The immunosuppressant FTY720 down-regulates sphingosine 1-phosphate G-protein-coupled receptors.
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.
Gräler
Markus H
MH
University of California, Room UB-8B, UC Box 0711, 533 Parnassus Ave., San Francisco, CA 94143-0711, USA. graeler@itsa.ucsf.edu
Goetzl
Edward J
EJ
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
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