Actions of a picomolar short-acting S1P1 agonist in S1P1-eGFP knock-in mice

Sphingosine 1-Phosphate Receptor 1 (S1P1) plays a critical role in lymphocyte recirculation and is a clinical target for treatment of multiple sclerosis. By generating a short-duration S1P1 agonist and mice where 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 following agonist treatment. S1P1 (Edg1) is a high-affinity G protein-coupled receptor (GPCR) for the zwitterionic lysophospholipid Sphingosine 1-Phosphate (S1P)1 and is essential for vascular development2,3 and integrity4, and modulates both lymphocyte development and recirculation5. Selective agonists of S1P1 induce effective lymphocyte sequestration of both T and B cells within the lymph node6,7, and have been investigated as potential therapeutics in transplantation8 and multiple sclerosis. FTY720 (fingolimod)9, a prodrug whose phosphorylated form is an agonist of S1P1,3–5, but is thought to strongly downmodulate S1P1 expression10, has recently received regulatory approval as the first oral treatment o