S1p1

S1P1, also known as S1PR1, is a G protein-coupled receptor for sphingosine-1-phosphate (S1P). It is one of five S1P receptors (S1PR1–S1PR5) and is encoded by the S1PR1 gene in humans (formerly referred to as EDG-1). The receptor functions as a key mediator of S1P signaling in multiple tissues, with prominent roles in the vascular and immune systems.

Expression and roles: S1P1 is expressed in endothelial cells, lymphoid tissues, and various other cell types, including some neurons. Through its signaling, S1P1 regulates lymphocyte egress from thymus and secondary lymphoid organs, vascular maturation, and endothelial barrier integrity. In the central nervous system, it participates in development and homeostasis of neural tissues.

Signaling: S1P1 primarily couples to Gi/o proteins, leading to inhibition of adenylyl cyclase and a reduction in cAMP, along with activation of downstream pathways such as MAPK/ERK and PI3K/Akt. It also influences cytoskeletal dynamics via Rac1 to reinforce endothelial adherens junctions and barrier function. Receptor activity is modulated by desensitization and internalization through beta-arrestin–mediated processes upon ligand binding.

Clinical relevance: Pharmacological modulation of S1P1 is used therapeutically to control immune cell trafficking. Fingolimod (FTY720) is a well-known S1P1 modulator that becomes phosphorylated and induces receptor internalization, causing lymphocyte sequestration in lymph nodes and reducing autoreactive cells in multiple sclerosis. Other selective S1P1 modulators, such as ozanimod andsiponimod, are approved or in use for similar indications. Potential adverse effects include bradycardia at first dose, macular edema, and hepatic enzyme elevations, underscoring the need for monitoring during treatment.

Research and development: Genetic deletion of S1PR1 in mice causes embryonic lethality due to vascular defects, highlighting the receptor’s essential role in vascular development and organismal viability.