Sphingosine 1-Phosphate Receptor 1 Signaling in Mammalian Cells

Abstract

The bioactive lipid, sphingosine 1-phosphate (S1P) binds to a family of G protein-coupled receptors, termed S1P1-S1P5. These receptors function in, for example, the cardiovascular system to regulate vascular barrier integrity and tone, the nervous system to regulate neuronal differentiation, myelination and oligodendrocyte/glial cell survival and the immune system to regulate T- and B-cell subsets and trafficking. S1P receptors also participate in the pathophysiology of autoimmunity, inflammatory disease, cancer, neurodegeneration and others. In this review, we describe how S1P1 can form a complex with G-protein and β-arrestin, which function together to regulate effector pathways. We also discuss the role of the S1P1-Platelet derived growth factor receptor β functional complex (which deploys G-protein/β-arrestin and receptor tyrosine kinase signaling) in regulating cell migration. Possible mechanisms by which different S1P-chaperones, such as Apolipoprotein M-High-Density Lipoprotein induce biological programmes in cells are also described. Finally, the role of S1P1 in health and disease and as a target for clinical intervention is appraised.

Mapping the allosteric sites of the A2A adenosine receptor

“…FTMap identified non‐orthosteric sites on this membrane receptor distributed in the lipid interface, the extracellular and intracellular surfaces. Many ligands do not bind to the lipid interface of the receptor, but there are known ligands that can partition into the lipid bilayer …”

“…Many ligands do not bind to the lipid interface of the receptor, but there are known ligands that can partition into the lipid bilayer. [36] First, we calculated the probe occupancy per residue. In the MD simulation representative clusters and the X-ray structures, probes mostly interacted with residues in the TM regions.…”

Sphingosine-1-phosphate receptors and innate immunity

“…Sphingosine‐1‐phosphate (S1P) is a signalling lipid that is an important regulator in inflammation, angiogenesis, vascular permeability, brain and cardiac development, and cancer growth and metastasis (reviewed in N. J. Pyne et al, ; Pyne, McNaughton, et al, ; N. Pyne & Pyne, ; S. Pyne, Adams, & Pyne, ). S1P is able to affect many processes by signalling extracellularly through S1P receptors (S1PRs).…”

“…The S1P pathway in mammalian systems has been studied in depth (reviewed in Mendelson, Evans, & Hla, ; N. Pyne & Pyne, ; Rosen & Goetzl, ; Strub, Maceyka, Hait, Milstien, & Spiegel, ; Figure ). S1P is produced by the phosphorylation of sphingosine by one of two sphingosine kinases (SK1 and SK2) (Wattenberg, Pitson, & Raben, ).…”

“…S1PR1 is one of the most widely studied receptors of S1P (Blaho & Hla, ; Garris et al, ; N. Pyne & Pyne, ). Recent evidence suggests that signalling through S1PR1 occurs via the binding of G i and β‐arrestin together to allow for binding of Src leading to receptor internalisation mediated by clathrin and dynamin‐2 and activation of downstream pathways (N. Pyne & Pyne, ).…”