Sphingosine 1-Phosphate Receptor Signaling

Abstract

The sphingosine 1-phosphate (S1P) receptor signaling system is a productive model system. A hydrophobic zwitterionic lysophospholipid ligand with difficult physical properties interacts with five high-affinity G protein-coupled receptors to generate multiple downstream signals. These signals modulate homeostasis and pathology on a steep agonist concentration-response curve. Ligand presence is essential for vascular development and endothelial integrity, while acute increases in ligand concentrations result in cardiac death. Understanding this integrated biochemical system has exemplified the impact of both genetics and chemistry. Developing specific tools with defined biochemical properties for the reversible modulation of signals in real time has been essential to complement insights gained from genetic approaches that may be irreversible and compensated. Despite its knife-edge between life and death, this system, based in part on receptor subtype-selectivity and in part on differential attenuation of deleterious signals, now appears to be on the cusp of meaningful therapy for multiple sclerosis.

Ongoing activation of sphingosine 1-phosphate receptors mediates maturation of exosomal multivesicular endosomes

“…Taken together, S1P 1 and/or S1P 3 receptors may be continuously activated on CD63-positive MVEs. S1P 1 receptors are known to be coupled exclusively with Gi/o, whereas the S1P 3 receptor is coupled with various G proteins such as Gi/o, Gq or G12/13, depending on cell types 42 . To characterize to what extent Gi is involved in the S1P 3 receptor signal, we conducted a FRET analysis using another FRET pair, that is, an S1P receptor subtype-CFP/Gg-YFP pair where FRET efficiency increases on receptor stimulation as previously reported 43 ( Fig.…”

Genetic elevation of Sphingosine 1-phosphate suppresses dystrophic muscle phenotypes in Drosophila

“…In mammals, there are five S1P receptors that share homology with G protein-coupled receptors (Rosen et al, 2009). Though flies do have G protein-coupled receptors, they do not appear to have the S1P receptors seen in vertebrates, suggesting that S1P receptor-mediated signaling might have evolved later in higher organisms.…”

“…In mammals, S1P is both an extracellular and intracellular signaling molecule and has been shown to bind five different G protein-coupled receptors (Rosen et al, 2009). There do not appear to be S1P G protein-coupled receptors in flies, so it is reasonable to assume that S1P acts intracellularly as it does in the budding yeast Saccharomyces cerevisiae (Strub et al, 2010).…”

Extracellular molecules in hematopoietic stem cell mobilisation

“…There are five G-protein coupled receptors for S1P, S1P 1 -S1P 5 , of which S1P 1 plays the dominant role on HSC [86,87]. S1P is a chemoattractant for many hematopoietic cell types, including HSC, and exists in a gradient between the bone marrow, where concentrations are kept low by degradative enzymes, such as sphingosine lyase [88], and the peripheral blood [89].…”