Different response patterns of several ligands at the sphingosine-1-phosphate receptor subtype 3 (S1P(3))

Br J Pharmacol. 2009 Apr;156(8):1305-11. doi: 10.1111/j.1476-5381.2009.00134.x. Epub 2009 Mar 20.


Background and purpose: Recently, some ligands targeting the sphingosine-1-phosphate receptor subtype 3 (S1P(3)) have become available. The characterization of these compounds was mainly based on one functional read-out system, although S1P(3) 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 S1P(3) 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 ([Ca(2+)](i)) and S1P(3) receptor internalization].

Key results: All compounds tested inhibited forskolin-induced cAMP accumulation, increased [Ca(2+)](i) and induced S1P(3) 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 G(i) inactivator Pertussis toxin, did not affect S1P-induced [Ca(2+)](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 S1P(3) 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 G(i)- whereas S1P activated G(i) and G(q)-coupled pathways.

Publication types

  • Comparative Study

MeSH terms

  • Adenylyl Cyclases / metabolism
  • Animals
  • CHO Cells
  • Calcium Signaling / drug effects
  • Colforsin / pharmacology
  • Cricetinae
  • Cricetulus
  • Cyclic AMP / metabolism
  • Dose-Response Relationship, Drug
  • Endocytosis / drug effects
  • Enzyme Activation
  • Enzyme Activators / pharmacology
  • GTP-Binding Protein alpha Subunits, Gi-Go / metabolism
  • GTP-Binding Protein alpha Subunits, Gq-G11 / metabolism
  • Humans
  • Ligands
  • Lysophospholipids / pharmacology
  • Organophosphates / pharmacology
  • Pertussis Toxin / pharmacology
  • Receptors, Lysosphingolipid / drug effects*
  • Receptors, Lysosphingolipid / genetics
  • Receptors, Lysosphingolipid / metabolism
  • Signal Transduction / drug effects*
  • Sphingosine / analogs & derivatives
  • Sphingosine / pharmacology*
  • Time Factors
  • Transfection


  • Enzyme Activators
  • FTY 720P
  • Ligands
  • Lysophospholipids
  • Organophosphates
  • Receptors, Lysosphingolipid
  • Colforsin
  • sphingosine 1-phosphate
  • Cyclic AMP
  • Pertussis Toxin
  • GTP-Binding Protein alpha Subunits, Gi-Go
  • GTP-Binding Protein alpha Subunits, Gq-G11
  • Adenylyl Cyclases
  • Sphingosine