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

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

Author information

1
Department of Pharmacology & Pharmacotherapy, Academic Medical Center, Amsterdam, The Netherlands.

Abstract

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.

PMID:
19309361
PMCID:
PMC2697734
DOI:
10.1111/j.1476-5381.2009.00134.x
[Indexed for MEDLINE]
Free PMC Article

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