Journal
FASEB JOURNAL
Volume 18, Issue 1, Pages 551-+Publisher
WILEY
DOI: 10.1096/fj.03-0910fje
Keywords
receptor internalization; calcium signaling; lymphocyte; immunity; transplantation
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FTY720 is an immunosuppressant that reduces circulating levels of naive 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 37degreesC 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.
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