Project Description
Kelley M. Argraves, PhD
Blood borne sphingosine-1-phosphate (S1P), carried on high density lipoprotein (HDL), is essential for endothelial barrier function. HDL-S1P promotes endothelial barrier function through interaction with the S1P receptor, S1PR1. An understudied aspect of HDL-S1P-S1PR1 signaling that appears to have profound importance to endothelial barrier homeostasis in physiological and pathophysiological state is regulation of S1PR1 turnover. Recent studies indicate that S1PR1 levels are downregulated after S1P stimulation by beta-arrestin-dependent endocytosis. Following endocytosis, a portion of the internalized S1PR1 pool undergoes proteasome-dependent degradation and a portion of the pool is recycled back to the cell surface. The S1P mimetic FTY720-P induces irreversible internalization of S1PR1, thereby suppressing S1PR1 signaling and inhibiting S1P-dependent egress of maturing T cells from the thymus, causing lymphopenia. Needed are new S1PR1 agonists that counteract loss of endothelial barrier function, as occurs in pulmonary edema, atherosclerosis, cancer and many inflammatory diseases. The ability to identify new drugs that promote S1P-S1PR1 signaling would benefit from a greater understanding of agonism-induced, beta-arrestin-dependent, S1PR1 internalization and endocytic vesicular trafficking.