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The immunosuppressant FTY720 down‐regulates sphingosine 1‐phosphate G protein‐coupled receptors
Author(s) -
Gräler Markus H.,
Goetzl Edward J.
Publication year - 2004
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.03-0910fje
Subject(s) - internalization , g protein coupled receptor , receptor , sphingosine 1 phosphate , sphingosine , agonist , chemistry , phosphorylation , microbiology and biotechnology , sphingosine 1 phosphate receptor , sphingosine kinase , biochemistry , pharmacology , biology
FTY720 is an immunosuppressant that reduces circulating levels of naïve lymphocytes by increasing their localization and sequestration in secondary lymphoid organs. It is considered to be an agonist for sphingosine 1‐phosphate (S1P) G protein‐coupled receptors (GPCRs) after phosphorylation at micromolar concentrations. We now describe its nonagonist and noncompetitive inhibitory activity at low nanomolar concentrations for types 1 and 5 S1P‐ GPCRs and of moderate potency for type 2 S1P‐GPCRs. FTY720 blocks S1P signaling through S1P 1,2,5 by inducing their internalization and intracellular partial degradation without affecting S1P 3 or S1P 4 . S1P‐R internalization is maximal several hours after only seconds of incubation with FTY720 at 37°C and washing, and continues for days before recovery of surface expression and functions. The timing and extent of S1P‐R internalization are highly dependent on FTY720 concentration. FTY720 is therefore an S1P‐GPCR‐selective and noncompetitive inhibitor with a unique mechanism of action.