPC23153 and VPC24191 were determined in three different assays [inhibition of cAMP accumulation, elevation of intracellular calcium concentrations ([Ca2+]i) and S1P3 receptor internalization]. Key results: All compounds tested inhibited forskolin‐induced cAMP accumulation, increased [Ca2+]i and induced S1P3 receptor internalization but with different potencies and maximal effects. S1P was the most potent compound in all assays followed by FTY720‐P. The VPC compounds were generally less potent than S1P and FTY720‐P. Regarding the maximal effects, all compounds except VPC23153, behaved as full agonists in the cAMP accumulation assay. In the calcium assay, FTY720‐P, VPC23019 and VPC24191 displayed partial and VPC23153 weak partial agonist activity, relative to S1P. Interestingly, treatment with the Gi inactivator Pertussis toxin, did not affect S1P‐induced [Ca2+]i elevations but inhibited those in response to the other compounds, by about 50%. Conclusions and implications: This study demonstrated differential response patterns at the S1P3 receptor for a range of ligands. These differences could indicate the presence of functional selectivity at this receptor as FTY720‐P and the VPC compounds seemed to signal predominantly via Gi– whereas S1P activated Gi and Gq‐coupled pathways.