title: The immunosuppressant FTY720 down-regulates sphingosine 1-phosphate G-protein-coupled receptors.
abstract: 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 S1P1,2,5 by inducing their internalization and intracellular partial degradation without affecting S1P3 or S1P4. S1P-R internalization is maximal several hours after only seconds of incubation with FTY720 at 37 degrees 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.
authors.affiliation: University of California, Room UB-8B, UC Box 0711, 533 Parnassus Ave., San Francisco, CA 94143-0711, USA. graeler@itsa.ucsf.edu
authors.forename: Markus H
authors.initials: MH
authors.lastname: Gräler
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Goetzl
mesh_terms: D000818:Animals; D002633:Chemotaxis / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D015195:Drug Design; D004705:Endocytosis; D000068876:Fingolimod Hydrochloride; D018390:Gene Targeting; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D019169:Jurkat Cells / Q000187:drug effects; D016131:Lymphocyte Subsets / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008231:Lymphopenia / Q000139:chemically induced; D008246:Lysophospholipids / Q000494:pharmacology*; D051379:Mice; D011409:Propylene Glycols / Q000494:pharmacology*; D020033:Protein Isoforms / Q000187:drug effects; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects* / Q000235:genetics; D049312:Receptors, Lysophospholipid; D011993:Recombinant Fusion Proteins / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013110:Sphingosine / Q000031:analogs & derivatives / Q000494:pharmacology*; D014161:Transduction, Genetic; D014162:Transfection
chemical_list: D007166:Immunosuppressive Agents; D008246:Lysophospholipids; D011409:Propylene Glycols; D020033:Protein Isoforms; D043562:Receptors, G-Protein-Coupled; D049312:Receptors, Lysophospholipid; D011993:Recombinant Fusion Proteins; C060506:sphingosine 1-phosphate; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine