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

A selective, short-acting agonist for the sphingosine-1-phosphate receptor S1P1 and GFP-S1P1 knock-in mouse model are used to show that both receptor degradation and receptor reserve underlie the mechanisms of lymphocyte sequestration by agonists. 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.