Abstract
Sphingosine 1-phosphate receptor 1 (S1P1) is critical for lymphocyte recirculation and is a clinical target for treatment of multiple sclerosis. By generating a short-duration S1P1 agonist and mice in which fluorescently tagged S1P1 replaces wild-type receptor, we elucidate physiological and agonist-perturbed changes in expression of S1P1 at a subcellular level in vivo. We demonstrate differential downregulation of S1P1 on lymphocytes and endothelia after agonist treatment.
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Acknowledgements
We acknowledge R. Proia and M. Capecchi for providing plasmids used in the generation of the Edg1eGFP targeting construct. We thank G. Martin and S. Kupriyanov for aid in generating Edg1eGFP/eGFP mice. We thank B. Webb for aid with mass spectrometry. S.M.C. is supported by a US National Institutes of Health Immunology Training Grant T32 AI007606. H.R. is supported by US National Institutes of Health Grants NIH U01 AI074564, R01 AI055509 and U54 MH084512.
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S.M.C. and H.R. designed the experiments and wrote the manuscript. S.M.C. generated the S1P1-eGFP knock-in mice and performed the in vivo experiments and flow cytometric analysis. P.J.G.-C. and N.N. performed biochemical experiments. G.S. performed two-photon experiments. M.-T.S. performed in vitro characterization of RP-001 and W146 competition. L.H. and A.Y. synthesized RP-001. B.C. and F.S. performed in vitro characterization of RP-001.
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H.R. is scientific co-founder of Receptos Pharmaceuticals.
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Supplementary Text and Figures
Supplementary Methods, Supplementary Scheme 1, Supplementary Tables 1–3 and Supplementary Figures 1–12 (PDF 2779 kb)
Supplementary Video 1
Intravital two-photon imaging of a Edg1eGFP/eGFP lymph node cortex (MOV 2855 kb)
Supplementary Video 2
Extravital two-photon imaging of lymph nodes from Edg1eGFP/eGFP mice in response to vehicle treatment (MOV 7212 kb)
Supplementary Video 3
Extravital two-photon imaging of lymph nodes from Edg1eGFP/eGFP mice in response to RP-001 treatment (MOV 1085 kb)
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Cahalan, S., Gonzalez-Cabrera, P., Sarkisyan, G. et al. Actions of a picomolar short-acting S1P1 agonist in S1P1-eGFP knock-in mice. Nat Chem Biol 7, 254–256 (2011). https://doi.org/10.1038/nchembio.547
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DOI: https://doi.org/10.1038/nchembio.547
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