Sphingosine-1-phosphate (S1P) displays sustained S1P1 receptor agonism and signaling through S1P lyase-dependent receptor recycling |
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| Institution: | 1. Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, 315 Ferst Drive, Atlanta, GA 30332, USA;2. Department of Chemical & Biomolecular Engineering, Lafayette College, 740 High Street, Easton, PA 18042, USA;3. Department of Pharmacology, University of Virginia, Charlottesville, VA 22903, USA;4. Department of Biomedical Engineering, University of Virginia, Charlottesville, VA 22903, USA;1. Actelion Pharmaceuticals Ltd, Allschwil, Switzerland;2. Department of Dermatology, University of Rome “Tor Vergata”, PTV—Policlinico di Tor Vergata, Rome, Italy;3. Department of Dermatology, Charles University, Third Faculty of Medicine, Prague, Czech Republic;4. Department of Dermatovenerology and Oncodermatology, Semmelweis University, Budapest, Hungary;5. Department of Dermatology, Municipal Hospital Hietzing, Vienna, Austria;1. Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore;2. Department of Biology, San Diego State University, San Diego, CA, USA;1. Department of Cellular Signalling, Mossakowski Medical Research Centre Polish Academy of Sciences, 5 Pawinski Street, 02-106, Warsaw, Poland;2. Laboratory of Experimental Neurosurgery, Department of Neurosurgery, Mossakowski Medical Research Centre Polish Academy of Sciences, 5 Pawinski Street, 02-106, Warsaw, Poland;3. Laboratory of Animal Models, Neurobiology Centre, Nencki Institute of Experimental Biology of Polish Academy of Sciences, 3 Pasteur Street, 02-093 Warsaw, Poland;4. Toxicology Research Laboratory, Mossakowski Medical Research Centre, Polish Academy of Sciences, 5 Pawinski Street, 02-106, Warsaw, Poland |
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| Abstract: | The sphingosine-1-phosphate (S1P) type 1 receptor (S1P1R) is a novel therapeutic target in lymphocyte-mediated autoimmune diseases. S1P1 receptor desensitization caused by synthetic S1P1 receptor agonists prevents T-lymphocyte egress from secondary lymphoid organs into the circulation. The selective S1P1 receptor agonist ponesimod, which is in development for the treatment of autoimmune diseases, efficiently reduces peripheral lymphocyte counts and displays efficacy in animal models of autoimmune disease. Using ponesimod and the natural ligand S1P, we investigated the molecular mechanisms leading to different signaling, desensitization and trafficking behavior of S1P1 receptors. In recombinant S1P1 receptor-expressing cells, ponesimod and S1P triggered Gαi protein-mediated signaling and β-arrestin recruitment with comparable potency and efficiency, but only ponesimod efficiently induced intracellular receptor accumulation. In human umbilical vein endothelial cells (HUVEC), ponesimod and S1P triggered translocation of the endogenous S1P1 receptor to the Golgi compartment. However, only ponesimod treatment caused efficient surface receptor depletion, receptor accumulation in the Golgi and degradation. Impedance measurements in HUVEC showed that ponesimod induced only short-lived Gαi protein-mediated signaling followed by resistance to further stimulation, whereas S1P induced sustained Gαi protein-mediated signaling without desensitization. Inhibition of S1P lyase activity in HUVEC rendered S1P an efficient S1P1 receptor internalizing compound and abrogated S1P-mediated sustained signaling. This suggests that S1P lyase – by facilitating S1P1 receptor recycling – is essential for S1P-mediated sustained signaling, and that synthetic agonists are functional antagonists because they are not S1P lyase substrates. |
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